# Alternate telomere maintenance mechanisms in high-risk neuroblastoma as prognostic indicators and therapeutic targets

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2020 · $349,988

## Abstract

ABSTRACT
Clinical behavior of the childhood cancer neuroblastoma (NB) extends from spontaneous regression of
untreated metastatic disease to relentless tumor progression causing death in spite of multi-modality intensive
therapy. Novel therapies are needed as ~50% of high-risk NB patients die from disease. Telomeres are
nucleoprotein complexes at eukaryotic chromosome ends that are essential for genomic stability by protecting
the terminal regions of chromosomes from erosion of coding DNA sequences. Cancer cells require a telomere
maintenance mechanism (TMM) and most activate telomerase, a ribonuclear protein containing a reverse-
transcriptase encoded by the TERT gene and an RNA template encoded by the TERC gene. Some cancers
are telomerase negative and employ a poorly understood alternate lengthening of telomeres (ALT)
mechanism; extra-chromosomal telomeric DNA c-circles are a marker of ALT. Neuroblastomas that manifest
ALT often have mutations in the alpha thalassemia/mental retardation x-linked (ATRX) gene. We established
a panel of NB cell lines and patient-derived xenografts (PDXs) that manifest ALT and our preliminary data
indicate that ALT can exist independent of ATRX mutations and that ALT is associated with multi-drug
resistance and with increased expression of DNA repair genes. In collaboration with the Children's Oncology
Group (COG) we demonstrated that high TERT mRNA expression was associated with risk of disease
progression in low-risk neuroblastomas. We will classify high-risk NB by telomere maintenance mechanisms
(TMM) by assessing telomerase expression, telomere content, and c-circles, and relate these in primary high-
risk neuroblastomas to ATRX mutations, clinical outcome, and gene expression signatures identified by RNA
sequencing. We will confirm our preliminary data indicating that ATM kinase is activated in ALT NB, serves as a
driver of ALT, and stimulates overexpression of genes involved in DNA repair, promoting resistance to
chemotherapy and radiation. These data will enable classification by TMM of high-risk NB into TERT-high, ALT
(TERT-low, c-circle +), and an ever-shorter telomere (EST) phenotype (TERT-low and c-circle negative) and will
enable determining the relationship of TMM to clinical outcome. We will knock-down, inhibit, or over-express
ATM kinase in NB cell lines (ALT and non-ALT) to demonstrate its role in TMM and in the ALT phenotype, in
driving expression of DNA repair genes, and in resistance to chemotherapy and radiation. Using shRNA and an
ATM kinase inhibitor we will demonstrate in ALT NB cell lines and PDXs that ATM kinase is molecular
therapeutic target in ALT neuroblastomas. This project employs the largest panel of ALT cell lines and PDXs
established for any cancer type and will define novel biomarkers and therapeutic targets for neuroblastoma.

## Key facts

- **NIH application ID:** 9966909
- **Project number:** 5R01CA217251-03
- **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:** 2020
- **Award amount:** $349,988
- **Award type:** 5
- **Project period:** 2018-08-29 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966909

## Citation

> US National Institutes of Health, RePORTER application 9966909, Alternate telomere maintenance mechanisms in high-risk neuroblastoma as prognostic indicators and therapeutic targets (5R01CA217251-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9966909. Licensed CC0.

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