# Targeting pancreatic cancer's metabolic addiction to HuR

> **NIH NIH R37** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $373,116

## Abstract

Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer death in the U.S. and is generally
refractory to chemotherapy. We discovered that the harsh PDA microenvironment primes cancer cells against
additional cytotoxic insults (e.g., chemotherapy) and promotes PDA aggressiveness. A better understanding of
the molecular underpinnings behind this adaptive program would expose PDAs metabolic vulnerabilities. We
identified the RNA binding protein, HuR (ELAVL1), as a major player in the acute pro-survival response. Upon
stress, HuR translocates from the nucleus to the cytoplasm with key survival transcripts, like IDH1 (an NADPH
generating enzyme). HuR enhances RNA stability and protein translation of target mRNAs, to rapidly adjust the
transcriptome in response to stress. Our research highlights two metabolic processes in the HuR adaptive
program: a) antioxidant defense and b) mitochondrial performance. HuR silencing in PDA cells produced
excessive ROS and NADPH depletion under low glucose or chemotherapy stress. An unbiased RNA seq
analysis of antioxidant genes in HuR deficient cells identified IDH1 as the leading antioxidant enzyme under
HuR control. RNA binding and RNA stability assays showed that HuR regulates IDH1 post-transcriptionally,
and HuR deficient PDA cells had markedly reduced IDH1 mRNA and protein expression. HuR-deficient cells
failed to engraft in nude mice, while IDH1 overexpression rescued PDA engraftment. HuR-deficient cells also
had dysfunctional mitochondria, reflected by reduced oxygen consumption, ATP, and mitochondrial
abundance. Based on this body of work, we hypothesize that PDAs reliance on HuR under low nutrient
conditions exposes new therapeutic opportunities. In Aim 1, we establish the survival impact of the HuR-
IDH1 axis, by editing out HuR binding sites (CRISPR) in the IDH1 3'UTR. We generated a conditional IDH1
knockout mouse, and will cross it with an established PDA model to validate IDH1 as a therapeutic target. We
will test an allosteric modulator of mutant IDH1 (GSK-321) as a novel wild type IDH1 inhibitor in PDA, and
launch hit-to-lead optimization to improve drug properties. In Aim 2, we identify specific aspects of
mitochondrial biology under HuR control through studies of mitochondrial structure and function in HuR-
deficient PDA cells. The importance of the HuR-IDH1 axis on mitochondrial ROS levels will be demonstrated.
Additional transcripts will impact HuR's regulation of mitochondrial performance will be identified. A novel
mitochondrial inhibitor, CPI-613, will be combined with HuR or IDH1 inhibition as a new synthetic lethal
approach against PDAs adaptive metabolic program. In Aim 3, we will use a diabetic mouse model to show
that a hyperglycemic state suppresses the HuR pro-survival network, and sensitizes PDA to chemotherapy.
Successful engraftment of HuR-deficient cells in hyperglycemic mice would suggest that HuR is less important
under these conditions. Our studies of HuR biology ...

## Key facts

- **NIH application ID:** 10247531
- **Project number:** 5R37CA227865-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Jordan M Winter
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,116
- **Award type:** 5
- **Project period:** 2018-09-13 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247531

## Citation

> US National Institutes of Health, RePORTER application 10247531, Targeting pancreatic cancer's metabolic addiction to HuR (5R37CA227865-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247531. Licensed CC0.

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