# Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2022 · $384,099

## Abstract

Abstract
Telomeres are nucleoproteins with TTAGGG DNA repeats at the ends of chromosomes that protect coding DNA from
erosion and detection as DNA damage. Telomere maintenance is necessary for cancer cells to have unlimited proliferation
capacity. Most cancers maintain their telomeres via activation of the ribonucleoprotein telomerase. Cancers with low or no
telomerase activity often use another mechanism to extend their telomeres, the Alternative Lengthening of Telomeres (ALT)
in which telomeres are maintained via homologous telomeric-DNA recombination, but the mechanism is still poorly
understood. ALT+ tumors contain extra-chromosomal telomeric DNA C-circles, which (detected with a unique PCR assay)
provides a specific and sensitive ALT biomarker. Employing the C-circle assay we have surveyed a variety of childhood
and adult cancers and found 11 cancer histologies with ALT-positivity ranging from 10% to 74% and an additional 5 cancer
histologies with 1 to 5% that are ALT+. ALT cancers have a poor clinical outcome and regardless of histology ALT+
cancer cell lines manifest high resistance to DNA damaging agents relative to telomerase+ cancers. ALT cancers have
dysfunctional telomeres, which provides unique vulnerabilities that can serve as novel therapeutic targets. We have recently
demonstrated high ATM kinase activation in ALT neuroblastoma leads to resistance to DNA damaging chemotherapy that
can be reversed with a clinical-stage ATM inhibitor AZD0156. Based on our data we hypothesize that ALT+ cancers share
both common mechanisms of resistance to standard therapies and common vulnerabilities that may be exploited for therapy.
To enhance studies of ALT+ cancer biology, discovery and validation of novel therapeutic targets, and to enable comparing
ALT+ cancers across a range of histologies we have assembled a large panel of ALT+ patient-derived cell lines (PDCLs)
and patient-derived xenografts (PDXs) and comparator telomerase+ PDCLs and PDXs, including pediatric cancers
(neuroblastoma, rhabdomyosarcoma, osteosarcoma) and adult cancers (triple negative breast cancer, colon cancer, soft
tissue sarcomas). Using this unique panel of patient-derived models we will demonstrate that ATM kinase activation
resulting from telomere dysfunction is a common feature of ALT+ cancers (regardless of histology). We will demonstrate
that clinical-stage investigational drugs leveraging the high ATM kinase activation in ALT+ cancers (the ATM kinase
inhibitor AZD1390 and the p53 activator APR-246) combined with irinotecan have significantly higher activity in ALT+
cancers relative to telomerase+ comparators. For cell lines and xenografts of selected histologies we will determine if
AZD1390 can reverse resistance to irinotecan. We hypothesize that ALT+ cancers tolerate ATM activation due to
dysfunctional p53, and that p53 restored to functionality by APR-246 will be activated (phosphorylated) by ATM. We will
demonstrate that APR-246 (alone or in combination with iri...

## Key facts

- **NIH application ID:** 10390601
- **Project number:** 1R01CA264949-01A1
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** CHARLES Patrick REYNOLDS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $384,099
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390601

## Citation

> US National Institutes of Health, RePORTER application 10390601, Targeting Shared Vulnerabilities in Alternate Telomere Lengthening (ALT) Cancers (1R01CA264949-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10390601. Licensed CC0.

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