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Telomere Maintenance Mechanisms as Prognostic Indicators for Neuroblastoma

Award Number: R01CA217251
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/29/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Telomere Maintenance Mechanisms as Prognostic Indicators for Neuroblastoma - 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 alternative lengthening of telomeres (ALT) mechanism; extra-chromosomal telomeric DNA C-circles are a marker of ALT. In the initial funding period of this grant, in collaboration with the Children’s Oncology Group (COG) we demonstrated that assessing TERT mRNA expression, DNA C-circles, and ultrabright telomere foci (FISH) defined 3 groups of high-risk neuroblastoma patients with distinct clinical outcomes: telomerase+ (TERT expressing), ALT+, ant TMM- negative. The COG is providing us primary tumor samples from patients enrolled on the most recent and for current national phase III clinical trials for high-risk neuroblastoma. We will classify high-risk NB by telomere maintenance mechanisms (TMM) by assessing telomerase expression, telomere content, telomeric DNA C- circles, and ultra-bright telomere foci, and relate these to clinical outcome. As we have shown that some patients currently classified as low/intermediate risk patients have the ALT phenotype and an apparent poor clinical outcome we will, in a case-control study, determine if TMM+ patients low/int risk patients have clinical outcomes that indicate they should be classified as high-risk. These data will enable classification by TMM of NB into TERT- high, ALT+ (TERT-low, C-circle +), and patients with no detectable TMM (TERT-low and C-circle negative). TMM classification will be used to analyze results from the clinical trials and in the future in patient risk stratification. We will also assess the specificity and sensitivity of the DNA C-circle assay for detecting ALT+ tumors using cfDNA from patient plasma and we will explore the potential of the cfDNA C-circle assay to provide a sensitive biomarker for ALT+ NB patients and to detect the ALT status of tumors in the brain, including pediatric high-grade gliomas. This project will validate a new set of biomarkers for risk-stratification of NB and will aid in interpretation of clinical outcome results from three national COG neuroblastoma phase III clinical trials. We will also validate the specificity and sensitivity of the cfDNA C-circle assay, which we hypothesize will overcome spatial tumor heterogeneity in detecting ALT and provide an optimal method for detecting ALT NB. Data from this project will impact ongoing and future clinical trials for neuroblastoma and will provide novel insights into cancer biomarkers and therapy of patients with ALT+ cancers applicable to other cancer types.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,105,938 )
2026	2026	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Treatment Research	000	6	9/17/2026	COMPETING CONTINUATION	$1,105,938
														Subtotal = $1,105,938

Issue Date FY: 2025 ( Subtotal = -$180 )
2025	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	5	8/26/2025	NON-COMPETING CONTINUATION	-$180
														Subtotal = -$180

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	5	8/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $342,988 )
2022	2022	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	5	7/11/2022	NON-COMPETING CONTINUATION	$342,988
														Subtotal = $342,988

Issue Date FY: 2021 ( Subtotal = $409,979 )
2021	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	001	4	8/20/2021	NON-COMPETING CONTINUATION	$349,988
2021	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	3	6/18/2021	SUPPLEMENT FOR EXPANSION	$59,991
														Subtotal = $409,979

Issue Date FY: 2020 ( Subtotal = $349,988 )
2020	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	3	7/29/2020	NON-COMPETING CONTINUATION	$349,988
														Subtotal = $349,988

Issue Date FY: 2019 ( Subtotal = $339,487 )
2019	2019	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	2	6/27/2019	NON-COMPETING CONTINUATION	$339,487
														Subtotal = $339,487

Issue Date FY: 2018 ( Subtotal = $349,988 )
2018	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Cause and Prevention Research	000	1	8/29/2018	NEW	$349,988
														Subtotal = $349,988

Grand Total All Awards = $2,898,188

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Telomere Maintenance Mechanisms as Prognostic Indicators for Neuroblastoma

Award Number: R01CA217251

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/29/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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