Overcoming the barriers to precision medicine in hepatocellular carcinoma
Unlike most solid tumors, hepatocellular carcinoma (HCC) has few targetable genetic mutations, limiting therapeutic options and research approaches. We have studied this extensively for HCC arising in the context of HBV infection. Using affinity purification-mass spectrometry and gene wide CRISPRi, we have found the ways that hepatitis B virus (HBV) alters protein networks and genetic dependencies. With the emergence of anti-vascular/immune therapy combinations for HCC, we are also studying the HCC contribution to response and resistance to these therapies.
Targeting oncogenic Protein Kinase A signaling
Protein Kinase A (PKA) has emerged as an oncogenic signal in tumors with mutations in PKA and the genes that regulate it, including GNAS and PRKAR1A. Oncogenic PKA signaling is particularly important in fibrolamellar carcinoma (FLC), a rare tumor of young adults. Potent and specific PKA inhibitors have been developed, but are not usable because of on-target toxicity for patients. We have used proteomics and functional genomics to characterize signaling dependencies downstream of PKA, and find translational activation to be particularly important. We are working on strategies to apply translational inhibition to FLC care.
Overcoming resistance to direct KRAS inhibitors in GI cancers
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. Small molecules targeting KRAS (G12C) have dramatically improved care for lung cancer but have much less benefit for patients with colon cancer. Using kinase proteomics, we have identified a colon cancer-specific co-target to overcome this resistance phenotype and are validating it in cells and PDX models.
Small molecule strategies to activate tumor suppressor signaling
Targeted inhibition of oncogenic signaling has transformed cancer care. We have explored the possibility that augmenting tumor suppressor signaling could have benefit as a complementary strategy. Focusing on the tumor suppressor LKB1, we have developed small molecules that can directly activate its signaling. Ongoing work seeks to characterize this novel therapeutic mechanism of action and develop in vivo active compounds.