# Molecular Mechanisms Regulating the Alternative Lengthening of Telomeres Pathway

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $377,438

## 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:** 9966890
- **Project number:** 5R01CA201446-05
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** RACHEL L. FLYNN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,438
- **Award type:** 5
- **Project period:** 2016-08-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966890

## Citation

> US National Institutes of Health, RePORTER application 9966890, Molecular Mechanisms Regulating the Alternative Lengthening of Telomeres Pathway (5R01CA201446-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966890. Licensed CC0.

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