# Targeting metabolic stress to induce pancreatic tumor cell death

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $401,714

## Abstract

ABSTRACT
Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors
underscoring this low survival rate is the lack of effective clinical treatments. Like most cancers, metabolic
processes in pancreatic cancer cells are altered to facilitate macromolecular biosynthesis and protect against
intra and extracellular stressors. Reactive oxygen species (ROS) are a byproduct of metabolism and represent
a notable metabolic stress to pancreatic cancer cells. Previously, we described a new metabolic pathway in
pancreatic cancer, mediated by cytosolic glutamate oxaloacetate transaminase 1 (GOT1), that is used to
manage ROS by facilitating the coordination of cytosolic and mitochondrial metabolism and maintaining
glutathione (GSH) pools.
Ferroptosis is a recently described form of iron-dependent, non-apoptotic cell death caused by lipid
peroxidation and mediated by loss of GSH pools. We found that GOT1 inhibition potentiated the activity of
known ferroptotic agents. Further, we also discovered that GOT1 inhibition can engage ferroptosis when nodes
in cysteine metabolism are inhibited. In this research proposal, we will determine how GOT1 inhibition
promotes ferroptosis. Mechanistic insight from these studies will then be used to selectively target pancreatic
cancers for ferroptotic cell death. This will be accomplished using metabolomics techniques in combination
with genetic and pharmacological inhibitors of metabolism. In parallel, we will test combinations of ferroptotic
agents with GOT1 inhibition in human patient-derived 3D culture models and in orthotopic mouse models to
determine the translation value. Given the safety profile of GOT1 and some ferroptosis-inducers, the profound
sensitivity of this combination in pancreatic cancer cells, and the desperate need for new strategies to treat
pancreatic cancer, there is now a critical need to understand mechanistically what confers sensitivity to these
combinations. Such insights may provide strategies to promote redox imbalance in pancreatic cancer, paving
the way for tumor-selective, ferroptosis-based therapies.

## Key facts

- **NIH application ID:** 10052225
- **Project number:** 1R01CA244931-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Costas Andreas Lyssiotis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $401,714
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052225

## Citation

> US National Institutes of Health, RePORTER application 10052225, Targeting metabolic stress to induce pancreatic tumor cell death (1R01CA244931-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052225. Licensed CC0.

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