Unknown

Dataset Information

0

Clinical candidate and genistein analogue AXP107-11 has chemoenhancing functions in pancreatic adenocarcinoma through G protein-coupled estrogen receptor signaling.


ABSTRACT: 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.

SUBMITTER: Mesmar F 

PROVIDER: S-EPMC6912054 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4413649 | BioStudies
2014-01-01 | S-EPMC4240628 | BioStudies
2019-01-01 | S-EPMC6891397 | BioStudies
2016-01-01 | S-EPMC4711922 | BioStudies
2017-01-01 | S-EPMC5654585 | BioStudies
2019-12-31 | GSE97766 | GEO
2014-01-01 | S-EPMC4144112 | BioStudies
2016-01-01 | S-EPMC4936403 | BioStudies
2012-01-01 | S-EPMC3414490 | BioStudies
2011-01-01 | S-EPMC3095647 | BioStudies