Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma
Intrahepatic cholangiocarcinoma (cancer of the bile ducts) is a devastating disease with limited treatment options. Research shows that fibroblast growth factor receptor 2 (FGFR2) is a driver of this cancer. However, many patients don't respond to FGFR2 inhibitors, and even in those who do respond, the response isn't durable.
Our goal is to address these therapeutic limitations. Our project investigators have identified that FGFR2 promotes cell growth via cross-talk with a second pathway termed Hippo. We're exploring how this cross-talk occurs and if it can be exploited therapeutically to improve the treatment of intrahepatic cholangiocarcinoma.
This project in the Mayo Clinic Hepatobiliary SPORE is examining the cellular mechanisms by which intrahepatic cholangiocarcinoma develops and progresses. We're determining if disruption of these signals results in tumor cell death and therapeutic cancer regression in preclinical models and in a proof-of-concept clinical trial.
Both the Hippo and fibroblast growth factor receptor 2 signaling pathways have been implicated as oncogenic mediators in intrahepatic cholangiocarcinoma. We're unifying these observations by positing cross-talk between the Hippo and FGFR2 signaling pathways in intrahepatic cholangiocarcinoma. The cross-talk seems to be mediated by Src family kinases.
We propose that intrahepatic cholangiocarcinoma progression can be driven by FGFR2 activation of the Hippo pathway effector YAP, and this activation of YAP is due to Src family kinase-mediated YAP tyrosine phosphorylation.
The aims of this project are to:
- Test the hypothesis that YAP drives specific FGFR2 expression, which in turn promotes YAP signaling by FGFR-mediated Src family kinases activation and YAP tyrosine phosphorylation
- Test the hypothesis that YAP nuclear localization serves as a biomarker for response to FGFR2-targeted therapy
- Test the hypothesis that inhibition of FGFR signaling is therapeutic in patients with intrahepatic cholangiocarcinoma who are receiving INCB054828, a panFGFR inhibitor by interruption of Hippo signaling pathways
The results of these studies have the potential to provide greater understanding of intrahepatic cholangiocarcinoma biology and identify new therapeutic strategies coupled with biomarkers to treat this cancer.