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Epigenetically regulated stemness program and stem cell niche as targets in pediatric DIPG

Award Number: R01NS131515
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Epigenetically regulated stemness program and stem cell niche as targets in pediatric DIPG - Understanding the role of cancer stem cells (CSCs) in diffuse intrinsic pontine glioma (DIPG) is crucial for preventing treatment resistance and tumor progression and for devising therapies that may prolong the lives of the 200-400 pediatric DIPG patients diagnosed each year. Radiotherapy remains the standard of care, but tumors recur in 100% of patients, resulting in dismal patient survival of 8-11 months. Over 250 clinical trials have failed to move these numbers. Mechanistic research is urgently needed to understand the underlying biology of CSCs and how they drive treatment resistance to develop innovative combinatorial therapies that can change the natural history of DIPG. Extensive preliminary data and existing literature, support the overarching hypothesis that aldehyde hydrogenase positive (ALDH+) CSC cause therapeutic resistance and drive tumor progression. We propose, in mechanistic studies, to characterize an epigenetically regulated stemness program and stem cell niche (Aim 1 and 2) as potential targets (Aim 3) in pediatric DIPG. Specifically, in Aim 1, we will determine the role and regulation of ALDH-positive CSCs in DIPG. We will evaluate the regulation of specific ALDH isoforms, particularly ALDH1A3 and ALDH2 by H3 K27M mutation, and by IL1β secreted by microglia, respectively, in carefully designed in vitro and in vivo assays using isogenic DIPG models. We will define the role of specific ALDH isoforms, including ALDH1A3 and ALDH2, in cell differentiation, tumor initiation and progression, and immunity. In Aim 2 we will evaluate whether ALDH+ CSCs are the cause of therapeutic resistance and responsible for tumor progression. We will modulate expression of disease relevant ALDH isoforms and evaluate whether therapeutic sensitivity can be restored. We will characterize the therapy induced stem cell niche and mechanisms of immune evasion with cutting-edge technologies, including single cell RNA sequencing (scRNA-seq) and CyTOF. In Aim 3, we will target ALDH+ CSCs as the cause of resistance to prevent tumor progression. In preclinical proof-of concept studies we will target ALDH (Disulfiram) and PI3K/mTOR (GDC- 0084), a cell intrinsic signaling of ALDH+ CSC, to enhance outcomes from standard of care (radiotherapy) and to prevent progression. Therefore, our studies will (1) confirm that CSCs present a mechanism of resistance and (2) provide a rationale to target these cells specifically and (3) address an unmet clinical need for efficacious therapies. In summary, our proposal will mechanistically address the role of ALDH+ CSCs in therapeutic resistance and tumor relapse of DIPG and provide druggable targets, which can accelerate clinical translation against this devastating pediatric disease.


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 = $439,778 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/19/2026	NON-COMPETING CONTINUATION	$439,778
														Subtotal = $439,778

Issue Date FY: 2025 ( Subtotal = $446,213 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/6/2025	NON-COMPETING CONTINUATION	$446,213
														Subtotal = $446,213

Issue Date FY: 2024 ( Subtotal = $424,220 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/9/2024	NON-COMPETING CONTINUATION	$424,220
														Subtotal = $424,220

Issue Date FY: 2023 ( Subtotal = $437,855 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/26/2023	NEW	$437,855
														Subtotal = $437,855

Grand Total All Awards = $1,748,066

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Epigenetically regulated stemness program and stem cell niche as targets in pediatric DIPG

Award Number: R01NS131515

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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