# A Pharmacogenomic Approach Using Precision Models of Hepatocellular Carcinoma to Identify Novel Therapeutics

> **NIH NIH F32** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $66,390

## Abstract

Project Summary:
This proposal uses a multidimensional approach for target validation and drug discovery in hepatocellular
carcinoma (HCC) that focuses on pharmacogenomic predictions, a proprietary chemical analog library built on
approved HCC KI scaffolds, and the use of multiple precision models of HCC: 1) Genetically defined murine
HCCs induced in a fully immunocompetent background. This will allow for in vivo drug testing and to assess
the drug impact in the context of the tumor microenvironment and in combination with checkpoint inhibitors; 2)
Three-dimensional tumor organoids derived from these same murine models, which allow scalability for drug
screening. Tumor organoids are a major breakthrough for convenient omics-based analyses of tumor biology
and preclinical drug discovery, and are shown to accurately recapitulate patient responses to anticancer
agents; 3) Patient derived organoids and 4) Patient derived xenografts (PDX), which allow testing of drug
efficacy in genetically complex primary human tumors. Our close collaborator, Arvin Dar, has successfully
applied aspects of this approach to kinases involved in medullary thyroid carcinoma (Dar et al., Nature, 2012;
Sonoshita et al., Nature Chemical Biology, 2018). We have also recently applied a simplified approach and
confirmed increased anti-tumoral activity of a new KI -AD80- compared to the standard-of-care (sorafenib) in
experimental HCC models (Yu et al, accepted). To date, no single study has combined the multidisciplinary
innovation presented in this proposal for drug discovery in liver cancer. The major hypothesis of this project is
that different HCC oncogenic drivers will establish unique therapeutic vulnerabilities within tumor organoid
lines. By using multiple precision models and informed modifications to KIs, we will be able to suggest
stratification strategies and identify better therapeutics for HCC patients. This rationale is currently
unprecedented in liver cancer research.

## Key facts

- **NIH application ID:** 10179334
- **Project number:** 5F32CA247414-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Alexander Rialdi
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $66,390
- **Award type:** 5
- **Project period:** 2020-06-24 → 2022-06-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179334

## Citation

> US National Institutes of Health, RePORTER application 10179334, A Pharmacogenomic Approach Using Precision Models of Hepatocellular Carcinoma to Identify Novel Therapeutics (5F32CA247414-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10179334. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*