# PAIRS: Validating telomerase reverse transcriptase (TERT) as an intrinsic vulnerability toward sensitizing cancer to radiation

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $437,187

## Abstract

Summary
 A favorable target for radiation synthetic combinations would be a feature of cancer cells critically
involved in growth, signaling, repair, or survival that can be blocked with an otherwise non-toxic drug, leaving
tumors vulnerable to radiation without adverse effects on normal tissue. This project is directed at validating
inhibition of telomerase reverse transcriptase (TERT) as a means to enhance the therapeutic index of radiation
and achieving key progress toward translating this strategy to the clinic. While TERT is not expressed in most
normal cells, approximately 90% of cancers display reactivation of TERT expression, supporting the catalytic
activity of telomerase to maintain telomere integrity despite deregulated growth. While drugs targeting TERT
have displayed sufficient safety in patients to evaluate effects of blocking telomere repeat synthesis, this has
failed in solid tumors, as telomere erosion is too slow to affect tumor progression. Beyond its essential role in
cancer cell immortality, TERT also contributes to pathways that support multiple cancer hallmarks. By limiting
oxidative stress, accelerating double strand break repair and supporting cell survival, TERT expression in
cancer cells may confer clinically significant resistance to radiation. This raises the question whether transiently
targeting TERT during radiotherapy to enhance the toxicity of the resulting DNA damage to the cancer cells
might significantly improve the therapeutic index of radiation.
 In recently published work, our groups described a novel class of TERT inhibitors inspired by the
antibiotic chrolactomycin. Like the natural product, our streamlined natural product analogs react with an active
site cysteine in the TERT reverse transcriptase active site. The optimized inhibitor, NU-1, is otherwise nontoxic
in vitro or in vivo, but inhibits telomerase activity at low micromolar concentrations. NU-1 confers sensitivity to
radiation to TERT-expressing cancer cells. Our data suggest that TERT may promote non-homologous end-
joining repair, thereby affecting repair pathway choice. Finally, using a syngeneic tumor model in BALB/c mice,
we have demonstrated marked sensitization to radiation in vivo, apparently mediated by persistent DNA
damage and increased anti-tumor immune response. With these preliminary studies in hand, we propose to 1)
Dissect the roles of TERT in double strand break repair and immune evasion, and 2) Improve the drug-like
properties of NU-1 and use these novel compounds to understand how best to obtain radiation sensitization
and an effective anti-tumor immune response.

## Key facts

- **NIH application ID:** 10846712
- **Project number:** 5R01CA282781-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Stephen J. Kron
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,187
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846712

## Citation

> US National Institutes of Health, RePORTER application 10846712, PAIRS: Validating telomerase reverse transcriptase (TERT) as an intrinsic vulnerability toward sensitizing cancer to radiation (5R01CA282781-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10846712. Licensed CC0.

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