Project 2: Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma
Lay summary
Cholangiocarcinoma (CCA) is a difficult-to-treat liver cancer that often develops resistance to current therapies. Our research has identified a protein called yes-associated protein (YAP) as a major contributor to this resistance.
We've discovered that blocking YAP's activity can potentially reverse this resistance, making existing treatments more effective. We're now conducting further studies to confirm this finding and exploring a new treatment strategy for people with cholangiocarcinoma.
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Scientific rationale
This project 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.
We have a strong rationale for investigating the mechanisms of YAP-driven CCA development and exploring the therapeutic potential of targeting YAP-TEAD signaling in preclinical and clinical studies. This is because of the central role of yes-associated protein/transcriptional coactivator with PDZ-binding motif (TAZ) in cholangiocarcinoma oncogenesis, its contribution to therapeutic resistance and its suppression of antitumor immunity.
Hypothesis
We propose that YAP-TEAD-mediated signaling drives therapeutic resistance in cholangiocarcinoma and that this resistance can be overcome by selective YAP-TEAD inhibition.
Project aims
This project has three aims:
- Aim 1. Determine the dependence of CCA tumor progression on persistent YAP-TEAD signaling and demonstrate that inhibiting YAP expression leads to tumor regression, establishing the therapeutic potential of the selective TEAD inhibitor CTX-1009685.
- Aim 2. Investigate how YAP-TEAD signaling in CCA alters the tumor immune microenvironment, specifically by examining its effects on myeloid-derived suppressor cell (MDSC) abundance and function, and determine if these effects are reversed by CTX-1009685 treatment.
- Aim 3. Conduct a phase 1 clinical trial of CTX-1009685 in people with unresectable locally advanced or metastatic CCA to assess its safety profile and demonstrate on-target effects of TEAD inhibition.
This research will establish the dependence of cholangiocarcinoma tumor growth on YAP-TEAD signaling, investigate the impact of this signaling pathway on the tumor immune microenvironment, and ultimately lead to a new, safe and effective treatment for people with advanced cholangiocarcinoma.
