# Targeting HuR to improve a synthetic lethal therapy for pancreatic cancer

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $360,416

## Abstract

ABSTRACT
Despite recent advancements, metastatic pancreatic cancer remains a lethal disease with an average
survival of less than one year. New targeted treatments are desperately needed. Identifying and expanding
patient subgroups that would benefit most from promising targeted agents will immediately impact patient
outcomes. The primary impact of our proposal relates to the clinical implementation of PARP inhibitors,
harnessing a proven synthetic lethal therapeutic strategy personalized for a subset of pancreatic cancer
patients. Recent whole genome sequencing of 100 pancreatic cancers highlighted the opportunity to use
PARP inhibitor therapy targeted for tumors with a `DNA repair-BRCA-signature' subtype. Our work will
expand three fronts of investigation and innovation in an effort to optimize the most promising drug class
for pancreatic ductal adenocarcinoma patients. Aim 1 will expand our recent discovery that a post-
transcriptional mechanism driven by the mRNA stability factor HuR, provides a resistance mechanism for
pancreatic cancer cells exposed to PARP inhibitors. In this aim, we will extend our pre-clinical mouse
modeling to establish HuR as a facilitator of PARP inhibitor resistance and establish that inhibiting HuR
may sensitize all pancreatic tumors, regardless of DNA repair status, to PARP inhibitors. Aim 2 will further
define, using cutting edge molecular and cell-based techniques and assays, a PARP inhibitor mechanism of
action which is contingent upon a novel HuR-regulated target [i.e., (Poly(ADP-ribose) glycohydrolase
(PARG)]. Aim 3 will leverage our molecular understanding of HuR biology and the identification of two small
molecule inhibitors of HuR to develop novel and translatable strategies to enhance PARP inhibitor efficacy
using a patient derived (i.e., organoid technology), live biobank from an ongoing PARP inhibitor trial
conducted by investigators from the present proposal. The translational significance of our work relates to
our efforts to improve upon a promising, personalized approach to pancreatic cancer through increased
understanding of a recently discovered PARP inhibitor resistance mechanism. Our ultimate aim is to
optimize a best-in-class treatment strategy presently limited to tumors harboring DNA repair deficiencies,
so that this therapeutic strategy may be extended to include all pancreatic cancers, regardless of the
DNA-repair status (i.e., BRCA2 mutant and wild type).

## Key facts

- **NIH application ID:** 10240962
- **Project number:** 7R01CA212600-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Jonathan Brody
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $360,416
- **Award type:** 7
- **Project period:** 2016-12-09 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240962

## Citation

> US National Institutes of Health, RePORTER application 10240962, Targeting HuR to improve a synthetic lethal therapy for pancreatic cancer (7R01CA212600-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240962. Licensed CC0.

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