# Preclinical Models for Cancer Therapeutic Development

> **NIH NIH R50** · COLD SPRING HARBOR LABORATORY · 2021 · $248,045

## Abstract

PROJECT SUMMARY/ABSTRACT
 Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal disease due to the poor efficacy
of current therapies. Therefore, my research focuses on development of preclinical models for the identification
of better therapeutic strategies. Two main distinct features of PDA are the high frequency of KRAS mutations
that is poorly responsive to targeted therapies and an extensive desmoplastic tumor microenvironment (TME)
composed of a dense extracellular matrix (ECM), acting as a barrier to therapy, and multiple non-neoplastic cell
types including cancer-associated fibroblasts (CAF), endothelial cells, and immune cells. These two prominent
features of PDA contribute to its intractability to current standard-of-care, calling for tailored targeted therapies
to improve patients’ survival.
 As we previously reported, activation of oncogenic Kras during PDA development results in alterations to
redox homeostasis and mitophagy pathways, providing evidence to support a redox-targeting approach. I will
employ genetically engineered mouse models (GEMMs), organoids, and organoid transplantation models of
PDA to test the potential efficacy of redox therapies, in particular mitochondrial inhibitors or ROS inducers in
combination with MEKi (downstream component of Kras signaling).
 Our prior work has also identified heterogeneity within the population of cancer-associated fibroblasts
(CAFs), each with their own distinct functions and active pathways. These fibroblasts include myofibroblastic
(myCAFs), inflammatory (iCAFs) and antigen-presenting (apCAFs) CAFs. Understanding the underlying
mechanisms of their active pathways is necessary for the development of therapeutic strategies to ablate tumor-
promoting fibroblasts specifically. We reported that JAKi shifted the CAF subtypes towards myCAFs and
suppressed tumor growth. I continue to target other active iCAF-signaling pathways through IL1R antagonism
or delivery of anti-LIF antibodies in combination with immunotherapy using our GEMM models. Understanding
how different types of CAFs contribute to tumor growth will provide a new avenue to develop strategies to ablate
the cancer cell-promoting CAFs. To this end, we will uncover the identities and functions of these CAFs in our
novel intraductally engrafted human organoid (IGO) model using a single-cell RNA sequencing approach. I will
establish a series of IGO models with patient-derived organoids and use these mice to test the efficacy of co-
targeting cancer cells and cancer-promoting CAFs by applying the findings from scRNA-seq analysis.
 Lastly, I will develop viral-induced GEMMs of PDA that can serve as a rapid platform to investigate the
importance of candidate genes identified in our transcriptomic or proteomic datasets derived from our organoid
and mouse models. Taken together, these multiple approaches I will employ to studying PDA, its primary driving
oncogene and aberrantly altered pathways, and the surrounding mic...

## Key facts

- **NIH application ID:** 10324176
- **Project number:** 2R50CA211506-06
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** YOUNGKYU PARK
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,045
- **Award type:** 2
- **Project period:** 2016-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10324176

## Citation

> US National Institutes of Health, RePORTER application 10324176, Preclinical Models for Cancer Therapeutic Development (2R50CA211506-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10324176. Licensed CC0.

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