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Tumor-Selective Delivery Approaches for Medulloblastoma

Award Number: R01NS116353
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: 03/15/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Tumor-Selective Delivery Approaches for Medulloblastoma - The majority of primary brain tumors result in high morbidity and very poor survival. Brain tumors are now unfortunately the leading cause of cancer-related death in children. Medulloblastoma is the most common malignant pediatric brain tumor resulting in the death of nearly one-third of afflicted children despite very aggressive therapies that include surgical resection, whole brain and spine radiation therapy, and systemic chemotherapy. Furthermore, the vast majority of surviving children have poor outcomes and significant neurocognitive deficits due to the toxicity of these therapies. A major barrier to improving outcomes for primary brain tumor patients is the relative ineffective delivery of therapeutic agents across the blood-brain barrier (BBB) specifically to brain tumor cells while sparing normal surrounding brain tissue. Heretofore, researchers have found few mechanisms to target therapies specifically to primary brain tumors, to avoid systemic toxicities. We seek to address this problem to improve drug therapeutic indices by proposing a strategy to target therapies specifically to brain tumor vasculature utilizing a novel nanoparticle- based drug delivery system that has high affinity to P-selectin on endothelial cells within tumors. Our preliminary studies show selective nanoparticle extravasation and targeting to tumors across the blood-brain barrier in a novel autochthonous GEM medulloblastoma model. Our team proposes a strategy to localize both conventional and precision drugs to brain tumor tissue by targeting therapies to P-selectin on tumor vasculature. We will employ a physiologically and genetically-relevant mouse model of Sonic hedgehog-driven medulloblastoma to identify synergy with radiation therapy in enhancing tumor-selective nanoparticle drug delivery, and will pursue the following specific aims: 1) To evaluate the P-selectin-mediated targeting, role of radiation, and mechanism of extravasation across the blood-brain barrier in medulloblastoma, 2) To assess the efficacy and toxicity of P-selectin-targeted chemotherapy/SHH pathway inhibition in Sonic hedgehog-driven medulloblastoma, and 3) To assess the effects of focal radiation therapy of primary medulloblastoma tumors on P-selectin and nanoparticle drug delivery to distant leptomeningeal brain tumor metastases within the central nervous system in vivo. We will utilize biochemical and imaging methods including intravital multiphoton microscopy, confocal immunofluorescence and immuno-EM, micro-CT for bone analysis, pharmacokinetic and biodistribution measurements, and molecular biology approaches to assess nanoparticle delivery mechanisms, treatment efficacy, and toxicity. Our primary endpoint is to identify tumor-selective strategies that synergize with current standard of care therapies for medulloblastoma. Should our results prove favorable, we envision clinical applicability to patients with medulloblastoma and other primary brain tumors as well as neurological diseases that have been shown to have endothelial inflammation including multiple sclerosis and stroke.


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 = -$227,720 )
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/17/2025	NON-COMPETING CONTINUATION	-$227,720
														Subtotal = -$227,720

Issue Date FY: 2024 ( Subtotal = $577,523 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/1/2024	NON-COMPETING CONTINUATION	$535,847
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	5/3/2024	NON-COMPETING CONTINUATION	-$17,862
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/10/2024	NON-COMPETING CONTINUATION	$59,538
														Subtotal = $577,523

Issue Date FY: 2023 ( Subtotal = $603,031 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/20/2022	NON-COMPETING CONTINUATION	$542,729
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/30/2023	NON-COMPETING CONTINUATION	$60,302
														Subtotal = $603,031

Issue Date FY: 2022 ( Subtotal = $608,977 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/31/2022	NON-COMPETING CONTINUATION	$60,897
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/21/2021	NON-COMPETING CONTINUATION	$548,080
														Subtotal = $608,977

Issue Date FY: 2021 ( Subtotal = $615,717 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/11/2021	NON-COMPETING CONTINUATION	$61,571
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/21/2020	NON-COMPETING CONTINUATION	$554,146
														Subtotal = $615,717

Issue Date FY: 2020 ( Subtotal = $662,109 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/13/2020	NEW	$662,109
														Subtotal = $662,109

Grand Total All Awards = $2,839,637

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Tumor-Selective Delivery Approaches for Medulloblastoma

Award Number: R01NS116353

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: 03/15/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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