# Innovative Genetic Approaches to Enhance Liver Repopulation and Reduce Cancer Risk and Progression

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $533,446

## Abstract

A better understanding of the liver’s response to toxic injury, which includes hepatocyte proliferation,
and – unfortunately – an increased risk for hepatocellular carcinoma (HCC), is a prerequisite for the
development of novel clinical treatments for chronic liver disease and improved cancer prevention. Existing
drug therapies for HCC such as sorafenib extend patient survival by only three months. We recently developed
a massively parallel in vivo screening platform to test the impact of genetic factors such as full-length cDNAs or
miRNAs on liver repopulation and tumorigenesis. We have used this screening technology to build a map of all
miRNAs active in liver regeneration. Here, we propose to exploit this innovative paradigm to conduct a
comprehensive evaluation of the effects of the 135 most abundant but evolutionarily conserved hepatic
miRNAs on the processes of recovery from toxic liver injury and HCC tumorigenesis. In Specific Aim 1, we will
determine the combined benefits of three miRNAs identified in our prior screen on liver repopulation following
toxic injuries, as a step toward using miRNA-mimetic drug therapies for liver diseases. This will be
accomplished through delivery of miRNA-encoding plasmids or nanoparticles singly and in all combination. In
Specific Aim 2, we will determine the impact of hepatic miRNAs and miRNA combinations on HCC tumor
development in vivo. To this end, we have developed two models of rapid HCC development in mice, in which
we will screen our library of 135 ‘tough decoys’ (“TuD’s”), or inhibitors of miRNA action, on tumor formation.
We will quantify the abundance of all TuD’s using high throughput sequencing in the tumor-loaded liver
compared to the input library. TuD’s enriched in after tumor formation target miRNAs that normally limit tumor
growth, and those found less abundant target miRNAs that promote tumorigenesis. We will then test the
combinations of the most potent miRNA effectors on tumor formation following systemic delivery. In Specific
Aim 3 we will perform a conditional screen of miRNAs that impact Sorafenib resistance to identify novel
combination treatments for the prevention or treatment of HCC. Together, our powerful genetic screens
promise to identify miRNA effectors that can be employed for the treatment of acute liver injury and, in
combination with Sorafenib, as a more effective treatment to prevent HCC initiation and progression.

## Key facts

- **NIH application ID:** 10434813
- **Project number:** 5R01CA249929-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KLAUS H KAESTNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,446
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434813

## Citation

> US National Institutes of Health, RePORTER application 10434813, Innovative Genetic Approaches to Enhance Liver Repopulation and Reduce Cancer Risk and Progression (5R01CA249929-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434813. Licensed CC0.

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