# Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $392,721

## Abstract

Hepatocellular carcinoma (HCC), the fifth most common cancer and the second most common cause of
cancer-related deaths worldwide, has no effective treatment for advanced disease. The present proposal
focuses on two interacting oncogenes, AEG-1 and MDA-9, promoting HCC development and progression.
Our studies over the last decade has firmly established that AEG-1 functions as a bona fide oncogene for
HCC and we have developed the methodology of targeted nanoplexes delivering AEG-1 siRNA (PAMAM-
AEG-1si) that markedly inhibits orthotopic human HCC xenografts in nude mice. We now document that
MDA-9 is overexpressed in human HCC patients and MDA-9 plays an important role in regulating invasion
and angiogenesis induced by HCC cells. TCGA database analysis reveals that AEG-1 and MDA-9 genes
are co-amplified in human HCC patients. We identify a novel interaction between AEG-1 and MDA-9 in cell
membrane of human HCC cells and demonstrate that they cooperate to promote HCC. We have now
developed a novel, specific small molecule inhibitor of MDA-9 (PDZ1i), displaying excellent PK and ADME
properties, which significantly reduces invasion by human HCC cells, and markedly inhibits human HCC
xenografts in combination with sorafenib, an FDA-approved drug for unresectable HCC. PDZ1i also shows
added inhibitory effect on the growth of xenografts of human HCC cells in which AEG-1 has been knocked
out. The long-term objective of the present proposal is to develop effective targeted therapies for HCC that
will provide significant survival benefit to HCC patients. Our immediate objective is to stringently evaluate
PDZ1i and PAMAM-AEG-1si, and PDZ1i and sorafenib combinatorial therapies in immunocompetent
mouse models of HCC, and decipher the molecular mechanism(s) by which AEG-1 and MDA-9 cooperate
to promote HCC. All these components are innovative and have high mechanistic and translational
significance. Sorafenib is routinely used for HCC treatment and combination of sorafenib and PDZ1i, if
proven successful in our proposed animal models, has the potential to be fast-tracked for evaluation in
Phase I/II clinical trials. For AEG-1 siRNA we have specifically chosen a nanoparticle delivery system
which is already FDA approved, and note that RNAi therapy is showing promise in current HCC clinical
trials, in the expectation of effective and rapid translation of results of PDZ1i and PAMAM-AEG-1si
combinatorial therapy to practice. Successful completion of our research holds promise for establishing an
effective therapeutic protocol for advanced HCC that will help significantly prolong the lives of scores of
HCC patients.

## Key facts

- **NIH application ID:** 10754229
- **Project number:** 5R01CA244993-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PAUL B FISHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $392,721
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754229

## Citation

> US National Institutes of Health, RePORTER application 10754229, Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma (5R01CA244993-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10754229. Licensed CC0.

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