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Developing new therapeutic strategies for pediatric tumors that lack clinically actionable mutations

Award Number: R01CA260060
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/17/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Developing new therapeutic strategies for pediatric tumors that lack clinically actionable mutations - PROJECT SUMMARY / ABSTRACT Cancer is the leading disease-related cause of death in children. Treatment has remained largely unchanged in decades, relying primarily on aggressive cytotoxic chemotherapy and radiation—these therapies have debilitating long-term consequences. Precision medicine has yet to make a major impact on childhood cancer because, while thousands of pediatric tumor genomes have been sequenced, most children have very few somatic mutations compared to adult cancers. This means targeted cancer drugs are not an option for most children and fewer tumor-specific neoantigens means most immunotherapies are ineffective. However, in the last 5 years, large-scale CRISPR and drug screening studies in cancer cell lines, such as the Dependency Map (DepMap), have shown that in many cancers, unmutated genes can also act as potent drug targets. These genes are known as non-oncogene dependencies. The overall goal of this project is to overcome the low mutation burden, by identifying the druggable non-oncogene dependencies of pediatric tumors and to perform the requisite in vitro and in vivo experimental work to move these therapies to the clinic. We will identify these non-oncogene dependencies by applying tools from machine learning to perform integrative analysis of large pre-clinical screening datasets (such as DepMap, CCLE, and PRISM) with patient tumor -omics data. This will allow us to nominate specific non-oncogene dependencies for pediatric tumor subtypes, defined based on, for example, whole-genome gene expression or methylation data. We will mechanistically validate the top hits using in vitro experimental assays. Additionally, almost all curative cancer treatments involve the rational combination of multiple therapies, however, existing methods to predict effective combinations perform poorly when tested on unseen data. Thus, our second aim is to apply an approach that we have developed based on targeted CRISPR knockout screening to identify synergistic drug combinations. We will validate these combinations in vivo using mouse models with patient-derived xenografts, leveraging shared resources already established at St. Jude. Finally, tumor heterogeneity is ultimately the downfall of every known cancer treatment; however, in pediatric tumors where the mutation burden is low, much of this heterogeneity is driven by cell state, rather than specific somatic mutations. We will dissect the influence of cell state on drug resistance using single-cell and spatial transcriptomics technologies applied to a drug-treated spontaneous mouse model of neuroblastoma. This will ultimately allow us to nominate new drug combinations explicitly targeting drug-resistant cell states. Overall, this research program will aim to build a pipeline at St. Jude to overcome some of the main challenges posed by the low number of somatic mutations in pediatric tumors and identify new therapeutic strategies for these patients. We have assembled a diverse world-class team of researchers with all components necessary for an eventual impact on patient care.


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: 2025 ( Subtotal = $479,150 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	5	9/3/2025	NON-COMPETING CONTINUATION	$479,150
														Subtotal = $479,150

Issue Date FY: 2024 ( Subtotal = $455,194 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	4	8/1/2024	NON-COMPETING CONTINUATION	$455,194
														Subtotal = $455,194

Issue Date FY: 2023 ( Subtotal = $469,566 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	3	8/28/2023	NON-COMPETING CONTINUATION	$469,566
														Subtotal = $469,566

Issue Date FY: 2022 ( Subtotal = $469,566 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	001	2	7/28/2022	NON-COMPETING CONTINUATION	$469,566
2022	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	1	4/25/2022	NEW	$0
														Subtotal = $469,566

Issue Date FY: 2021 ( Subtotal = $486,599 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	1	3/17/2021	NEW	$486,599
														Subtotal = $486,599

Grand Total All Awards = $2,360,075

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Developing new therapeutic strategies for pediatric tumors that lack clinically actionable mutations

Award Number: R01CA260060

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/17/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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