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  • 1. Aaltonen, Kirsimari
    et al.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eerola, Hannaleena
    Aittomäki, Kristiina
    Heikkilä, Päivi
    Nevanlinna, Heli
    Familial breast cancers without mutations in BRCA1 or BRCA2 have low cyclin E and high cyclin D1 in contrast to cancers in BRCA mutation carriers2008In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 14, no 7, 1976-83 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation-negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied. EXPERIMENTAL DESIGN: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors. RESULTS: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones. CONCLUSIONS: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.

  • 2. Armstrong, A J
    et al.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Stadler, W M
    Gingrich, J R
    Assikis, V
    Polikoff, J
    Damber, J E
    Belkoff, L
    Nordle, O
    Forsberg, G
    Carducci, M A
    Pili, R
    Long-term Survival and Biomarker Correlates of Tasquinimod Efficacy in a Multicenter Randomized Study of Men with Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer.2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 24, 6891-6901 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial.

    EXPERIMENTAL DESIGN: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS).

    RESULTS: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit.

    CONCLUSIONS: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio. 

  • 3. Bahce, Idris
    et al.
    Smit, Egbert F
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    van der Veldt, Astrid A M
    Yaqub, Maqsood
    Windhorst, Albert D
    Schuit, Robert C
    Thunnissen, Erik
    Heideman, Daniëlle A M
    Postmus, Pieter E
    Lammertsma, Adriaan A
    Hendrikse, N Harry
    Development of [11C]erlotinib Positron Emission Tomography for In Vivo Evaluation of EGF Receptor Mutational Status2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, 183-193 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To evaluate whether, in patients with non-small cell lung carcinoma (NSCLC), tumor uptake of [(11)C]erlotinib can be quantified and imaged using positron emission tomography and to assess whether the level of tracer uptake corresponds with the presence of activating tumor EGF receptor (EGFR) mutations.EXPERIMENTAL DESIGN: Ten patients with NSCLCs, five with an EGFR exon 19 deletion, and five without were scanned twice (test retest) on the same day with an interval of at least 4 hours. Each scanning procedure included a low-dose computed tomographic scan, a 10-minute dynamic [(15)O]H(2)O scan, and a 1-hour dynamic [(11)C]erlotinib scan. Data were analyzed using full tracer kinetic modeling. EGFR expression was evaluated using immunohistochemistry.RESULTS: The quantitative measure of [(11)C]erlotinib uptake, that is, volume of distribution (V(T)), was significantly higher in tumors with activating mutations, that is, all with exon 19 deletions (median V(T), 1.76; range, 1.25-2.93), than in those without activating mutations (median V(T), 1.06; range, 0.67-1.22) for both test and retest data (P = 0.014 and P = 0.009, respectively). Good reproducibility of [(11)C]erlotinib V(T) was seen (intraclass correlation coefficient = 0.88). Intergroup differences in [(11)C]erlotinib uptake were not correlated with EGFR expression levels, nor tumor blood flow.CONCLUSION: [(11)C]erlotinib V(T) was significantly higher in NSCLCs tumors with EGFR exon 19 deletions.

  • 4.
    Bandopadhayay, Pratiti
    et al.
    Departments of Cancer Biology and Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
    Bergthold, Guillaume
    Departments of Cancer Biology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
    Nguyen, Brian
    Schubert, Simone
    Gholamin, Sharareh
    Tang, Yujie
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schumacher, Steven E.
    Zeid, Rhamy
    Masoud, Sabran
    Yu, Furong
    Vue, Nujsaubnusi
    Gibson, William J.
    Paolella, Brenton R.
    Mitra, Siddhartha S.
    Cheshier, Samuel H.
    Qi, Jun
    Liu, Kun-Wei
    Wechsler-Reya, Robert
    Weiss, William A.
    Department of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, California.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kieran, Mark W.
    Bradner, James E.
    Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
    Beroukhim, Rameen
    Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts;.
    Cho, Yoon-Jae
    Departments of Neurology and Neurological Sciences and Neurosurgery, Stanford University School of Medicine; Stanford Cancer Institute, Stanford University Medical Center, Stanford.
    BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma2014In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 4, 912-925 p.Article in journal (Refereed)
    Abstract [en]

    Purpose:

    MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.

    Experimental Design:

    We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.

    Results:

    Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.

    Conclusion:

    JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

  • 5. Biggar, Robert J.
    et al.
    Johansen, Julia S.
    Smedby, Karin Ekström
    Rostgaard, Klaus
    Chang, Ellen T.
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hamilton-Dutoit, Stephen
    Melbye, Mads
    Hjalgrim, Henrik
    Serum YKL-40 and interleukin 6 levels in Hodgkin lymphoma2008In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 14, no 21, 6974-8 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Serum levels of the inflammatory markers YKL-40 and interleukin 6 (IL-6) are increased in many conditions, including cancers. We examined serum YKL-40 and IL-6 levels in patients with Hodgkin lymphoma, a tumor with strong immunologic reaction to relatively few tumor cells, especially in nodular sclerosis Hodgkin lymphoma. EXPERIMENTAL DESIGN: We analyzed Danish and Swedish patients with incident Hodgkin lymphoma (N=470) and population controls from Denmark (n=245 for YKL-40; n=348 for IL-6). Serum YKL-40 and IL-6 levels were determined by ELISA, and log-transformed data were analyzed by linear regression, adjusting for age and sex. RESULTS: Serum levels of YKL-40 and IL-6 increased in Hodgkin lymphoma patients compared with controls (YKL-40, 3.6-fold; IL-6, 8.3-fold; both, P<0.0001). In pretreatment samples from pretreatment Hodgkin lymphoma patients (n=176), levels were correlated with more advanced stages (P(trend), 0.0001 for YKL-40 and 0.013 for IL-6) and in those with B symptoms; however, levels were similar in nodular sclerosis and mixed cellularity subtypes, by EBV status, and in younger (<45 years old) and older patients. Patients tested soon after treatment onset had significantly lower levels than pretreatment patients; however, even >or=6 months after treatment onset, serum YKL-40 and IL-6 levels remained significantly increased compared with controls. In patients who died (n=12), pretreatment levels for YKL-40 and IL-6 were higher than in survivors, although not statistically significantly. CONCLUSIONS: Serum YKL-40 and IL-6 levels were increased in untreated Hodgkin lymphoma patients and those with more advanced stages but did not differ significantly by Hodgkin lymphoma histology. Following treatment, serum levels were significantly lower.

  • 6.
    Bikos, Vasilis
    et al.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Karypidou, Maria
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Papadopoulos, George
    CERTH, Informat Technol Inst, Thessaloniki, Greece..
    Agathangelidis, Andreas
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncohematol, Milan, Italy.;Ist Sci San Raffaele, Milan, Italy..
    Papadopoulou, Evdoxia
    CERTH, Informat Technol Inst, Thessaloniki, Greece..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Algara, Patricia
    Hosp Virgen Salud, Dept Pathol, Toledo, OH, Spain..
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Traverse-Glehen, Alexandra
    Univ Lyon, Hosp Civils Lyon, Dept Pathol & Hematol, Lyon, France..
    Mollejo, Manuela
    Hosp Virgen Salud, Dept Pathol, Toledo, OH, Spain..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy..
    Gonzalez, David
    Inst Canc Res, Sect Haematooncol, London SW3 6JB, England..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Matutes, Estella
    Inst Canc Res, Sect Haematooncol, London SW3 6JB, England..
    Angel Piris, Miguel
    Hosp Univ Marques de Valdecilla, Santander, Spain..
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncohematol, Milan, Italy.;Ist Sci San Raffaele, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Darzentas, Nikos
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Tzovaras, Dimitrios
    CERTH, Informat Technol Inst, Thessaloniki, Greece..
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece..
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 8, 2032-2040 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV) 1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P = 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

  • 7.
    Botling, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lohr, Miriam
    Hellwig, Birte
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Berglund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    König, André
    Fernandes, Oswaldo
    Karlsson, Mats
    Helenius, Gisela
    Karlsson, Christina
    Rahnenführer, Jörg
    Hengstler, Jan G
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, 194-204 p.Article in journal (Refereed)
    Abstract [en]

    Background:

    Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multi-gene signatures in clinical practice is unclear and the biological importance of individual genes is difficult to assess as the published signatures virtually do not overlap

    Methods:

    Here we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data was used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level p<0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n=860).

    RESULTS:

    The meta-analysis revealed 14 genes that were significantly associated with survival (p<0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from two independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    CONCLUSIONS:

    Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

  • 8.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Backman, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.2015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 19, 4451-4460 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter- and intratumor genetic heterogeneity has not yet been defined.

    EXPERIMENTAL DESIGN: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees.

    RESULTS: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.

    CONCLUSIONS: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient.

  • 9. D'Arcy, Padraig
    et al.
    Linder, Stig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Molecular Pathways: Translational Potential of Deubiquitinases as Drug Targets2014In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 15, 3908-3914 p.Article in journal (Refereed)
    Abstract [en]

    The ubiquitin proteasome system (UPS) is the main system for controlled protein degradation and a key regulator of fundamental cellular processes. The dependency of cancer cells on a functioning UPS coupled with the clinical success of bortezomib for the treatment of multiple myeloma have made the UPS an obvious target for drug development. Deubiquitinases (DUB) are components of the UPS that encompass a diverse family of ubiquitin isopeptidases that catalyze the removal of ubiquitin moieties from target proteins or from polyubiquitin chains, resulting in altered signaling or changes in protein stability. Increasing evidence has implicated deregulation of DUB activity in the initiation and progression of cancer. The altered pattern of DUB expression observed in many tumors can potentially serve as a clinical marker for predicting disease outcome and therapy response. The finding of DUB overexpression in tumor cells suggests that they may serve as novel targets for the development of anticancer therapies. Several specific and broad-spectrum DUB inhibitors are shown to have antitumor activity in preclinical in vivo models with low levels of systemic toxicity. Future studies will hopefully establish the clinical potential for DUB inhibitors as a strategy to treat cancer.

  • 10. de Graan, Anne-Joy M.
    et al.
    Elens, Laure
    Smid, Marcel
    Martens, John W.
    Sparreboom, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nieuweboer, Annemieke J. M.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elbouazzaoui, Samira
    Wiemer, Erik A. C.
    van der Holt, Bronno
    Verweij, Jaap
    van Schaik, Ron H. N.
    Mathijssen, Ron H. J.
    A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 18, 5210-5217 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. Experimental Design: In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training-and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. Results: A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). Conclusions: In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance. 

  • 11. de Graan, Anne-Joy M.
    et al.
    Elens, Laure
    Sprowl, Jason A.
    Sparreboom, Alex
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    van der Holt, Bronno
    de Raaf, Pleun J.
    de Bruijn, Peter
    Engels, Frederike K.
    Eskens, Ferry A. L. M.
    Wiemer, Erik A. C.
    Verweij, Jaap
    Mathijssen, Ron H. J.
    van Schaik, Ron H. N.
    CYP3A4*22 Genotype and Systemic Exposure Affect Paclitaxel-Induced Neurotoxicity2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 12, 3316-3324 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Paclitaxel is used for the treatment of several solid tumors and displays a high interindividual variation in exposure and toxicity. Neurotoxicity is one of the most prominent side effects of paclitaxel. This study explores potential predictive pharmacokinetic and pharmacogenetic determinants for the onset and severity of neurotoxicity. Experimental Design: In an exploratory cohort of patients (n = 261) treated with paclitaxel, neurotoxicity incidence, and severity, pharmacokinetic parameters and pharmacogenetic variants were determined. Paclitaxel plasma concentrations were measured by high-performance liquid chromatography or liquid chromatography/tandem mass spectrometry, and individual pharmacokinetic parameters were estimated from previously developed population pharmacokinetic models by nonlinear mixed effects modeling. Genetic variants of paclitaxel pharmacokinetics tested were CYP3A4*22, CYP2C8*3, CYP2C8*4, and ABCB1 3435 C>T. The association between CYP3A4*22 and neurotoxicity observed in the exploratory cohort was validated in an independent patient cohort (n = 239). Results: Exposure to paclitaxel ((log)AUC) was correlated with severity of neurotoxicity (P < 0.00001). Female CYP3A4*22 carriers were at increased risk of developing neurotoxicity (P = 0.043) in the exploratory cohort. CYP3A4*22 carrier status itself was not associated with pharmacokinetic parameters (CL, AUC, C-max, or T->0.05) of paclitaxel in males or females. Other genetic variants displayed no association with neurotoxicity. In the subsequent independent validation cohort, CYP3A4*22 carriers were at risk of developing grade 3 neurotoxicity (OR = 19.1; P = 0.001). Conclusions: Paclitaxel exposure showed a relationship with the severity of paclitaxel-induced neurotoxicity. In this study, female CYP3A4*22 carriers had increased risk of developing severe neurotoxicity during paclitaxel therapy. These observations may guide future individualization of paclitaxel treatment.

  • 12. de Graan, Anne-Joy M.
    et al.
    Lancaster, Cynthia S.
    Obaidat, Amanda
    Hagenbuch, Bruno
    Elens, Laure
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Bruijn, Peter
    Hu, Shuiying
    Gibson, Alice A.
    Bruun, Gitte H.
    Corydon, Thomas J.
    Mikkelsen, Torben S.
    Walker, Aisha L.
    Du, Guoqing
    Loos, Walter J.
    van Schaik, Ron H. N.
    Baker, Sharyn D.
    Mathijssen, Ron H. J.
    Sparreboom, Alex
    Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel2012In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 16, 4433-4440 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination.

    Experimental Design: Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213).

    Results: Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05).

    Conclusions: The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.

  • 13. de Graan, Anne-Joy M.
    et al.
    Loos, Walter J.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Baker, Sharyn D.
    van der Bol, Jessica M.
    van Doorn, Leni
    Wiemer, Erik A. C.
    van der Holt, Bronno
    Verweij, Jaap
    Mathijssen, Ron H. J.
    Influence of Smoking on the Pharmacokinetics and Toxicity Profiles of Taxane Therapy2012In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 16, 4425-4432 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Cigarette smoke is known to interact with the metabolism of several anticancer drugs. It may also affect the incidence and severity of adverse events and efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the pharmacokinetics and toxicities of patients treated with docetaxel or paclitaxel.

    Experimental Design: Smoking status, toxicity profiles, and pharmacokinetic parameters (calculated by nonlinear mixed-effect modeling population analysis) were determined in 566 patients (429 nonsmokers and 137 smokers) treated with docetaxel or paclitaxel.

    Results: Smokers treated with docetaxel showed less grade IV neutropenia (35% vs. 52%; P = 0.01) than nonsmokers. Smokers treated with paclitaxel had less grade III-IV leukopenia than nonsmokers (12% vs. 25%; P = 0.03), and the white blood cell (WBC) nadir was lower in nonsmokers (median, 2.7 x 10(9)/L; range, 0.05 x 10(9) to 11.6 x 10(9)/L) than in smokers (median, 3.3 x 10(9)/L; range 0.8 x 10(9) to 10.2 x 10(9)/L; P = 0.02). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in nonsmoking patients treated with paclitaxel (P = 0.0001). Pharmacokinetic parameters were similar in smokers and nonsmokers for both taxanes.

    Conclusion: Cigarette smoking does not alter the pharmacokinetic determinants of docetaxel and paclitaxel. Smokers treated with docetaxel and paclitaxel have less neutropenia and leukopenia, but further research is warranted to elucidate this potential protective effect.

  • 14. Dyrskjøt, Lars
    et al.
    Zieger, Karsten
    Real, Francisco X.
    Malats, Núria
    Carrato, Alfredo
    Hurst, Carolyn
    Kotwal, Sanjeev
    Knowles, Margaret
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Allory, Yves
    Vordos, Dimitri
    Caillault, Aurélie
    Radvanyi, François
    Hein, Anne-Mette K.
    Jensen, Jens L
    Jensen, Klaus M. E.
    Marcussen, Niels
    Orntoft, Torben F.
    Gene expression signatures predict outcome in non-muscle-invasive bladder carcinoma: a multicenter validation study2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 12, 3545-3551 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Clinically useful molecular markers predicting the clinical course of patients diagnosed with non–muscle-invasive bladder cancer are needed to improve treatment outcome. Here, we validated four previously reported gene expression signatures for molecular diagnosis of disease stage and carcinoma in situ (CIS) and for predicting disease recurrence and progression.

    Experimental Design: We analyzed tumors from 404 patients diagnosed with bladder cancer in hospitals in Denmark, Sweden, England, Spain, and France using custom microarrays. Molecular classifications were compared with pathologic diagnosis and clinical outcome.

    Results: Classification of disease stage using a 52-gene classifier was found to be highly significantly correlated with pathologic stage (P < 0.001). Furthermore, the classifier added information regarding disease progression of Ta or T1 tumors (P < 0.001). The molecular 88-gene progression classifier was highly significantly correlated with progression-free survival (P < 0.001) and cancer-specific survival (P = 0.001). Multivariate Cox regression analysis showed the progression classifier to be an independently significant variable associated with disease progression after adjustment for age, sex, stage, grade, and treatment (hazard ratio, 2.3; P = 0.007). The diagnosis of CIS using a 68-gene classifier showed a highly significant correlation with histopathologic CIS diagnosis (odds ratio, 5.8; P < 0.001) in multivariate logistic regression analysis.

    Conclusion: This multicenter validation study confirms in an independent series the clinical utility of molecular classifiers to predict the outcome of patients initially diagnosed with non–muscle-invasive bladder cancer. This information may be useful to better guide patient treatment.

  • 15. Eechoute, Karel
    et al.
    Fransson, Martin N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Reyners, An K.
    De Jong, Floris A.
    Sparreboom, Axel
    Van Der Graaf, Winette T. A.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiavon, Gaia
    Wiemer, Erik A. C.
    Verweij, Jaap
    Loos, Walter J.
    Mathijssen, Ron H. J.
    De Giorgi, Ugo
    A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients2012In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 20, 5780-5787 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Imatinib minimal (trough) plasma concentrations after one month of treatment have shown a significant association with clinical benefit in patients with gastrointestinal stromal tumors (GIST). Considering that a retrospective pharmacokinetic analysis has also suggested that imatinib clearance increases over time in patients with soft tissue sarcoma and GIST, the primary aim of this study was to assess systemic exposure to imatinib at multiple time points in a long-term prospective population pharmacokinetic study. As imatinib is mainly metabolized in the liver, our secondary aim was to elucidate the potential effects of the volume of liver metastases on exposure to imatinib. Experimental Design: Full pharmacokinetic blood sampling was conducted in 50 patients with GIST on the first day of imatinib treatment, and after one, six, and 12 months. In addition, on day 14, and monthly during imatinib treatment, trough samples were taken. Pharmacokinetic analysis was conducted using a compartmental model. Volume of liver metastases was assessed by computed tomographic (CT) imaging. Results: After 90 days of treatment, a significant decrease in imatinib systemic exposure of 29.3% compared with baseline was observed (P &lt; 0.01). For every 100 cm 3 increase of metastatic volume, a predicted decrease of 3.8% in imatinib clearance was observed. Conclusions: This is the first prospective pharmacokinetic study in patients with GIST, showing a significant decrease of approximately 30% in imatinib exposure after long-term treatment. This means that future "trough level - clinical benefit" analyses should be time point specific. GIST liver involvement, however, has a marginal effect on imatinib clearance.

  • 16.
    Ekeblad, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dunder, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution2008In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 14, no 23, 7798-7803 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Unequivocal pathologic markers for the prognosis of pancreatic endocrine tumors are often lacking. Suggestions for prognostic guidance include the WHO classification. Recently, a tumor-node-metastasis (TNM) staging system was proposed. We evaluate this system, as well as assess other potential prognostic factors such as tumor Ki67, size, endocrine syndrome, heredity, body mass index (BMI), and plasma chromogranin A, in a large patient material treated at a single institution.

    EXPERIMENTAL DESIGN:

    A total of 324 patients with pancreatic endocrine tumor, consecutively diagnosed and treated at a tertiary referral center, were retrospectively evaluated. Median follow-up was 54 months (range, 1-423 months). Patient and tumor data were extracted from medical records. Univariate and multivariate analyses were done to recognize factors of prognostic value.

    RESULTS:

    The median overall survival was 99 months (95% confidence interval, 81-117). Five- and 10-year survival rates were 64% and 44%, respectively. In univariate analysis, TNM stage, radical surgery, WHO classification, nonfunctioning tumor, Ki67 ≥2%, chromogranin A ≥3 times the upper normal limit, BMI <20 kg/m2, sporadic tumor, tumor size, and referral from our primary uptake area had a significant prognostic effect. In multivariate analysis, TNM stage, WHO classification, radical surgery, and Ki67 ≥2% retained their significance. Having a nonfunctioning tumor was not an independent marker of poor prognosis and neither was heredity.

    CONCLUSIONS:

    The recently suggested TNM staging system emerged as a useful clinical tool.

  • 17.
    Ekeblad, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dunder, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kozlovacki, Gordana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Örlefors, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sigurd, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 10, 2986-2991 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: A retrospective analysis of the toxicity and efficacy of temozolomide in advanced neuroendocrine tumors. Experimental Design: Thirty-six patients with advanced stages of neuroendocrine tumor (1 gastric, 7 thymic and 13 bronchial carcinoids, 12 pancreatic endocrine tumors, 1 paraganglioma, 1 neuroendocrine foregut, and 1 neuroendocrine cecal cancer) were treated with temozolomide (200 mg/m2) for 5 days every 4 weeks. Patients had previously received a mean of 2.4 antitumoral medical regimens. Tumor response was evaluated radiologically according to the Response Evaluation Criteria in Solid Tumors every 3 months on an intent-to-treat basis. The circulating tumor marker plasma chromogranin A was also assessed. The expression of 06-methylguanine DNA methyltransferase, an enzyme implicated in chemotherapy resistance, was studied by immunohistochemistry (n = 23) and compared with response to temozolomide. Results: Median overall time to progression was 7 months (95% confidence interval, 3-10). Radiologic response was seen in 14% of patients and stable disease in 53%. Side effects were mainly hematologic; 14% experienced grade 3 or 4 thrombocytopenia (National Cancer Institute toxicity criteria). Ten patients had tumors with 06-methylguanine DNA methyltransferase immunoreactivity in <10% of nuclei, whereas four patients showed radiologic responses. Conclusions: Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses.

  • 18.
    Eriksson, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Milenova, Ioanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ståhle, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Leja-Jarblad, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Immuneed AB, Uppsala, Sweden.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Department of Oncology, Uppsala University Hospital, Uppsala, Sweden.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Moreno, Raphael
    IDIBELL-Institute Catalá d'Oncologia, Barcelona, Spain.
    Alemany, Ramon
    IDIBELL-Institute Catalá d'Oncologia, Barcelona, Spain.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Lokon Pharma AB, Uppsala, Sweden.
    Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus.2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265Article in journal (Refereed)
    Abstract [en]

    Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma.Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses.Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells.Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 1-12. ©2017 AACR.

  • 19.
    Fjallskog, Marie-Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, BK
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of molecular targets for tyrosine kinase receptor antagonistsin malignant endocrine pancreatic tumors2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 4, 1469-1473 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment.

    EXPERIMENTAL DESIGN:

    Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR).

    RESULTS:

    All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals.

    CONCLUSIONS:

    We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.

  • 20.
    Fjällskog, Marie-Louise H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lejonklou, Margareta H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 4, 1469-1473 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment.

    EXPERIMENTAL DESIGN:

    Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR).

    RESULTS:

    All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals.

    CONCLUSIONS:

    We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.

  • 21.
    Fjällskog, Marie-Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Expression of molecular targets for tyrosine kinase antagonists in malignant endocrine pancreatic tumors2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 4, 1469-1473 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment.

    EXPERIMENTAL DESIGN:

    Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR).

    RESULTS:

    All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals.

    CONCLUSIONS:

    We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.

  • 22. Grövdal, Michael
    et al.
    Khan, Rasheed
    Aggerholm, Anni
    Antunovic, Petar
    Astermark, Jan
    Bernell, Per
    Engström, Lena-Maria
    Kjeldsen, Lars
    Linder, Olle
    Nilsson, Lars
    Olsson, Anna
    Wallvik, Jonas
    Tangen, Jon Magnus
    Öberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jacobsen, Sten Eirik
    Hokland, Peter
    Porwit, Anna
    Hellström-Lindberg, Eva
    Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 23, 7107-7112 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.

  • 23.
    Hawinkels, Lukas J. A. C.
    et al.
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gastroenterol Hepatol, NL-2300 RC Leiden, Netherlands..
    de Vinuesa, Amaya Garcia
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Paauwe, Madelon
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gastroenterol Hepatol, NL-2300 RC Leiden, Netherlands..
    Kruithof-de Julio, Marianna
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Wiercinska, Eliza
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Pardali, Evangelia
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Mezzanotte, Laura
    Leiden Univ, Med Ctr, Dept Radiol, Expt Mol Imaging Grp, NL-2300 RC Leiden, Netherlands..
    Keereweer, Stijn
    Leiden Univ, Med Ctr, Dept Radiol, Expt Mol Imaging Grp, NL-2300 RC Leiden, Netherlands..
    Braumuller, Tanya M.
    Netherlands Canc Inst, Div Mol Genet, NL-1066 CX Amsterdam, Netherlands..
    Heijkants, Renier C.
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Jonkers, Jos
    Netherlands Canc Inst, Div Mol Pathol, Amsterdam, Netherlands..
    Lowik, Clemens W.
    Leiden Univ, Med Ctr, Dept Radiol, Expt Mol Imaging Grp, NL-2300 RC Leiden, Netherlands..
    Goumans, Marie-Jose
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    ten Hagen, Timo L.
    Erasmus MC, Lab Expt Surg Oncol, Dept Surg Oncol, Rotterdam, Netherlands..
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 1, 96-106 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap. Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis. Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. Animmunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone. Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc.

  • 24. Heikkinen, Tuomas
    et al.
    Kärkkäinen, Hanni
    Aaltonen, Kirsimari
    Milne, Roger L.
    Heikkilä, Päivi
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Nevanlinna, Heli
    The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype2009In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 15, no 9, 3214-22 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival. EXPERIMENTAL DESIGN: We defined the PALB2 mutation status in 947 familial and 1,274 sporadic breast cancer patients and 1,079 population controls, and compared tumor characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases. RESULTS: The PALB2 1592delT mutation was found in 19 familial [2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P < 0.0001] and eight sporadic patients (0.6%; odds ratio, 3.40; 95% CI, 0.68-32.95; P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype more often (54.5%; P < 0.0001) than those of other familial (12.2%) or sporadic (9.4%) breast cancer patients. They were also more often of higher grade (P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 (P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24; P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up (P = 0.04). CONCLUSIONS: The PALB2 1592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.

  • 25. Heinonen, Mira
    et al.
    Fagerholm, Rainer
    Aaltonen, Kirsimari
    Kilpivaara, Outi
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Heikkilä, Päivi
    Haglund, Caj
    Nevanlinna, Heli
    Ristimäki, Ari
    Prognostic role of HuR in hereditary breast cancer2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 23, 6959-6963 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: HuR is an mRNA-binding protein that enhances the stability of certain transcripts and can regulate their translation. Elevated cytoplasmic expression of HuR protein has been linked to carcinogenesis and is associated with reduced survival in breast, ovarian, and gastric adenocarcinomas. Experimental Design: Here, we have explored the relevance of HuR in familial breast cancer. Tumor samples were collected from patients with identified BRCA1 (n = 51) or BRCA2 (n = 47) mutations or familial non-BRCA1/2 cases (n = 525), and analyzed by immunohistochemistry. Results: Among familial non-BRCAI/2 breast cancer patients, cytoplasmic HuR protein expression was present in 39.4% of the cases and was associated with estrogen receptor negativity, progesterone receptor negativity, p53 positivity, high tumor grade, and ductal type of the tumor. In multivariate analysis, cytoplasmic HuR expression was an independent marker of reduced survival in the non-BRCAI/2 group along with tumor size >2 cm, lymph node metastasis, and high histologic grade. In patients with BRCA1 or BRCA2 mutations, cytoplasmic HuR expression was more frequent (62.7% for BRCA1 and 61.7% for BRCA2) than in the non-BRCA1/ 2 group, but in BRCA -mutated subgroups cytoplasmic HuR expression did not associate with survival. Conclusions: Our results show that HuR is an important prognostic factor in familial breast cancer patients and may contribute to carcinogenesis in this disease.

  • 26.
    Hovstadius, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Skov, Torsten
    Kissmeyer, Ann-Marie
    Krasilnikoff, Klaus
    Bergh, Jonas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lönnebo, Anna
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    A Phase I Study of CHS 828 in Patients with Solid Tumor Malignancy2002In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 8, no 9, 2843-2850 p.Article in journal (Refereed)
    Abstract [en]

    CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1–5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 ± 1.3 h and half-life was 2.1 ± 0.52 h (mean ± SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.

  • 27.
    Humphries, Matthew P.
    et al.
    Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England..
    Rajan, Sreekumar Sundara
    Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England..
    Droop, Alastair
    Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England.;Univ Leeds, MRC Med Bioinformat Ctr, Leeds, W Yorkshire, England..
    Suleman, Charlotte A. B.
    St James Univ Hosp, Dept Histopathol, Leeds, W Yorkshire, England..
    Carbone, Carmine
    Azienda Osped Univ Integrata, Ctr Comprehens Canc, Verona, Italy..
    Nilsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Honarpisheh, Hedieh
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Cserni, Gabor
    Bacs Kiskun Cty Teaching Hosp, Dept Pathol, Kecskemet, Hungary..
    Dent, Jo
    Calderdale Hosp, Halifax, England..
    Fulford, Laura
    Surrey & Sussex NHS Trust, Redhill, Surrey, England..
    Jordan, Lee B.
    Univ Dundee, NHS Tayside, Dundee, Scotland..
    Jones, J. Louise
    Barts Canc Inst, London, England..
    Kanthan, Rani
    Univ Saskatchewan, Dept Pathol & Lab Med, Saskatoon, SK, Canada..
    Litwiniuk, Maria
    Poznan Univ Med Sci, Greater Poland Canc Ctr, Poznan, Poland..
    Di Benedetto, Anna
    Regina Elena Inst Canc Res, Dept Pathol, Rome, Italy..
    Mottolese, Marcella
    Regina Elena Inst Canc Res, Dept Pathol, Rome, Italy..
    Provenzano, Elena
    Addenbrookes Hosp, Dept Histopathol, Cambridge, England..
    Shousha, Sami
    Imperial Coll Healthcare NHS Trust, Dept Histopathol, London, England.;Charing Cross Hosp, Imperial Coll, London, England..
    Stephens, Mark
    Univ Hosp North Staffordshire, Stoke On Trent, Staffs, England..
    Walker, Rosemary A.
    Univ Leicester, Canc Studies & Mol Med, Leicester, Leics, England..
    Kulka, Janina
    Semmelweis Univ, Dept Pathol 2, Budapest, Hungary..
    Ellis, Ian O.
    Nottingham City Hosp, Fac Med & Hlth Sci, Nottingham, England..
    Jeffery, Margaret
    Queen Alexandra Hosp, Pathol Ctr, Dept Histopathol, Portsmouth, Hants, England..
    Thygesen, Helene H.
    Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England..
    Cappelletti, Vera
    Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Milan, Italy..
    Daidone, Maria G.
    Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol & Mol Med, Milan, Italy..
    Hedenfalk, Ingrid A.
    Lund Univ, Dept Oncol & Pathol, Clin Sci, Lund, Sweden.;Lund Univ, CREATE Hlth Strateg Ctr Translat Canc Res, Lund, Sweden..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Melisi, Davide
    Azienda Osped Univ Integrata, Ctr Comprehens Canc, Verona, Italy.;Univ Verona, Dept Med, Digest Mol Clin Oncol Res Unit, Verona, Italy..
    Stead, Lucy F.
    Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England..
    Shaaban, Abeer M.
    Queen Elizabeth Hosp Birmingham, Dept Cellular Pathol, Birmingham, W Midlands, England.;Univ Birmingham, Birmingham, W Midlands, England..
    Speirs, Valerie
    Univ Leeds, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England..
    A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 10, 2575-2583 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Breast cancer affects both genders, but is understudied in men. Although still rare, male breast cancer (MBC) is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar.

    Experimental Design: A transcriptomic investigation of male and female breast cancer was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n = 477, training; n = 220, validation set) and quantified in pre- and posttreatment samples from an MBC patient receiving everolimus and PI3K/mTOR inhibitor.

    Results: Gender-specific gene expression patterns were identified. eIF transcripts were upregulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (log-rank P = 0.013; HR = 1.77, 1.12-2.8 and P = 0.035; HR = 1.68, 1.03-2.74, respectively), or when coexpressed (P = 0.01; HR = 2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis [ eIF4E P = 0.016; HR = 2.38 (1.18-4.8), eIF5 P = 0.022; HR = 2.55 (1.14-5.7); coexpression P = 0.001; HR = 7.04 (2.22-22.26)]. Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/everolimus, with extended survival.

    Conclusions: Translational initiation pathway inhibition could be of clinical utility in MBC patients overexpressing eIF4E and eIF5. With mTOR inhibitors that target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required.

  • 28. Joerger, Markus
    et al.
    Huitema, Alwin D. R.
    Richel, Dick J.
    Dittrich, Christian
    Pavlidis, Nikolas
    Briasoulis, Evangelos
    Vermorken, Jan B.
    Strocchi, Elena
    Martoni, Andrea
    Sorio, Roberto.
    Sleeboom, Henk P.
    Izquierdo, Miguel A.
    Jodrell, Duncan I.
    Calvert, Hilary
    Boddy, Alan V.
    Hollema, Harry
    Féty, Regine
    Van der Vijgh, Wjf J F.
    Hempel, Georg
    Chatelut, Etienne
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wilkins, Justin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tranchand, Brigitte
    Schrijvers, Ad H. G. J.
    Twelves, Christian
    Beijnen, Jos H.
    Schellens, Jan H. M.
    Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group.2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 21, 6410-6418 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC > 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients.

    Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data.

    Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10−4).

    Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

  • 29. Karlsson, Anna
    et al.
    Ringner, Markus
    Lauss, Martin
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Planck, Maria
    Staaf, Johan
    Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History2014In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 18, 4912-4924 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood. Experimental Design: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n = 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups. Results: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies similar to 60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of never-smokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma. Conclusions: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers.

  • 30. Kloft, Charlotte
    et al.
    Wallin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Henningsson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chatelut, Etienne
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs2006In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, no 18, 5481-5490 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs.

    Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made.

    Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha(1)-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction.

    Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.

  • 31. Kokhaei, Parviz
    et al.
    Abdalla, Amir Osman
    Hansson, Lotta
    Mikaelsson, Eva
    Kubbies, Manfred
    Haselbeck, Anton
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mellstedt, Håkan
    Österborg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Expression of erythropoietin receptor and in vitro functional effects of epoetins in B-cell malignancies2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 12, 3536-3544 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Erythropoietin (EPO) and EPO receptor (EPO-R) expression have been reported in solid tumors and are claimed to regulate tumor growth; however, no data have been published on this issue in B-cell malignancies or normal lymphoid cells. This report describes genomic/protein EPO-R expression and in vitro effects of recombinant human EPO (epoetin) in B-cell chronic lymphocytic leukemia (B-CLL), mantle-cell lymphoma (MCL), and multiple myeloma (MM).

    Experimental Design: Blood samples were obtained from patients with B-CLL, MCL, and healthy volunteers, and bone marrow was obtained from MM patients. EPO-R mRNA was detected by reverse transcription-PCR. EPO-R surface expression was investigated by flow cytometry using digoxigenin-labeled epoetin and polyclonal rabbit anti–EPO-R antibody for intracellular receptor. Tumor cell stimulation was determined in vitro using [3H]thymidine incorporation and CD69 expression after exposure to epoetin α or β or darbepoetin α.

    Results: EPO-R mRNA was detected in mononuclear cells from 32 of 41 (78%) B-CLL and 5 of 7 (71%) MCL patients, and 21 of 21 (100%) MM samples. Expression was also detected in highly purified T cells from six of eight B-CLL patients, four of four MM patients, and normal donor B and T cells. Surface EPO-R protein was not detected. Intracellular EPO-R staining with anti–EPO-R antibodies was unspecific. No tumor-stimulatory effect was observed with high epoetin concentrations.

    Conclusions:EPO-R gene is frequently expressed in lymphoid malignancies and normal B and T cells. However, there was no surface protein expression and no epoetin-induced in vitro stimulation of tumor B cells, indicating that epoetin therapy in vivo is likely to be safe in patients with lymphoid malignancies.

  • 32. Lehmann, Sören
    et al.
    Paul, Crister
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Retinoid receptor expression and its correlation to retinoid sensitivity in non-M3 acute myeloid leukemia blast cells2001In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 7, no 2, 367-372 p.Article in journal (Refereed)
    Abstract [en]

    All-trans-retinoic acid (ATRA) has significantly improved the treatment results in acute promyelocytic leukemia (M3). In non-M3 acute myeloid leukemia (AML), the effects are less clear, and there is a pronounced heterogeneity in the sensitivity to the growth-inhibitory effects of retinoids in leukemic cells from different non-M3 AML patients. Retinoids exert their effects through a number of nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. In this study, we determined the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha by real-time PCR in four cell lines and in blast cells from patients with non-M3 AML before and after ATRA incubation. All four receptors were expressed in cells from all 18 tested patient samples and in four myeloid cell lines. In the majority of the patient samples as well as in the cell lines, there was a pattern of high expression of RAR alpha and RXR alpha and low expression of RAR beta and RAR gamma. There was no correlation between the basal expression of any of the retinoid receptors and sensitivity to ATRA. A 24-h exposure to ATRA increased the expression of RAR alpha, RAR beta, RAR gamma, and RXR alpha in 46%, 77%, 30%, and 38% of the samples, respectively. The mean increase in receptor expression was most pronounced for RAR beta and RXR alpha. There was a significant correlation between an increase in RAR beta expression in response to ATRA and sensitivity to ATRA (P < 0.014). No such correlations were found for RAR alpha, RAR gamma, and RXR alpha. The expression of the monocytoid marker CD14 was significantly correlated with increased expression of RAR alpha (P = 0.03). We conclude that RAR alpha, RAR beta, RAR gamma, and RXR alpha are expressed in non-M3 AML blast cells and that ATRA-induced expression of RAR beta may be a marker for retinoid sensitivity.

  • 33. Leitner, Stephan
    et al.
    Sweeney, Katrina
    Öberg, Daniel
    Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London.
    Davies, Derek
    Miranda, Enrique
    Lemoine, Nick R
    Halldén, Gunnel
    Oncolytic adenoviral mutants with E1B19K gene deletions enhance gemcitabine-induced apoptosis in pancreatic carcinoma cells and anti-tumor efficacy in vivo.2009In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 15, no 5, 1730-40 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE Pancreatic adenocarcinoma is a rapidly progressive malignancy that is highly resistant to current chemotherapeutic modalities and almost uniformly fatal. We show that a novel targeting strategy combining oncolytic adenoviral mutants with the standard cytotoxic treatment, gemcitabine, can markedly improve the anticancer potency.

    EXPERIMENTAL DESIGN Adenoviral mutants with the E1B19K gene deleted with and without E3B gene expression (AdDeltaE1B19K and dl337 mutants, respectively) were assessed for synergistic interactions in combination with gemcitabine. Cell viability, mechanism of cell death, and antitumor efficacy in vivo were determined in the pancreatic carcinoma cells PT45 and Suit2, normal human bronchial epithelial cells, and in PT45 xenografts.

    RESULTS The DeltaE1B19K-deleted mutants synergized with gemcitabine to selectively kill cultured pancreatic cancer cells and xenografts in vivo with no effect in normal cells. The corresponding wild-type virus (Ad5) stimulated drug-induced cell killing to a lesser degree. Gemcitabine blocked replication of all viruses despite the enhanced cell killing activity due to gemcitabine-induced delay in G1/S-cell cycle progression, with repression of cyclin E and cdc25A, which was not abrogated by viral E1A-expression. Synergistic cell death occurred through enhancement of gemcitabine-induced apoptosis in the presence of both AdDeltaE1B19K and dl337 mutants, shown by increased cell membrane fragmentation, caspase-3 activation, and mitochondrial dysfunction.

    CONCLUSIONS Our data suggest that oncolytic mutants lacking the antiapoptotic E1B19K gene can improve efficacy of DNA-damaging drugs such as gemcitabine through convergence on cellular apoptosis pathways. These findings imply that less toxic doses than currently practiced in the clinic could efficiently target pancreatic adenocarcinomas when combined with adenoviral mutants.

  • 34.
    Leja, Justyna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Dzojic, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Gustafson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    A novel chromogranin-A promoter-driven oncolytic adenovirus for midgut carcinoid therapy2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 8, 2455-2462 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene.

    Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases.

    Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes.

    Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.

  • 35. Lemaire, Miguel
    et al.
    Fristedt, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Menu, Eline
    Van Valckenborgh, Els
    De Bruyne, Elke
    Osterborg, Anders
    Atadja, Peter
    Larsson, Olle
    Axelson, Magnus
    Van Camp, Ben
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Vanderkerken, Karin
    The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin2012In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 8, 2230-2239 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.

    Experimental Design: The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.

    Results: In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G2-M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice.

    Conclusions: The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589.

  • 36.
    Loskog, Angelica S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fransson, Moa E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    AdCD40L gene therapy counteracts T regulatory cells and cures aggressive tumors in an orthotopic bladder cancer model2005In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 11, no 24 Pt 1, 8816-8821 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to develop an immunostimulating gene therapy for the treatment of orthotopic bladder carcinoma by transferring the gene for CD40L into the tumor site. CD40L stimulation of dendritic cells induces interleukin-12 expression that drives Th1 type of immune responses with activation of cytotoxic T cells.

    EXPERIMENTAL DESIGN: The gene for murine CD40L was transferred into bladders of tumor-bearing mice using an adenoviral vector construct. To facilitate viral uptake, the bladders were pretreated with Clorpactin. Survival of mice as well as transgene expression and immunologic effect, such as resistance to tumor challenge and presence of T regulatory cells, were monitored.

    RESULTS: On viral vector instillation, CD40L expression could be detected by reverse transcription-PCR. As a sign of transgene function, interleukin-12 (IL-12) expression was significantly increased. AdCD40L gene therapy cured 60% of mice with preestablished tumors. The cured mice were completely resistant to subcutaneous challenge with MB49 tumor cells, whereas the growth of a syngeneic irrelevant tumor was unaltered. Furthermore, the mRNA expression level of the T regulatory cell transcription factor Foxp3 was evaluated both in tumor biopsies and lymph nodes. There were no differences within the tumors of the different treatment groups. However, Foxp3 mRNA levels were down-regulated in the lymph nodes of AdCD40L-treated mice. Correspondingly, T cells from AdCD40L-treated mice were not able to inhibit proliferation of naive T cells as opposed to T cells from control-treated, tumor-bearing mice.

    CONCLUSIONS: AdCD40L gene therapy evokes Th1 cytokine responses and counteracts T regulatory cell development and/or function.

  • 37.
    Lu, Donghao
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sinnott, Jennifer A.
    Ohio State Univ, Dept Stat, 1958 Neil Ave, Columbus, OH 43210 USA.;Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA..
    Valdimarsdottir, Unnur
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Univ Iceland, Sch Hlth Sci, Ctr Publ Hlth Sci, Fac Med, Reykjavik, Iceland..
    Fang, Fang
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gerke, Travis
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Univ Florida, Coll Med, Dept Epidemiol, Gainesville, FL USA.;Univ Florida, Coll Publ Hlth & Hlth Profess, Gainesville, FL USA..
    Tyekucheva, Svitlana
    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA..
    Fiorentino, Michelangelo
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA.;St Orsola Marcello Malpighi Hosp, Addarii Inst, Pathol Unit, Bologna, Italy..
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sesso, Howard D.
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA..
    Sweeney, Christopher J.
    Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA..
    Wilson, Kathryn M.
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Univ Iceland, Sch Hlth Sci, Ctr Publ Hlth Sci, Fac Med, Reykjavik, Iceland..
    Giovannucci, Edward L.
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA..
    Loda, Massimo
    Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA.;Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA..
    Mucci, Lorelei A.
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA..
    Fall, Katja
    Harvard Univ, Dept Epidemiol, TH Chan Sch Publ Hlth, Boston, MA 02115 USA.;Univ Orebro, Clin Epidemiol & Biostat, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Stress-Related Signaling Pathways in Lethal and Nonlethal Prostate Cancer2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 3, 765-772 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and non-lethal disease. Experimental Design: We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians' Health Study (n = 150; n = 82 with normal) and the Health Professionals Follow-Up Study (n = 254; n = 120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome and to biomarkers as secondary outcomes. Results: Differential mRNA expression of genes within the adrenergic (P = 0.001), glucocorticoid (P < 0.0001), serotoninergic (P = 0.0019), and muscarinic (P = 0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (P = 0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and nonlethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion. Conclusions: Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies.

  • 38.
    Malmström, Per-Uno
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Loskog, Angelica S. I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Lindqvist, Camilla A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mangsbo, Sara M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gårdmark, Truls
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    AdCD40L Immunogene Therapy for Bladder Carcinoma: The First Phase I/IIa Trial2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 12, 3279-3287 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Immunotherapy with bacillus Calmette-Guérin (BCG) instillation is recommended for high-risk non-muscle invasive bladder cancer. BCG is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40L (AdCD40L) has shown efficacy in tumor models. CD40L stimulates systemic immunity and may be effective in local and invasive human disease. EXPERIMENTAL DESIGN: Patients with invasive bladder cancer scheduled for cystectomy or patients with Ta tumors were enrolled in a Phase I/IIa trial. Patients were treated with three cycles of intra-bladder Clorpactin WCS-90 prewash followed by AdCD40L instillation one week apart. Safety, gene transfer, immune effects and anti-tumor responses were monitored. RESULTS: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies and bladders were heavily infiltrated with T-cells. The effector marker IFNg increased in biopsies while levels of circulating T regulatory cells were reduced. Histological evaluation indicated that AdCD40L therapy reduced the load of malignant cells. CONCLUSION: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first utilizing AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation and should be further evaluated as single or adjuvant therapy for urothelial malignancies.

  • 39.
    Mangsbo, Sara M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Broos, Sissela
    Fletcher, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Veitonmäki, Niina
    Furebring, Christina
    Dahlén, Eva
    Norlén, Per
    Lindstedt, Malin
    Tötterman, Thomas H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ellmark, Peter
    The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T cell dependent tumor immunity2015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 5, 1115-1126 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013. Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 has been investigated in human and murine in vitro models. The in vivo effect has been investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse. Results: Activation of dendritic cells (DCs) by ADC-1013 results in up-regulation of the co-stimulatory molecules CD80 and CD86, and secretion of IL-12. ADC-1013 also activates dendritic cells from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated dendritic cells induce antigen-specific T cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant anti-tumor effects and long-term tumor-specific immunity. Further, ADC-1013 demonstrates significant anti-tumor effects in a human bladder cancer transplanted into immunodeficient NSG mice. Conclusions: Our data demonstrate that ADC-1013 induces long-lasting anti-tumor responses and immunological memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.

  • 40. Mathijssen, Ron H J
    et al.
    Marsh, Sharon
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Xie, Rujia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Baker, Sharyn D
    Verweij, Jaap
    Sparreboom, Alex
    McLeod, Howard L
    Irinotecan pathway genotype analysis to predict pharmacokinetics2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 9, 3246-3253 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.

  • 41. Micke, Patrick
    et al.
    Basrai, Maryam
    Faldum, Andreas
    Bittinger, Fernando
    Rönnstrand, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Blaukat, Andree
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Beeh, Kai Michael
    Oesch, Franz
    Fischer, Berthold
    Buhl, Roland
    Hengstler, Jan Georg
    Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 1, 188-194 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The tyrosine-kinase receptor c-kit and its ligand stem cell factor are coexpressed in many small cell lung cancer (SCLC) cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop. To further evaluate the frequency and pathogenic relevance of c-kit expression, tumor tissue together with the corresponding clinical data of SCLC patients was analyzed. EXPERIMENTAL DESIGN: Tumor tissue of 102 consecutive SCLC cancer patients was analyzed immunohistochemically using an affinity-purified polyclonal c-kit antibody. Immunostaining data were correlated with survival and other relevant clinical parameters. RESULTS: A positive c-kit expression was observed in 37% of patients. c-kit expression was associated with decreased survival in the likelihood-ratio-forward selection model of the Cox regression including clinically relevant risk factors (c-kit expression, age, gender, stage, tumor stage, node stage, metastasis stage, weight loss, performance status, response to chemotherapy, lactate dehydrogenase, neuronspecific enolase, hemoglobin). Only c-kit expression [hazard ratio, 2.00; confidence interval (CI), 1.17-3.41; P = 0.012], response to chemotherapy (hazard ratio, 4.49; CI, 2.36-8.55; P < 0.001), and tumor stage (hazard ratio, 2.11; CI, 1.18-3.74; P = 0.008) were explanatory prognostic factors. These factors and all possible interactions between them were further analyzed in a second Cox regression model. As expected, response to chemotherapy had the highest impact on survival (hazard ratio, 3.06; CI, 1.69-5.54; P < 0.001). In patients with extensive disease, minor response to chemotherapy, and positive c-kit expression, the risk to die increased to 8.4 (hazard ratio, 2.74; CI, 1.52-4.91; P = 0.002). In a Kaplan-Meier analysis median survival of patients with minor response to chemotherapy and extensive stage was 288 days (CI, 255-321 days) when c-kit expression was negative compared with only 71 days (CI, 0-237 days) for c-kit-positive patients (log rank test: P = 0.003). CONCLUSIONS: c-kit represents a new prognostic factor in SCLC. c-kit expression is of particular clinical relevance in patients with advanced disease and poor response to chemotherapy. Given the very limited therapeutic options and unfavorable prognosis of these patients, clinical studies aimed at targeting c-kit (e.g., STI571) are clearly warranted.

  • 42. Noguchi, Satoshi
    et al.
    Saito, Akira
    Horie, Masafumi
    Mikami, Yu
    Suzuki, Hiroshi I.
    Morishita, Yasuyuki
    Ohshima, Mitsuhiro
    Abiko, Yoshimitsu
    Mattsson, Johanna S. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Koenig, Helena
    Lohr, Miriam
    Edlund, Karolina
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nagase, Takahide
    An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non-Small Cell Lung Cancer2014In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 17, 4660-4672 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (n =SCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis. Experimental Design: We characterized TAZ at the DNA (n = 192), mRNA (n = 196), and protein levels (n = 345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n = 1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis. Results: Higher TAZmRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway. Conclusion: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies.

  • 43.
    Pandzic, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ban, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. NUS, Yong Loo Lin Sch Med, A STAR, Dept Biochem,Inst Mol & Cell Biol, Singapore, Singapore..
    Ali, Muhammad Akhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hellström, Anders R.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schuh, Anna
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Clifford, Ruth
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Blakemore, Stuart J.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Baumann, Tycho
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Lopez-Guillermo, Armando
    Hosp Clin Barcelona, IDIBAPS, Serv Hematol, Barcelona, Spain..
    Campo, Elias
    Univ Barcelona, IDIBAPS, Hosp Clin, Unitat Hematol, Barcelona, Spain..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 24, 6217-6227 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy.

  • 44.
    Parry, Marina
    et al.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Rose-Zerilli, Matthew J. J.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gibson, Jane
    Univ Southampton, Ctr Biol Sci, Southampton, Hants, England..
    Wang, Jun
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Walewska, Renata
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Parker, Helen
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Parker, Anton
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Gardiner, Anne
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    McIver-Brown, Neil
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Kalpadakis, Christina
    Univ Crete, Dept Hematol, Sch Med, Iraklion, Greece..
    Xochelli, Aliki
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Div Mol Oncol, Dept Oncohaematol, IRCCS Ist Sci San Raffaele, Milan, Italy..
    de Castro, David Gonzalez
    Inst Canc Res, Heamatooncol Unit, Div Mol Pathol, Sutton, Surrey, England..
    Dearden, Claire
    Inst Canc Res, Heamatooncol Unit, Div Mol Pathol, Sutton, Surrey, England..
    Pratt, Guy
    Univ Birmingham, Sch Canc Studies, Birmingham, W Midlands, England.;Heart England NHS Fdn Trust, Dept Haematol, Birmingham, W Midlands, England..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ashton-Key, Margaret
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Forconi, Francesco
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Collins, Andrew
    Univ Southampton, Fac Med, Genet Epidemiol & Bioinformat, Southampton SO9 5NH, Hants, England..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Mol Oncol, Dept Oncohaematol, IRCCS Ist Sci San Raffaele, Milan, Italy..
    Matutes, Estella
    Univ Barcelona, Haematopathol Unit, Hosp Clin, Barcelona, Spain..
    Pangalis, Gerassimos
    Athens Med Ctr, Dept Hematol, Athens, Greece..
    Stamatopoulos, Kostas
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Oscier, David
    Strefford, Jonathan C.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing2015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 18, 4174-4183 p.Article in journal (Refereed)
    Abstract [en]

    Purpose:<bold> </bold>Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design:<bold> </bold>We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P = 0.03). Conclusions:<bold> </bold>We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

  • 45. Ponthan, Frida
    et al.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gleissman, Helena
    Fuskevåg, Ole M.
    Segerström, Lova
    Sveinbjörnsson, Baldur
    Redfern, Christopher P. F.
    Eksborg, Staffan
    Kogner, Per
    Johnsen, John I.
    Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 3, 1036-1044 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2- specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. Results: Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin, etoposide, irinotecan or vincristine in vitro. In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. Conclusions: Celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. Celecoxib could also be a potential drug for treatment of minimal residual disease.

  • 46.
    Ramachandran, Mohanraj
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dyczynski, Matheus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Pathol & Oncol, CCK, Stockholm, Sweden..
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lulla, Aleksei
    Institute of Technology, University of Tartu, Estonia..
    Lulla, Valeria
    Institute of Technology, University of Tartu, Estonia..
    Saul, Sirle
    Institute of Technology, University of Tartu, Estonia..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Merits, Andres
    Institute of Technology, University of Tartu, Estonia..
    Leja-Jarblad, Justyna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus2017In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, no 6, 1519-1530 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN-β in inhibiting therapeutic efficacy was investigated.

    RESULTS:

    The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT-2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN-β by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFN-β response and interferon-α⁄β receptor (IFNAR)-1 expression.

    CONCLUSIONS:

    SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN-β secretion.

  • 47. Schmidt, Marcus
    et al.
    Hellwig, Birte
    Hammad, Seddik
    Othman, Amnah
    Lohr, Miriam
    Chen, Zonglin
    Böhm, Daniel
    Gebhard, Susanne
    Petry, Ilka Brigitte
    Lebrecht, Antje
    Cadenas, Cristina
    Marchan, Rosemarie
    Stewart, Joanna
    Solbach, Christine
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Göransson Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Rody, Achim
    Berglund, Anders
    Lambe, Mats
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Karn, Thomas
    Müller, Volkmar
    Gerhold-Ay, Aslihan
    Cotarelo, Christina
    Sebastian, Martin
    Kronenwett, Ralf
    Bojar, Hans
    Lehr, Hans-Anton
    Sahin, Ugur
    Koelbl, Heinz
    Gehrmann, Mathias
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Rahnenführer, Jörg
    Hengstler, Jan G
    A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors2012In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 9, 2695-2703 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Although the central role of the immune system for tumor prognosis is generally accepted a single robust marker is not yet available.

    EXPERIMENTAL DESIGN:

    Based on ROC (receiver operating characteristic) analyses robust markers were identified from a 60 gene B-cell derived metagene and analyzed in gene expression profiles of 1810 breast cancer, 1056 non-small cell lung cancer, 513 colorectal and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin embedded tissue of 330 breast cancer patients. The cell types were identified using immunohistochemical co-staining and confocal fluorescence microscopy.

    RESULTS:

    We identified immunoglobulin kappa C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis free survival across different molecular subtypes in node-negative breast cancer (n=965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n=845) [P less than 0.001]. In addition, IGKC gene expression was prognostic in non-small cell lung cancer and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin embedded tissues of 330 breast cancer patients. Tumor infiltrating plasma cells were identified as the source of IGKC expression

    CONCLUSION:

    Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anti-cancer therapy. It could be validated in several independent cohorts and performed similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.

  • 48. Schmidt, Marcus
    et al.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Hengstler, Jan G.
    IGKC and Prognosis in Breast Cancer-Letter2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, 304-304 p.Article in journal (Refereed)
  • 49. Sclafani, Francesco
    et al.
    de Castro, David Gonzalez
    Cunningham, David
    Wilson, Sanna Hulkki
    Peckitt, Clare
    Capdevila, Jaume
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Keraenen, Susana Rosello
    Wotherspoon, Andrew
    Brown, Gina
    Tait, Diana
    Begum, Ruwaida
    Thomas, Janet
    Oates, Jacqueline
    Chau, Ian
    Fc gamma RIIa and Fc gamma RIIIa Polymorphisms and Cetuximab Benefit in the Microscopic Disease2014In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 17, 4511-4519 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Fc gamma R polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX +/- cetuximab in high-risk, locally advanced rectal cancer. Experimental Design: Fc gamma RIIa-H131R and Fc gamma RIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation fromthe Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. Fc gamma RIIa-131R (HR, 0.38; P = 0.058) and Fc gamma RIIIa-158F alleles (HR, 0.21; P = 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P = 0.017) and remained significant after adjusting for prognostic variables (P = 0.003). Conclusion: This is the first study investigating Fc gamma RIIa and Fc gamma RIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

  • 50. Skoglund, Johanna
    et al.
    Song, Bo
    Dalén, Johan
    Dedorson, Stefan
    Edler, David
    Hjern, Fredrik
    Holm, Jörn
    Lenander, Claes
    Lindforss, Ulrik
    Lundqvist, Nils
    Olivecrona, Hans
    Olsson, Louise
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Rutegård, Jörgen
    Smedh, Kennet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Törnqvist, Anders
    Houlston, Richard S.
    Lindblom, Annika
    Lack of an association between the TGFBR1*6A variant and colorectal cancer risk2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 12, 3748-3752 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies.

    Experimental Design: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted.

    Results: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A.

    Conclusion: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.

12 1 - 50 of 67
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