# Evaluation of deoxynucleosides as a novel resistance mechanism for radiotherapy

> **NIH NIH UM1** · OHIO STATE UNIVERSITY · 2021 · $124,999

## Abstract

Abstract
Lutetium-177 dotatate significantly improves progression free survival, response rate, overall survival and quality
of life over standard therapy for patients with gastrointestinal neuroendocrine tumors, however, overall response
rates remain low (18%), likely due to endogenous repair of DNA. To repair DNA damaged by lutetium-177
dotatate, cancer cells require deoxyribonucleotide triphosphates, which can be generated by either the de novo
or salvage DNA repair pathway. Triapine blocks the de novo pathway, and the combination of lutetium and
triapine is being evaluated in the ETCTN trial #10388. However when the de novo pathway is inhibited, the
salvage pathway is upregulated and causes resistance to radiation therapy. We propose to measure
deoxynucleosides, generated by the salvage pathway, as a biomarker of radiation sensitivity in patients enrolled
in ETCTN #10388. In addition, we will evaluate the ability of ATR inhibitors to inhibit the salvage pathway and
explore the preclinical activity of the combination of radiation therapy, triapine and ATR inhibition. The proposed
aims are highly innovative and would; 1) elucidate a mechanism of resistance for cancer cells to the cytotoxic
effects of radiopharmaceuticals and triapine; 2) better resolve the source for single deoxyribonucleosides used
in the salvage DNA repair pathway; 3) support the development of a novel combination strategy of triapine and
ATR inhibitors to inhibit both the de novo and salvage pathways for DNA repair and enhance the therapeutic
activity of lutetium.

## Key facts

- **NIH application ID:** 10336852
- **Project number:** 3UM1CA186712-06S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** SUSANNE M ARNOLD
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $124,999
- **Award type:** 3
- **Project period:** 2014-03-28 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336852

## Citation

> US National Institutes of Health, RePORTER application 10336852, Evaluation of deoxynucleosides as a novel resistance mechanism for radiotherapy (3UM1CA186712-06S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10336852. Licensed CC0.

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