ExpLoiting thErapeutic VulnerAbilities in hepaTocEllular carcinoma (ELEVATE)

OVERALL: SUMMARY Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcomes. With the alarming rise in global obesity incidence, obesity-induced non-alcoholic steatohepatitis (NASH) is becoming a leading cause of HCC. HCC is usually diagnosed at an advanced stage when the tumor is unresectable. The most effective FDA-approved treatment for advanced non-resectable HCC is a combination of anti-PD-L1 (atezolizumab) and anti-VEGF (bevacizumab) antibodies, providing an overall response rate of 27%. Apart from immunotherapy, systemic therapy with tyrosine kinase inhibitors (TKIs, such as sorafenib or lenvatinib) provides only a modest (~3 months) increase in overall survival and causes drug resistance within six months. Recent studies document that immunotherapy may be less effective in patients with NASH-HCC than in HCC patients with viral hepatitis. Thus, there is an unmet need to develop novel and effective modalities of treatment for advanced HCC. This P01 proposal ExpLoiting theErapeutic VulnerAbilities in hepaTocEllular carcinoma (ELEVATE), which involves four projects, an administrative core (Core 1), a mouse model and pathological analysis core (Core 2), and a biostatistics and bioinformatics core (Core 3; BBC), aims to interrogate molecular changes in HCC and exploit them to develop combinatorial treatment approaches especially targeted to NASH-HCC. The overall objectives include interrogation of molecular mechanisms regulating NASH-HCC and the development of novel combinatorial treatment approaches based on the identified molecular abnormalities, evaluation of approaches that improve efficacy of approved immunotherapy using an authentic NASH-HCC mouse model, and development and evaluation of novel approaches that engage the immune system to counteract HCC (inflammatory and NASH-HCC). To achieve this objective, this P01 comprises experts, with an established history of highly integrated interaction, in HCC biology and mouse modeling, liver physiology and pathology, medicinal chemistry, cancer immunotherapy, pathological diagnosis, nanoparticle delivery, and bioinformatics and biostatistics. Successful completion of the proposed studies will significantly advance our understanding of the molecular mechanism of HCC pathogenesis and novel therapeutics and generate translationally relevant data from pre-clinical models having the potential to radically transform the management of HCC patients facilitating prolonged survival. Thus, this innovative P01 grant has high mechanistic and translational significance. ELEVATE brings together the expertise of a highly integrated team providing synergistic outcomes that may not be delivered by each project alone.