# IDH1 is a novel therapeutic target in pancreatic cancer

> **NIH NIH F32** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $69,306

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States
and survival rates have only marginally improved in recent decades. Conventional cytotoxic agents remain the
standard of care, and mainly target cancer genome integrity. A search for alternative therapeutic strategies is
critical to bend the survival curve and save lives. The pancreatic cancer microenvironment provides a promising
opportunity, because it creates metabolic vulnerabilities in PDA cells that do not exist in normal cells (i.e., a
therapeutic window). The PDA microenvironment comprises 80% of the tumor mass, and is characterized by a
dense, poorly vascularized stroma. Such austere, hypoxic conditions and nutrient-deprived conditions result in
a highly oxidative state, which necessitates a robust anti-oxidant response just to survive these conditions, along
with other insults like chemotherapy. The antioxidant defense system is complex and multi-pronged, but nearly
the entire mechanism is dependent upon the ultimate reductive currency of the cell: NADPH. Along with my lab
colleagues, I have shown that one of the NADPH synthesizing enzymes, cytosolic isocitrate dehydrogenase 1
(IDH1), is especially important to PDA cells for this purpose. For instance, knockout of IDH1 using CRISPR gene
editing sensitizes PDA cells to nutrient conditions present in the austere PDA microenvironment, and markedly
impaired xenograft tumor growth. Herein, we aim to decipher the role of the two key byproducts of IDH1 in PDA
adaptive survival under low nutrient stress: NADPH and α-ketoglutarate (Aim 1). Our preliminary discoveries
suggest that both of these byproducts impact redox homeostasis and mitochondrial function, and cell-based and
metabolomics studies in this proposal will elucidate the mechanisms of IDH1-driven adaptive survival and
growth. Moreover, this work will further validate IDH1 as a promising therapeutic target. Additionally, we will work
with our long-standing collaborators at Genisphere (Co-Sponsor Dr. Getts) to develop a new therapeutic strategy
to target IDH1 in PDA cells (Aim 2). In this aim, we build on preliminary data to test a novel biodegradable DNA-
dendrimer derivatized with si.IDH1 oligos (3DNA-si.IDH1). We recently demonstrated effective IDH1 mRNA
silencing after systemic injection of 3DNA-si.IDH1 in nude mice bearing PDA xenografts. Herein, we will test
systemic efficacy in orthotopic and autochthonous PDA mouse models. Through the work detailed in this
proposal, along with the training plan under the mentorship of Drs. Winter, Brody, Getts and Brunengraber, I will
have the opportunity to catapult my career and lay the foundation to achieve my dream as an independent cancer
researcher.

## Key facts

- **NIH application ID:** 9911116
- **Project number:** 1F32CA247466-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Ali Vaziri-Gohar
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 1
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911116

## Citation

> US National Institutes of Health, RePORTER application 9911116, IDH1 is a novel therapeutic target in pancreatic cancer (1F32CA247466-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9911116. Licensed CC0.

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