Novel Target in YAP Pathway for Treating Liver Cancer
Inventors: Fernando Camargo, Wei-Chien Yuan
Invention Types: Therapeutics
Research Areas: Oncology/Hematology
Keywords: Drug Discovery, Hepactic, Protein, Target, Molecular biology, Cell SignalingFor More Information Contact: Freytsis, Marina
Liver cancer is responsible for more than 25,000 cancer deaths per year in the in the US and is the second most common cause of death from cancer worldwide. Patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinomas (IHC) have a high mortality rate (>90%) and apart from the multikinase-inhibitor Sorafenib, which has limited efficacy, no systemic treatment is available; thus new drugs are sorely needed. |
The Hippo pathway is one of the most powerful regulators of liver cell proliferation and cell fate. Clinical evidence suggests that a key downstream regulator of the pathway, YAP/TAZ, is activated (as measured by immunohistochemistry) in approximately 60% of HCC and more than 70% of IHC, and that this correlates with lower survival rates. However, no drugs that could antagonize YAP/TAZ activity have been reported. One major caveat in developing such agents is the lack of traditional druggable targets in the pathway. |
Recent work from the Camargo lab utilized an unbiased screen approach to identify the Kinase X as a critical downstream molecule of YAP in the context of liver growth and tumorigenesis. Multiple lines of experimental evidence demonstrate that Kinase X is selectively required for the growth of YAP-driven tumors in vivo and in cancer cell models. Importantly, the group has identified a small molecule antagonist of Kinase X. This inhibitor is a tool compound that is being optimized and developed as a therapeutic for liver cancer.
• Treatment of liver cancers
• Potential therapy for other epithelial cancers with increased YAP activation, including pancreatic, melanoma, and ovarian
• Novel mechanism to treat liver cancers
• Assay to screen for additional novel targets in Hippo pathway
License, Collaboration, or Sponsored Research
Key Publications: 1) Yimlamai D, Christodoulou C, Galli GG. Hippo pathway activity influences liver cell fate. Cell. 2014 June 05; 6(157):1324-38.
2) Yimlamai D, Fowler BH, Camargo FD (2015). Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol, Dec;63(6):1491-501.
3) Galli G, Carrara M, Yuan WC, Valdes-Quezada C, Gurung B, Pepe-Mooney B, Zhang T, Geeven G, Gray NS, de Laat W, Calogero RA, and Camargo FD (2015). YAP drives growth by controlling transcriptional pause release from dynamic enhancers. Mol Cell, Oct 15;60(2):328-337.
IPStatus: Pat. in Prep.