# Measuring and Modulating Oxidative DNA Damage Surveillance Pathways

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $493,411

## Abstract

Project Summary
Despite exciting progress made recently in precision medicine, several common cancers remain difficult
to treat, including lung, colorectal, and pancreatic cancer, which together account for over 200,000
deaths annually. One common molecular factor in these tumors is high levels of reactive oxygen species,
which lead to oxidative damage in DNA – most notably, 8-oxoguanine (8-OG), which is both toxic and
mutagenic. As a result, tumor cells evolve strategies to support rapid growth, and thus often misregulate
the enzymes that combat this damage: namely MTH1 and OGG1, which remove 8-OG from the
nucleotide pool and from DNA itself. We hypothesize that developing approaches to control the activities
of these enzymes will provide new and promising strategies for controlling tumor growth. However, until
very recently no one has been able to measure or modulate these enzymes' activities.
 In preliminary work leading up to this proposal, novel and sensitive chemical probes have been
devised that are the only existing reporters that can measure the cellular activities of MTH1 and OGG1.
In addition, these probes have been used to identify new small-molecule modulators of these pathways,
including, excitingly, the only known activators of the two enzymes. Third, new hypotheses have been
developed regarding how modulating the activities of these pathways via small molecules, singly or in
combination, can provide biologically important, and potentially clinically useful, outcomes in cancer.
 The Kool/Ford collaborative team will develop and employ these molecular tools to investigate the
promise of modulating these important repair pathways. The specific aims for the four-year term of the
project are to develop new probes to quantify repair activities in tumor cells and tissues; to identify and
develop new small-molecule inhibitors and activators of the enzymes; to test novel biological hypotheses
regarding how targeted up- or down-regulation may suppress tumor growth; and to test a new hypothesis
for preventing tumorigenesis in individuals who are genetically susceptible to developing cancer.
 This research is important because it addresses multiple common and deadly cancers that remain
difficult to treat. In addition, the collaborative team will develop several molecular tools that are likely to
be useful to the cancer research community as a whole. Moreover, if successful, this work may lead to
new targeted strategies for cancer treatment, and practical methods for evaluating patients for these
therapies. This research plan is innovative in several ways: it will develop and apply novel molecular tools
for assessing damage repair pathways; it will lead to the development of the only known small-molecule
activators of damage repair, and it presents new hypotheses regarding how modulating repair activities
will be helpful in treatment - and even prevention - of these serious malignancies.

## Key facts

- **NIH application ID:** 9924487
- **Project number:** 5R01CA217809-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** ERIC T. KOOL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,411
- **Award type:** 5
- **Project period:** 2017-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924487

## Citation

> US National Institutes of Health, RePORTER application 9924487, Measuring and Modulating Oxidative DNA Damage Surveillance Pathways (5R01CA217809-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9924487. Licensed CC0.

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