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Clinical candidate and genistein analogue AXP107-11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein-coupled estrogen receptor signaling
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab. Univ Houston, Ctr Nucl Receptors & Cell Signaling, Dept Biol & Biochem, Houston, TX USA.;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, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634Article in journal (Refereed) Epub ahead of print
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
WILEY , 2019.
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)
Identifiers
URN: urn:nbn:se:kth:diva-262970DOI: 10.1002/cam4.2581ISI: 000490096700001PubMedID: 31568691Scopus ID: 2-s2.0-85073938260OAI: oai:DiVA.org:kth-262970DiVA, id: diva2:1367683
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20191104

Available from: 2019-11-04 Created: 2019-11-04 Last updated: 2019-11-04Bibliographically approved

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Ibrahim, AhmedWilliams, Cecilia

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