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Clinical candidate and genistein analogue AXP107-11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein-coupled estrogen receptor signaling
Univ Houston, Dept Biol & Biochem, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA;KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, S-17121 Solna, Sweden;Indiana Univ, Sch Informat Comp & Engn, Dept Intelligent Syst Engn, Bloomington, IN USA.
Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA.
KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, S-17121 Solna, Sweden.
KTH Royal Inst Technol, Dept Prot Sci, Sci Life Lab, S-17121 Solna, Sweden;Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 18, p. 7705-7719Article in journal (Refereed) Published
Abstract [en]

Despite advances in cancer therapeutics, pancreatic cancer remains difficult to treat and often develops resistance to chemotherapies. We have evaluated a bioavailable genistein analogue, AXP107-11 which has completed phase Ib clinical trial, as an approach to sensitize tumor cells to chemotherapy. Using organotypic cultures of 14 patient-derived xenografts (PDX) of pancreatic ductal adenocarcinoma, we found that addition of AXP107-11 indeed sensitized 57% of cases to gemcitabine treatment. Results were validated using PDX models in vivo. Further, RNA-Seq from responsive and unresponsive tumors proposed a 41-gene treatment-predictive signature. Functional and molecular assays were performed in cell lines and demonstrated that the effect was synergistic. Transcriptome analysis indicated activation of G-protein-coupled estrogen receptor (GPER1) as the main underlying mechanism of action, which was corroborated using GPER1-selective agonists and antagonists. GPER1 expression in pancreatic tumors was indicative of survival, and our study proposes that activation of GPER1 may constitute a new avenue for pancreatic cancer therapeutics.

Place, publisher, year, edition, pages
2019. Vol. 8, no 18, p. 7705-7719
Keywords [en]
AXP107-11, chemoresistance, genistein, GPER1, pancreatic ductal adenocarcinoma
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-407436DOI: 10.1002/cam4.2581ISI: 000514852600021PubMedID: 31568691OAI: oai:DiVA.org:uu-407436DiVA, id: diva2:1417074
Funder
EU, FP7, Seventh Framework Programme, 291795Swedish Cancer Society, CAN2015/591Swedish Cancer Society, CAN2018/596Swedish Research Council, 2017-01658VinnovaStockholm County Council, 2017-0587Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-26Bibliographically approved

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DiLorenzo, Sebastian

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