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Nygren, Peter
Publications (10 of 121) Show all publications
Karlsson, H., Fryknäs, M., Strese, S., Gullbo, J., Westman, G., Bremberg, U., . . . Nygren, P. (2017). Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity. OncoTarget, 8(18), 30217-30234.
Open this publication in new window or tab >>Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, 30217-30234 p.Article in journal (Refereed) Published
Abstract [en]

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keyword
cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-323035 (URN)10.18632/oncotarget.16324 (DOI)000400456200055 ()28415818 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-11-29Bibliographically approved
Blom, K., Nygren, P., Larsson, R. & Andersson, C. R. (2017). Predictive Value of Ex Vivo Chemosensitivity Assays for Individualized Cancer Chemotherapy: A Meta-Analysis. SLAS TECHNOLOGY, 22(3), 306-314.
Open this publication in new window or tab >>Predictive Value of Ex Vivo Chemosensitivity Assays for Individualized Cancer Chemotherapy: A Meta-Analysis
2017 (English)In: SLAS TECHNOLOGY, ISSN 2472-6303, Vol. 22, no 3, 306-314 p.Article in journal (Refereed) Published
Abstract [en]

Current treatment strategies for chemotherapy of cancer patients were developed to benefit groups of patients with similar clinical characteristics. In practice, response is very heterogeneous between individual patients within these groups. Precision medicine can be viewed as the development toward a more fine-grained treatment stratification than what is currently in use. Cell-based drug sensitivity testing is one of several options for individualized cancer treatment available today, although it has not yet reached widespread clinical use. We present an up-to-date literature meta-analysis on the predictive value of ex vivo chemosensitivity assays for individualized cancer chemotherapy and discuss their current clinical value and possible future developments.

Keyword
tumor cell, ex vivo, chemotherapy, individualized cancer therapy
National Category
Cancer and Oncology Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-323769 (URN)10.1177/2472630316686297 (DOI)000401736700008 ()28378608 (PubMedID)
Available from: 2017-06-09 Created: 2017-06-09 Last updated: 2017-06-09Bibliographically approved
Hultman, B., Gunnarsson, U., Nygren, P., Sundbom, M., Glimelius, B. & Mahteme, H. (2017). Prognostic factors in patients with loco-regionally advanced gastric cancer. World Journal of Surgical Oncology, 15, Article ID 172.
Open this publication in new window or tab >>Prognostic factors in patients with loco-regionally advanced gastric cancer
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2017 (English)In: World Journal of Surgical Oncology, ISSN 1477-7819, E-ISSN 1477-7819, Vol. 15, 172Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The aim of this study was to investigate epidemiologic and prognostic factors relevant to the treatment of loco-regionally advanced gastric cancer (GC).

METHODS: Two hundred and fifty-five patients with GC were identified in Uppsala County between 2000 and 2009. Patient records were analyzed for loco-regionally advanced GC defined as tumor with peritoneal involvement, excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. The presence or not of distant metastasis (DM), including hematogenous metastases (e.g., liver, lung, and bone) and/or distant lymph node metastases, was also analyzed. The Cox proportional hazard model was used for multivariate analysis of factors influencing survival.

RESULTS: One hundred and twenty patients (47% of all patients with GC; median age 70.5 years) had loco-regionally advanced disease, corresponding to an incidence of 3.8 per 100,000 person-years. Forty-one percent of these also had DM. Median overall survival (mOS) from the time of the diagnosis of loco-regionally advanced disease was 4.8 months for the total patient cohort, 5.1 months for the subgroup of patients without DM, and 4.7 months for the subgroup with DM. There was no significant difference in mOS between the subgroups with synchronous versus metachronous loco-regionally advanced GC: 4.8 months (range 0.0-67.4) versus 4.7 months (range 0.0-28.3). Using multivariate Cox analysis, positive prognostic factors for survival were good performance status at diagnosis and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative prognostic factor. The mOS did not differ when comparing the time period 2000-2004 (5.1 months, range 0-67.4) with the period 2005-2009 (4.0 months, range 0.0-28.3).

CONCLUSION: Peritoneal involvement occurred in almost half of the patients with GC in this study and was associated with short life expectancy. New treatment strategies are warranted.

Keyword
Gastric cancer, Loco-regionally advanced cancer, Metastases, Peritoneal, Prognostic factor, Surgery
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333265 (URN)10.1186/s12957-017-1243-z (DOI)000410928100002 ()28915886 (PubMedID)
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2017-12-12Bibliographically approved
Blom, K., Senkowski, W., Jarvius, M., Berglund, M., Rubin, J., Lenhammar, L., . . . Larsson, R. (2017). The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation. Immunopharmacology and immunotoxicology, 39(4), 199-210.
Open this publication in new window or tab >>The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation
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2017 (English)In: Immunopharmacology and immunotoxicology, ISSN 0892-3973, E-ISSN 1532-2513, Vol. 39, no 4, 199-210 p.Article in journal (Refereed) Published
Abstract [en]

Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1 beta and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1 beta secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1 release. MBZ-induced IL-1 release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.

Keyword
Repositioning, cancer therapy, monocytes, macrophages, mebendazole
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-329149 (URN)10.1080/08923973.2017.1320671 (DOI)000403934300005 ()28472897 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2018-01-13Bibliographically approved
Godskesen, T., Kihlbom, U., Nordin, K., Silen, M. & Nygren, P. (2016). Differences in trial knowledge and motives for participation among cancer patients in phase 3 clinical trials. European Journal of Cancer Care, 25(3), 516-523.
Open this publication in new window or tab >>Differences in trial knowledge and motives for participation among cancer patients in phase 3 clinical trials
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2016 (English)In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 25, no 3, 516-523 p.Article in journal (Refereed) Published
Abstract [en]

While participants in clinical oncology trials are essential for the advancement of cancer therapies, factors decisive for patient participation have been described but need further investigation, particularly in the case of phase 3 studies. The aim of this study was to investigate differences in trial knowledge and motives for participation in phase 3 clinical cancer trials in relation to gender, age, education levels and former trial experience. The results of a questionnaire returned from 88 of 96 patients (92%) were analysed using the Mann-Whitney U-test. There were small, barely relevant differences in trial knowledge among patients when stratified by gender, age or education. Participants with former trial experience were less aware about the right to withdraw. Male participants and those aged ≥65 years were significantly more motivated by a feeling of duty, or by the opinions of close ones. Men seem more motivated than women by external factors. With the awareness that elderly and single male participants might be a vulnerable group and participants with former trial experience are less likely to be sufficiently informed, the information consent process should focus more on these patients. We conclude that the informed consent process seems to work well, with good results within most subgroups.

Keyword
adults, cancer, clinical trials, patient education, patient information, phase 3 trials
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-252539 (URN)10.1111/ecc.12319 (DOI)000375066900018 ()25904313 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2017-12-04Bibliographically approved
Blom, K., Nygren, P., Alvarsson, J., Larsson, R. & Andersson, C. R. (2016). Ex Vivo Assessment of Drug Activity in Patient Tumor Cells as a Basis for Tailored Cancer Therapy. JALA, 21(1), 178-187.
Open this publication in new window or tab >>Ex Vivo Assessment of Drug Activity in Patient Tumor Cells as a Basis for Tailored Cancer Therapy
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2016 (English)In: JALA, ISSN 2211-0682, Vol. 21, no 1, 178-187 p.Article in journal (Refereed) Published
Abstract [en]

Although medical cancer treatment has improved during the past decades, it is difficult to choose between several first-line treatments supposed to be equally active in the diagnostic group. It is even more difficult to select a treatment after the standard protocols have failed. Any guidance for selection of the most effective treatment is valuable at these critical stages. We describe the principles and procedures for ex vivo assessment of drug activity in tumor cells from patients as a basis for tailored cancer treatment. Patient tumor cells are assayed for cytotoxicity with a panel of drugs. Acoustic drug dispensing provides great flexibility in the selection of drugs for testing; currently, up to 80 compounds and/or combinations thereof may be tested for each patient. Drug response predictions are obtained by classification using an empirical model based on historical responses for the diagnosis. The laboratory workflow is supported by an integrated system that enables rapid analysis and automatic generation of the clinical referral response.

Keyword
tumor cell, ex vivo, chemotherapy, tailored cancer therapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-277993 (URN)10.1177/2211068215598117 (DOI)000368772400019 ()26246423 (PubMedID)
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2016-02-23Bibliographically approved
Padhan, N., Nordling, T. E. M., Sundström, M., Åkerud, P., Birgisson, H., Nygren, P., . . . Claesson-Welsh, L. (2016). High sensitivity isoelectric focusing to establish a signaling biomarker for the diagnosis of human colorectal cancer. BMC Cancer, 16, Article ID 683.
Open this publication in new window or tab >>High sensitivity isoelectric focusing to establish a signaling biomarker for the diagnosis of human colorectal cancer
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2016 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, 683Article in journal (Refereed) Published
Abstract [en]

Background: The progression of colorectal cancer (CRC) involves recurrent amplifications/mutations in the epidermal growth factor receptor (EGFR) and downstream signal transducers of the Ras pathway, KRAS and BRAF. Whether genetic events predicted to result in increased and constitutive signaling indeed lead to enhanced biological activity is often unclear and, due to technical challenges, unexplored. Here, we investigated proliferative signaling in CRC using a highly sensitive method for protein detection. The aim of the study was to determine whether multiple changes in proliferative signaling in CRC could be combined and exploited as a "complex biomarker" for diagnostic purposes. Methods: We used robotized capillary isoelectric focusing as well as conventional immunoblotting for the comprehensive analysis of epidermal growth factor receptor signaling pathways converging on extracellular regulated kinase 1/2 (ERK1/2), AKT, phospholipase C gamma 1 (PLC gamma 1) and c-SRC in normal mucosa compared with CRC stage II and IV. Computational analyses were used to test different activity patterns for the analyzed signal transducers. Results: Signaling pathways implicated in cell proliferation were differently dysregulated in CRC and, unexpectedly, several were downregulated in disease. Thus, levels of activated ERK1 (pERK1), but not pERK2, decreased in stage II and IV while total ERK1/2 expression remained unaffected. In addition, c-SRC expression was lower in CRC compared with normal tissues and phosphorylation on the activating residue Y418 was not detected. In contrast, PLC gamma 1 and AKT expression levels were elevated in disease. Immunoblotting of the different signal transducers, run in parallel to capillary isoelectric focusing, showed higher variability and lower sensitivity and resolution. Computational analyses showed that, while individual signaling changes lacked predictive power, using the combination of changes in three signaling components to create a "complex biomarker" allowed with very high accuracy, the correct diagnosis of tissues as either normal or cancerous. Conclusions: We present techniques that allow rapid and sensitive determination of cancer signaling that can be used to differentiate colorectal cancer from normal tissue.

Keyword
Colorectal cancer, Isoelectric focusing, Signal transduction, Proliferation, ERK, c-SRC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-305935 (URN)10.1186/s12885-016-2725-z (DOI)000384194500001 ()27562229 (PubMedID)
Funder
Swedish Cancer Society, CAN2013/661Knut and Alice Wallenberg Foundation, KAW 2015.0275eSSENCE - An eScience Collaboration
Available from: 2016-11-14 Created: 2016-10-24 Last updated: 2017-11-29Bibliographically approved
Senkowski, W., Jarvius, M., Rubin, J., Lengqvist, J., Gustafsson, M. G., Nygren, P., . . . Fryknäs, M. (2016). Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids. CELL CHEMICAL BIOLOGY, 23(11), 1428-1438.
Open this publication in new window or tab >>Large-Scale Gene Expression Profiling Platform for Identification of Context-Dependent Drug Responses in Multicellular Tumor Spheroids
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2016 (English)In: CELL CHEMICAL BIOLOGY, ISSN 2451-9448, Vol. 23, no 11, 1428-1438 p.Article in journal (Refereed) Published
Abstract [en]

Cancer cell lines grown as two-dimensional (2D) cultures have been an essential model for studying cancer biology and anticancer drug discovery. However, 2D cancer cell cultures have major limitations, as they do not closely mimic the heterogeneity and tissue context of in vivo tumors. Developing three-dimensional (3D) cell cultures, such as multicellular tumor spheroids, has the potential to address some of these limitations. Here, we combined a high-throughput gene expression profiling method with a tumor spheroid-based drug-screening assay to identify context-dependent treatment responses. As a proof of concept, we examined drug responses of quiescent cancer cells to oxidative phosphorylation (OXPHOS) inhibitors. Use of multicellular tumor spheroids led to discovery that the mevalonate pathway is upregulated in quiescent cells during OXPHOS inhibition, and that OXPHOS inhibitors and mevalonate pathway inhibitors were synergistically toxic to quiescent spheroids. This work illustrates how 3D cellular models yield functional and mechanistic insights not accessible via 2D cultures.

National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-311191 (URN)10.1016/j.chembiol.2016.09.013 (DOI)000388373200015 ()27984028 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-01-13Bibliographically approved
Carlier, C., Strese, S., Viktorsson, K., Velander, E., Nygren, P., Uustalu, M., . . . Gullbo, J. (2016). Preclinical activity of melflufen (J1) in ovarian cancer. OncoTarget, 7(37), 59322-59335.
Open this publication in new window or tab >>Preclinical activity of melflufen (J1) in ovarian cancer
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 37, 59322-59335 p.Article in journal (Refereed) Published
Abstract [en]

Ovarian cancer carries a significant mortality. Since symptoms tend to be minimal, the disease is often diagnosed when peritoneal metastases are already present. The standard of care in advanced ovarian cancer consists of platinum-based chemotherapy combined with cytoreductive surgery. Unfortunately, even after optimal cytoreduction and adjuvant chemotherapy, most patients with stage III disease will develop a recurrence. Intraperitoneal administration of chemotherapy is an alternative treatment for patients with localized disease. The pharmacological and physiochemical properties of melflufen, a peptidase potentiated alkylator, raised the hypothesis that this drug could be useful in ovarian cancer and particularily against peritoneal carcinomatosis. In this study the preclinical effects of melflufen were investigated in different ovarian cancer models. Melflufen was active against ovarian cancer cell lines, primary cultures of patient-derived ovarian cancer cells, and inhibited the growth of subcutaneous A2780 ovarian cancer xenografts alone and when combined with gemcitabine or liposomal doxorubicin when administered intravenously. In addition, an intra-and subperitoneal xenograft model showed activity of intraperitoneal administered melflufen for peritoneal carcinomatosis, with minimal side effects and modest systemic exposure. In conclusion, results from this study support further investigations of melflufen for the treatment of peritoneal carcinomatosis from ovarian cancer, both for intravenous and intraperitoneal administration.

Keyword
ovarian cancer, melflufen, preclinical, in vivo, intraperitoneal treatment
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-310031 (URN)10.18632/oncotarget.11163 (DOI)000387153900046 ()27528037 (PubMedID)
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
Eriksson, A., Gustafsson, M., Fryknäs, M., Gullbo, J., Nygren, P., Höglund, M. & Larsson, R. (2016). Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects. Paper presented at 21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK. Haematologica, 101, 367-368.
Open this publication in new window or tab >>Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, 367-368 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-301452 (URN)000379484601269 ()
Conference
21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK
Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
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