uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Nygren, Peter
Publications (10 of 130) Show all publications
Mody, K., Mansfield, A. S., Vemireddy, L., Nygren, P., Gullbo, J. & Borad, M. (2019). A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors. Investigational new drugs, 37(4), 684-692
Open this publication in new window or tab >>A phase I study of the safety and tolerability of VLX600, an Iron Chelator, in patients with refractory advanced solid tumors
Show others...
2019 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 37, no 4, p. 684-692Article in journal (Refereed) Published
Abstract [en]

Introduction VLX600 is a novel iron chelator designed to interfere with intracellular iron metabolism, leading to inhibition of mitochondrial respiration and bioenergetic catastrophe and resultant tumor cell death. Methods We conducted a multicenter, phase 1, dose escalation study to determine the safety and adverse event profile and the maximum tolerated dose and recommended phase 2 dose of VLX600. Other endpoints included pharmacokinetics, and preliminary evidence of anti-cancer efficacy as assessed according to RECIST 1.1 criteria. VLX600 was administered intravenously on days 1, 8, and 15 of each 28-day treatment cycle. Results Nineteen patients were enrolled, and seventeen received at least one dose of VLX600. Dose increments were reduced to 50% after dose level 3 (40mg) due to the occurrence of a grade 3 pulmonary embolism. The study was then closed early due to slow recruitment. No maximum tolerated dose (MTD) nor RP2D had been identified at the time of study closure. Overall, the drug was well tolerated and no DLTs were observed. Fourteen patients experienced drug-related adverse events of any grade. The most frequently reported drug-related AEs were fatigue, nausea, constipation, vomiting, increased alkaline phosphatase, anemia, and decreased appetite. No formal efficacy or survival analyses were performed. No objective responses were observed, though six patients (32%) had stable disease as best response. Conclusion VLX600 was reasonably well tolerated and, together with preclinical data, there is support for further efforts to explore its activity as single agent and in combination with drugs or radiation.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Clinical trial, Phase 1, Iron chelating agents, VLX600
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-390390 (URN)10.1007/s10637-018-0703-9 (DOI)000475627500010 ()30460505 (PubMedID)
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically approved
Glimelius, B. & Nygren, P. (2019). Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer. Acta Oncologica, 58(4), 395-397
Open this publication in new window or tab >>Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer
2019 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 4, p. 395-397Article in journal, Editorial material (Refereed) Published
Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-382767 (URN)10.1080/0284186X.2019.1584405 (DOI)000463726300001 ()30882261 (PubMedID)
Available from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-05-03Bibliographically approved
Månsson, C., Brahmstaedt, R., Nygren, P., Nilsson, A., Urdzik, J. & Karlson, B.-M. (2019). Percutaneous Irreversible Electroporation as First Line Treatment of Locally Advanced Pancreatic Cancer. Anticancer Research, 39(5), 2509-2512
Open this publication in new window or tab >>Percutaneous Irreversible Electroporation as First Line Treatment of Locally Advanced Pancreatic Cancer
Show others...
2019 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 39, no 5, p. 2509-2512Article in journal (Refereed) Published
Abstract [en]

Background/Aim:

Irreversible electroporation (IRE) has recently been used as an experimental ablation treatment following systemic chemotherapy in locally advanced pancreatic cancer (LAPC). The primary aim of this study was to evaluate survival of LAPC patients after IRE prior to chemotherapy. The secondary aim was to examine the complication rates.

Patients and Methods:

Twenty-four patients with LAPC were included and treated with percutaneous ultrasound-guided IRE under general anesthesia. Survival data from the National Quality Registry for Pancreatic and Periampullary Cancer for LAPC during the same period were used for comparison.

Results:

The median survival after diagnosis was 13.3 months in the IRE group compared to 9.9 months in the registry group (p=0.511). Six patients had a severe complication after IRE treatment.

Conclusion:

No obvious gain in survival was observed with IRE as the first line treatment of LAPC and IRE was associated with severe complications. This study does not support percutaneous IRE in this setting.

Keywords
Pancreatic Neoplasms, Electroporation, Interventional Ultrasonography
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-365201 (URN)10.21873/anticanres.13371 (DOI)000469427800032 ()31092446 (PubMedID)
Available from: 2018-11-11 Created: 2018-11-11 Last updated: 2019-06-26Bibliographically approved
Daskalakis, K., Norlén, O., Karakatsanis, A., Hellman, P., Larsson, R., Nygren, P. & Stålberg, P. (2018). Ex Vivo Activity of Cytotoxic Drugs and Targeted Agents in Small Intestinal Neuroendocrine Tumors. Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 189-189
Open this publication in new window or tab >>Ex Vivo Activity of Cytotoxic Drugs and Targeted Agents in Small Intestinal Neuroendocrine Tumors
Show others...
2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 189-189Article in journal, Meeting abstract (Other academic) Published
Keywords
ex vivo activity, cytotoxic drugs, targeted agents, small intestinal neuroendocrine tumors
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-354378 (URN)10.1159/000487699 (DOI)000427285300187 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: H06

Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Daskalakis, K., Norlén, O., Karakatsanis, A., Hellman, P., Larsson, R., Nygren, P. & Stålberg, P. (2018). Ex vivo activity of cytotoxic drugs and targeted agents in small intestinal neuroendocrine tumors. Endocrine-Related Cancer, 25(4), 471-480
Open this publication in new window or tab >>Ex vivo activity of cytotoxic drugs and targeted agents in small intestinal neuroendocrine tumors
Show others...
2018 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 4, p. 471-480Article in journal (Refereed) Published
Abstract [en]

Small intestinal neuroendocrine tumors (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumor samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinicopathological variables and pre-treatment biomarkers. For cytotoxic drugs, SI-NETs demonstrated similar or higher sensitivity to 5-FU, platinum, gemcitabine and doxorubicin compared with CRC. For several of the targeted kinase inhibitors, SI-NET was among the most sensitive solid tumor types. CLL and ovarian cancer were generally the most sensitive tumor types to both cytotoxic drugs and protein kinase inhibitors. SI-NET was more sensitive to the mTOR inhibitor sirolimus than the other solid tumor types tested. Individual SI-NET samples demonstrated great variability in ex vivo sensitivity for most drugs. Cross-resistance between different drugs also varied considerably, being higher among protein kinase inhibitors. Age, stage, grade, peritoneal carcinomatosis and extra-abdominal metastases as well as serum chromogranin A and urine 5-HIAA concentrations at diagnosis did not correlate to drug sensitivity ex vivo. SI-NETs exhibit intermediate sensitivity ex vivo to cytotoxic and targeted drugs. Clinicopathological factors and currently used biomarkers are not clearly associated to ex vivo sensitivity, challenging these criteria for treatment decisions in SI-NET. The great variability in drug sensitivity calls for individualized selection of therapy.

Keywords
ex vivo activity, cytotoxic drugs, targeted agents, small intestinal neuroendocrine tumor
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-354255 (URN)10.1530/ERC-17-0404 (DOI)000430730300013 ()29440231 (PubMedID)
Available from: 2018-06-28 Created: 2018-06-28 Last updated: 2018-06-28Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A. H., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
Show others...
2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

National Category
Cancer and Oncology Urology and Nephrology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-325565 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2019-03-29Bibliographically approved
Kashif, M., Andersson, C., Mansoori, S., Larsson, R., Nygren, P. & Gustafsson, M. G. (2017). Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism. OncoTarget, 8(61), 103952-103967
Open this publication in new window or tab >>Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103952-103967Article in journal (Refereed) Published
Abstract [en]

We analyzed survival effects for 15 different pairs of clinically relevant anticancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair. COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy (TM) II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing. In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line. In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
synergy analysis, combinations, iso-genic, COMBIA, R package
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345218 (URN)10.18632/oncotarget.21895 (DOI)000419562500095 ()29262612 (PubMedID)
Available from: 2018-03-09 Created: 2018-03-09 Last updated: 2018-03-09Bibliographically approved
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
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, p. 30217-30234Article 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
Keywords
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
Wickström, M., Nygren, P., Larsson, R., Harmenberg, J., Lindberg, J., Sjoberg, P., . . . Gullbo, J. (2017). Melflufen: a peptidase-potentiated alkylating agent in clinical trials. OncoTarget, 8(39), 66641-66655
Open this publication in new window or tab >>Melflufen: a peptidase-potentiated alkylating agent in clinical trials
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 39, p. 66641-66655Article, review/survey (Refereed) Published
Abstract [en]

Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target. Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described. Consequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. This review summarizes the current preclinical and clinical knowledge of melflufen.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
melflufen, aminopeptidase, cancer, targeted chemotherapy
National Category
Cancer and Oncology Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-346504 (URN)10.18632/oncotarget.18420 (DOI)000410291200163 ()29029544 (PubMedID)
Available from: 2018-03-19 Created: 2018-03-19 Last updated: 2018-03-19Bibliographically 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, p. 306-314Article 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.

Keywords
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
Organisations

Search in DiVA

Show all publications