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

Cancer Med. 2019 Dec;8(18):7705-7719. doi: 10.1002/cam4.2581. Epub 2019 Sep 30.

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.

Keywords: AXP107-11; GPER1; chemoresistance; genistein; pancreatic ductal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / diagnosis
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Genistein / analogs & derivatives
  • Genistein / pharmacology*
  • Genistein / therapeutic use
  • Humans
  • Mice
  • Models, Biological
  • Mucin-1 / genetics
  • Pancreatic Neoplasms / diagnosis
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • MUC1 protein, human
  • Mucin-1
  • Protein Kinase Inhibitors
  • Receptors, Estrogen
  • Deoxycytidine
  • gemcitabine
  • Genistein