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.

Pharmacologic Activation of the G Protein–Coupled Estrogen Receptor Inhibits Pancreatic Ductal Adenocarcinoma

“…28 Also consistent with our data, high GPER expression is correlated with improved survival in PDAC, and genistein analogs that activate GPER have chemoenhancing functions in PDAC patient-derived xenografts. 29 Together with our previous study on melanoma, this work raises the possibility that the highly specific GPER agonist G-1 may have therapeutic utility against a wide array of GPERexpressing cancer types and critically may extend the utility of modern immune therapeutics to tumors that have thus far been resistant to immune therapy such as PDAC. 30 These data highlight the importance of GPER signaling in cancer, demonstrate that GPER activity is tumor suppressive in cancers that are not classically considered hormone responsive, and suggest that GPER activity may contribute to biological differences between the sexes that influence cancer progression and response to modern therapies.…”

“… 28 Also consistent with our data, high GPER expression is correlated with improved survival in PDAC, and genistein analogs that activate GPER have chemoenhancing functions in PDAC patient-derived xenografts. 29 …”

Pancreatic Cancer (PDAC): Introduction of Evidence-Based Complementary Measures into Integrative Clinical Management

“…In gemcitabine-resistant PDAC cells in vivo, genistein (combined with an inhibitor of miR-223) suppressed invasiveness, by reversing epithelial-to-mesenchymal transition and prolonged survival [ 252 ]. Similarly, in a PDX model of PDAC, a genistein analogue, AXP107-11 (APX), showed gemcitabine-enhancing effects by reducing tumor growth ( Figure 12 A) [ 253 ]. Molecular analysis revealed the G protein-coupled estrogen receptor 1 (GPER1) to be one of the genes involved in the sensitizing effect of genistein on PDAC cells.…”

“…Molecular analysis revealed the G protein-coupled estrogen receptor 1 (GPER1) to be one of the genes involved in the sensitizing effect of genistein on PDAC cells. Indeed, in a cohort of PDAC patients, a higher expression of GPER1 mRNA was associated with improved overall survival ( Figure 12 B) [ 253 ].…”

“…A relative high level of GPER1 mRNA expression was significantly associated with better overall survival ( p = 0.019). Modified from Mesmar et al [ 253 ].…”