# Preclinical Models for Cancer Therapeutic Development

> **NIH NIH R50** · COLD SPRING HARBOR LABORATORY · 2020 · $174,117

## Abstract

Project Summary/Abstract:
Pancreatic Ductal Adenocarcinoma (PDA) is a highly aggressive and lethal disease in part due
to the poor efficacy of current therapies. Therefore, my research focuses on the identification of
better therapeutic strategies for PDAC. We recently developed an ex vivo, pancreatic ductal
organoid system to culture normal pancreas, early-stage pancreatic cancer and PDAC-derived
tissue inside a three dimensional, Matrigel matrix. Using these organoids, we identified gene
expression alterations between normal and malignant cells using transcriptomic and proteomic
approaches. The effect of these genes on tumor growth or maintenance will be functionally
validated using orthotopically grafted organoid (OGO) mouse transplantation models. Validated
key drivers will then be exploited to develop new therapeutic strategies. In addition to finding
novel candidate drug targets, we have further investigated the role of Nrf2, a transcription factor
we found to be important for PDAC progression, in the response of pancreatic tumors to
traditional and novel therapeutic interventions. Our initial experiments suggest that Nrf2 serves
as an anti-oxidant defense mechanism and that oxidants sensitize PDAC cells to translation
inhibition, which can be used as a new therapeutic approach for the treatment of PDAC. We
perform pre-clinical studies using genetically modified mouse models (GEMM) that express
conditional oncogenic Kras and mutated p53 in the pancreas, as well as both mouse and
human OGO models. The GEMM and OGO models develop PDAC, which accurately
recapitulates human disease and provides excellent platforms to model therapeutic intervention.
We will assess the efficacy of drug combinations identified from both gene expression changes
as well as from drug screening approaches. Drug combinations to be tested include, but are not
limited to, irreversible ErbB pathway inhibitors, inhibitors of AKT and MEK, several compounds
with oxidant properties, and translation inhibitors. These efforts will focus on compounds that
either already have FDA approval or have promising phase III trial results to facilitate rapid
translation of our findings to the clinic. My role in these studies includes generation of an
organoid library for global molecular analyses, as well as improving tools to identify candidate
drug targets. Furthermore, I will continue to manage the in vivo preclinical studies that focus on
discovering new therapeutic options for pancreatic cancer. Ultimately, my role will be to ensure
the efficiency, reproducibility and accuracy of preclinical studies thereby facilitating the efficient
translation of our findings into clinical trials.

## Key facts

- **NIH application ID:** 9996508
- **Project number:** 5R50CA211506-05
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** YOUNGKYU PARK
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $174,117
- **Award type:** 5
- **Project period:** 2016-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996508

## Citation

> US National Institutes of Health, RePORTER application 9996508, Preclinical Models for Cancer Therapeutic Development (5R50CA211506-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996508. Licensed CC0.

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