# Identifying Metabolic Dependencies of Pancreatic Cancers

> **NIH NIH R35** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $1,017,000

## Abstract

Project Summary:
 The focus of my research has been on the study of pancreatic ductal adenocarcinoma (PDAC). This is a
deadly tumor that is predicted by 2020 to be the second leading cause of death in the U.S. The disease is
typically detected late in its course and unfortunately has proven to be highly treatment refractory to most
therapeutic approaches. Over the past decade, our group has been focused on understanding how PDAC
rewire their metabolism to support a high proliferative rate and cell survival in a nutrient poor, austere tumor
microenvironment. We have used novel mouse models to understand how oncogenic Kras, the signature
genetic mutation in PDAC, orchestrates metabolic reprogramming of these tumors towards a more anabolic
state. In fact, one of the critical ways that this oncogene supports pancreatic cancer growth is through its role
in tumor metabolism. Through further analysis of carbon source utilization in PDAC, we identified a novel
pathway that is critical for PDAC redox balance through the production of NADPH. This pathway utilizes
glutamine carbon and portions of the malate-aspartate shuttle ultimately ending with malic enzyme conversion
of malate to NADPH and pyruvate. Disruption at any node of this metabolic pathway results in redox imbalance
and decreased growth.
 One of the major themes that emerged from our work is that PDAC have an amazing metabolic plasticity.
This is likely an important adaptation to flourish in an environment where fuel sources and oxygen are rate
limiting and rapidly shifting. Understanding these adaptations will be essential in order to target metabolic
vulnerabilities for therapeutic gain. Indeed, we have shown that that these tumors can: 1) rapidly reprogram
their metabolic pathways in response to fuel source limitations, 2) use lysosomal scavenging pathways to
provide necessary metabolic intermediates, and 3) cooperate with stromal cells through novel metabolic
interactions. However, the integration of these metabolic adaptations and how this influences key metabolic
dependencies of PDAC in vivo is not yet known and will be critical to understand in order to develop effective
therapeutic approaches. Here, we will take a comprehensive approach to answer these key questions. We will
use sophisticated syngeneic models of pancreatic cancer to comprehensively assess metabolic dependencies
using a custom designed murine CRISPR metabolism library combined with metabolic tracer studies. We will
use co-culture systems to identify metabolic cross-talk between tumor cells and the multiple other cell types in
the tumor micro-environment (immunocytes, neurons, fibroblast populations). Using in vivo models, we will
dissect nutrient scavenging pathways and identify how these nutrients are utilized and potentially shared
between cell populations. Lastly, we will utilize the knowledge gained from these studies to develop the most
robust metabolic targets which will be tested in vivo using genetic and pharmacol...

## Key facts

- **NIH application ID:** 10212980
- **Project number:** 5R35CA232124-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Alec Kimmelman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,017,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212980

## Citation

> US National Institutes of Health, RePORTER application 10212980, Identifying Metabolic Dependencies of Pancreatic Cancers (5R35CA232124-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212980. Licensed CC0.

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