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Overcoming medulloblastoma resistance to treatment using in vivo perturb-seq and preclinical therapeutics

Award Number: R01CA316038
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Overcoming medulloblastoma resistance to treatment using in vivo perturb-seq and preclinical therapeutics - PROJECT SUMMARY Brain tumors are the most common solid malignancies in children and the most common cause of disease- related death in children in the United States. Medulloblastoma is the most common malignant brain tumor in children, and medulloblastoma treatment is comprised of surgery, craniospinal radiotherapy, and high-dose cytotoxic chemotherapy. Current medulloblastoma therapies cure 70% of pediatric patients, but survivors suffer from life-long neurocognitive, endocrine, and growth impairments from treatment. Moreover, most survivors of pediatric medulloblastoma do not live independently as adults and have increased rates of treatment-induced malignancies later in life. Thus, there is an urgent, unmet need to validate new druggable targets and new therapies that improve survival and have reduced toxicity for patients with pediatric medulloblastoma. Our groups and others have repurposed CRISPR-Cas9 systems for epigenetic editing, providing new tools to functionally investigate how the epigenetic landscape gives rise to specialized cell functions. Among the diverse functional genomic approaches we and others have developed, perturb-seq, which will be used in this proposal, combines pooled CRISPR interference (CRISPRi) screens with single-cell transcriptomics to link genetic perturbations to transcriptional phenotypes. This innovative functional genomic technique analyzes individual cells as independent experiments, connecting genetic perturbations to high-resolution transcriptional maps and cellular phenotypes across thousands of measurements. Anatomic and physiologic barriers have broadly hindered in vivo applications of perturb-seq and have also encumbered our understanding of brain tumor biology, including the discovery and development of targeted therapies to treat patients with medulloblastoma. Using convection enhanced delivery to transduce intracranial brain tumors with programmable sgRNAs in mice, we developed a robust platform for in vivo perturb-seq. Our central hypothesis is that integrating in vivo perturb-seq with conventional mechanistic and functional approaches will reveal druggable dependencies that clarify mechanisms of medulloblastoma response or resistance to treatment. To test this hypothesis, we will use (1) conventional gain- and loss-of-function approaches in the context of standard-of-care therapies to define mechanisms underlying medulloblastoma responses to therapy, and (2) in vivo perturb-seq to validate and generalize our findings for rapid conversion of molecular data to combination or sequential molecular therapies. We will perform these experiments using innovative organoid and iPSC-derived preclinical models of medulloblastoma as well as patient-derived xenografts, allografts, and a novel mouse genetic model that expresses CRISPRi machinery throughout the tumor microenvironment. Successful completion of this proposal establishes methods for integrating in vivo perturb-seq with developmental therapeutics for high-throughput preclinical target validation and development in medulloblastoma. More broadly, our studies will lay a foundation for personalized medical therapies to treat patients with cancers that are resistant to standard interventions.


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 = $680,600 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	7/2/2026	NEW	$680,600
														Subtotal = $680,600

Grand Total All Awards = $680,600

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Overcoming medulloblastoma resistance to treatment using in vivo perturb-seq and preclinical therapeutics

Award Number: R01CA316038

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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