AN INTEGRATED PLATFORM FOR NOVEL PERSONALIZED LIVER CANCER THERAPEUTICS

SUMMARY Hepatocellular carcinoma (HCC) is a major health problem, with increasing mortality rates. In the US, HCC mortality is strongly affected by race/ethnicity and the highest mortality is found among racial minorities such as Black, Indigenous and People of Color (BIPOC). This is partly due to (a) limited efficacy of current FDA-approved

therapies and (b) a lack of personalized (biomarker-guided) therapeutic options, which is compounded by a lack of HCC preclinical models from diverse race-ethnic backgrounds. Thus, there is an urgent need to identify novel personalized therapeutic options that are validated in preclinical HCC models that represent the racial/ethnic diversity observed in HCC patients.

In this proposal for a supplement to our parental RO1, we expand our original team to integrate new expertise in equity research, qualitative analytics, communications research community-based participatory research, implementation, and organizational research (Mohamed, Bickell), to the existing one in clinical management of

liver disease (Villanueva), chemical biology (Dar), HCC animal models (Lujambio) and patient derived-organoids and 2D lines (Guccione). The major hypothesis that we seek to test is that BIPOC patients will report significant barriers to tissue donation and that by facilitating the creation of such preclinical models (i.e. PDO) from diverse etiology and a

broad spectrum of ethnic/racial backgrounds, we will identify differences in drug efficacy and toxicity in relation to specific tumor genetic and epigenetic backgrounds. We propose to (a) Elucidate BIPOC HCC patients’ barriers and facilitators to donate tissue; (b) Develop and test a culturally tailored educational intervention for diverse racial-ethnic groups, to encourage tissue donation

from HCC patients; and to (c) Establish better preclinical models (i.e. patient derived organoids, PDOs) that take into account differences in etiology and racial-ethnic background. The latter models will then feed into our original pipeline for drug screening, with the aim to identify new precision therapeutic leads.

The proposed research will increase our understanding of the barriers that limit or enable tissue donation from BIPOC HCC patients and to tailored intervention strategies to improve availability of preclinical models from BIPOC patients, ultimately resulting in improved preclinical studies and translation into the clinics.

Key deliverables include new preclinical models and leads for drug discovery derived from well-validated chemical starting points and mechanistic insights into patient stratification and therapeutics for HCC.