# Nrf2 Regulation of Ductal Pancreatic Cancer Etiology and Treatment Response

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2020 · $615,683

## Abstract

Abstract: Nrf2 Regulation of Ductal Pancreatic Cancer Etiology and Treatment
We seek to leverage the unique capability of Pancreatic Ductal Adenocarcinoma (PDA) cells to resist
oxidative stress towards the development of effective therapies for this malignancy. Indeed, in addition to
the advanced stage of disease that patients typically have at presentation, the lethality of PDA largely
reflects the poor response of their tumors to systemic therapeutics. We previously reported that PDA
initiation in a mouse model required the Nrf2 transcription factor, in part through the ability of Nrf2 to direct
the expression of many genes that collectively reduce intracellular reactive oxygen species (ROS).
Additional work by others demonstrated that somatic mutations in NRF2 or its binding protein KEAP1 occur
commonly in lung and breast cancer, resulting in the activation of the NRF2 pathway and increased drug
resistance. To determine how Nrf2 promotes cancer formation and therapeutic resistance in PDA we have
generated new conditional models and developed mouse and human pancreatic cancer organoid cultures.
The new mouse models and organoids will serve two complementary purposes: to unequivocally determine
whether Nrf2 functions solely in a cell intrinsic manner in promoting PDA, and as model systems to
discover the Nrf2 effector pathways and explore new therapeutic strategies in vivo and ex vivo (Aim 1).
Accordingly, we have found that Nrf2 regulates protein translation through its antioxidant function to
promote cell proliferation in PDA organoids, and we will define the biochemical mechanisms involved and
determine whether they represent new therapeutic opportunities (Aim 2). Furthermore, we have identified
new, non-antioxidant related Nrf2 target genes in PDA organoids, and we will determine their role in PDA
pathogenesis (Aim 3). Our project will utilize bespoke model systems and state-of-the-art mass
spectrometric, genomic, transcriptomic, and bioinformatics methods in order to identify new mediators of
Nrf2 function in PDA. Nrf2 effector pathways and target genes discovered in our work will be assessed for
their individual importance in PDA biology and therapeutic resistance, and the most promising candidates
will be validated in organoid and mouse models using genetic and pharmacological approaches. We
anticipate that our results will explain fundamental aspects of oncogenesis in PDA and will lead to the
development of more effective therapies for this deadly malignancy.

## Key facts

- **NIH application ID:** 9830019
- **Project number:** 5R01CA188134-04
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** David A Tuveson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,683
- **Award type:** 5
- **Project period:** 2016-12-07 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830019

## Citation

> US National Institutes of Health, RePORTER application 9830019, Nrf2 Regulation of Ductal Pancreatic Cancer Etiology and Treatment Response (5R01CA188134-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830019. Licensed CC0.

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