# Molecular Mechanisms Regulating the Alternative Lengthening of Telomeres Pathway

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $49,916

## Abstract

PROJECT SUMMARY/ABSTRACT
 Telomeres cap the ends of linear chromosomes and provide a molecular barrier for the human genome.
Following each cell division, progressive telomere shortening erodes that barrier and threatens the stability of
the genome. Critically short, or dysfunctional telomeres induce replicative senescence and/or cell death and
ultimately, lead to cellular aging. Cancer cells, however, overcome the replicative senescence associated with
critically short telomeres by exploiting mechanisms of telomere elongation. Reactivation of the enzyme
telomerase, or activation of the Alternative Lengthening of Telomeres (ALT) pathway, account for cellular
immortalization in the majority of human cancers. Telomere lengthening mechanisms are active in the majority
of all cancer cells, however, they are absent or ineffective, in normal somatic cells making them ideal candidates
for targeted cancer therapies. Currently, clinical trials are underway to test the efficacy of telomerase inhibitors
in the treatment of cancer, however, there are no treatments for cancers that rely on the ALT pathway for
telomere maintenance. These efforts have been limited, in part, by an incomplete understanding of the molecular
mechanisms regulating the ALT pathway. Recently, we demonstrated that the ataxia telangiectasia and Rad3-
related (ATR) DNA damage response kinase was a critical regulator of the ALT pathway. Inhibition of ATR
kinase activity not only decreased telomeric recombination, but also led to significant and selective lethality in
ALT positive cancer cells. While these studies were the first to demonstrate a functional requirement for ATR in
maintenance of the ALT pathway, exactly how ATR regulates ALT activity and whether ATR can be targeted
therapeutically in the context of ALT cancers, remains unclear. Therefore, the goal of this proposal is to tease
apart the function of ATR within the ALT pathway, validate the therapeutic efficacy of ATR inhibition in ALT
positive cancers, and continue to define the molecular mechanisms regulating ALT activity.

## Key facts

- **NIH application ID:** 10630558
- **Project number:** 3R01CA201446-05S1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** RACHEL L. FLYNN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $49,916
- **Award type:** 3
- **Project period:** 2022-06-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10630558

## Citation

> US National Institutes of Health, RePORTER application 10630558, Molecular Mechanisms Regulating the Alternative Lengthening of Telomeres Pathway (3R01CA201446-05S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10630558. Licensed CC0.

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