Characterizing the impact of hepatitis viruses on liver cancer behavior and response to treatment
Unlike most solid tumors, hepatocellular carcinoma (HCC) has few targetable genetic mutations, limiting therapeutic options and research approaches. We have found that infection with hepatitis B virus (HBV) predicts distinct tumor biology and response to mTOR inhibitors. In collaboration with Nevan Krogan’s group, we are now studying how individual HBV proteins modify HCC proliferation and other mechanisms in HCC oncogenesis.
Developing small molecule strategies to target Hippo pathway dysregulation
The Hippo pathway impacts proliferation and drug resistance by regulating the oncogenic transcriptional co-activator YAP, but has been challenging to target therapeutically. We have studied several small molecules known to impact YAP, and identified mechanistic predictors of their efficacy in liver cancers. We are also collabortively developing small molecules to directly activate this pathway.
Mapping oncogenic kinase signaling and its response to targeted therapeutics
Targeted signaling inhibitors have dramatically improved the treatment of many solid tumors. Unfortunately, the benefit is often temporary and some oncogenic drivers have proven relatively intractable to these kinds of approaches. We are using proteomics to define the mechanisms of response and resistance to multiple therapeutically relevant agents, including FGFR and KRAS inhibitors. We also study signaling downstream of PKA in fibrolamellar liver cancers to identify essential mediators as potential therapeutic targets.