# Investigating Mechanisms of Deregulated Nucleotide Metabolism in Cancer

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $367,144

## Abstract

PROJECT SUMMARY
Many cancers are currently treated by cytotoxic chemotherapies that exploit those cancers' dependence on
enhanced nucleotide biosynthesis. However, the cytotoxic properties which make these compounds so
efficacious in killing cancer cells also wreak havoc on normal proliferating cells and tissues. In order to
understand how to exploit this vulnerability more effectively and more safely, we must focus our efforts on
targets that are specifically required by cancer cell, but not normal cell, proliferation and survival. My
discoveries have identified one such target – the enzyme phosphoribosyl pyrophosphate synthetase 2
(PRPS2). PRPS2, and its homolog PRPS1, generate a critical precursor necessary for producing all
nucleotides and function as a `molecular throttle' capable of increasing or decreasing the rate at which these
genetic building blocks are made. This proposal seeks to unravel the molecular basis for this selectivity
through use of metabolic flux analysis, elegant structure/function studies, and bioorthogonal chemistry and
molecular biology approaches. Our studies will open up new avenues for understanding the metabolic
vulnerabilities of cancer cells and may lead to intelligently-designed rational therapeutic strategies of the future.
We will conduct our studies using models of MYC-driven lymphoma and myeloma, using both genetically-
engineered mouse models and human cancer cell lines. Importantly, MYC has been characterized as the
transcriptional engine of cancer and its ability to stimulate nucleotide and nucleic acid production are signature
features of its pro-growth anabolic program necessary to drive malignancies in the B cell lineage. Using our
genetic approaches that block PRPS2 function in MYC overexpressing cells, we can leverage this dependency
to decipher the mechanistic basis for the deregulation of nucleotide metabolism in MYC-overexpressing cancer
cells and uncover novel connections between critical nodes in the nucleotide metabolism network. For
example, our proposed studies will elucidate the economics of nucleotide metabolism by determining how
disrupting nucleotide supply affects the machineries it fuels, and vice-versa. Collectively, the proposed studies
will be transformative in our understanding of the roles of these key molecules in the normal and cancer
setting, and provide a new conceptual paradigm which can be the foundation for the development of the next
generation of safer, more effective precision-based therapies and approaches.

## Key facts

- **NIH application ID:** 10225501
- **Project number:** 5R01CA230904-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Tom Cunningham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $367,144
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225501

## Citation

> US National Institutes of Health, RePORTER application 10225501, Investigating Mechanisms of Deregulated Nucleotide Metabolism in Cancer (5R01CA230904-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225501. Licensed CC0.

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