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Theranostics for Pediatric Brain Cancer

Award Number: R01HD103638
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Theranostics for Pediatric Brain Cancer - THERANOSTICS FOR PEDIATRIC BRAIN CANCER Glioblastoma (GBM) is the most frequently diagnosed primary malignant brain tumor in children with median survival of less than one year. Disease recurrence is common and is caused by the presence of glioma-initiating cells (GICs) that are unreceptive to conventional therapies, underscoring the urgent need for new therapeutic options. We aim to develop a novel strategy to specifically disrupt the lifeline of GICs, without causing toxic effects to the normal brain. The highly vascularized nature of GBMs and the critical function of the perivascular niche for nutritional supply of GICs have spurred much interest in novel vascular-disruptive agents (VDAs). Intravenously administered VDAs easily reach GBM vessels and do not rely on the enhanced permeability and retention effect, which can limit the delivery of macromolecules to the tumor tissue. VDA-mediated blood vessel disruption causes efficient drug delivery to the GIC niche and starvation of many tumor cells. In contrast to classical anti-angiogenesis drugs, VDAs not only disrupt the tumor vasculature, but also cause significant GIC apoptosis through direct cytotoxic effects. While being highly effective for cancer treatment, initial VDA formulations also caused significant toxicity to the normal brain. This is particularly concerning for children, as the developing brain is more vulnerable to toxic side effects compared to the adult brain. To solve this problem, we developed novel VDA-loaded theranostic (combined therapeutic and diagnostic) nanoparticles, which are specifically activated in brain tumors by matrix metalloproteinases 14 (MMP-14). The normal brain does not express MMP-14 and therefore, does not activate the theranostic drug, thereby creating highly effective cancer therapy without side effects. The major goal of our project is to develop MMP-14-activatable theranostic nanoparticles (TNPs) for curative treatment of GBM, without causing toxicity to the normal brain. The approach relies on the high prevalence of MMP-14 in GBM, a proven MMP-14-activatable prodrug strategy, and a nanocarrier platform based on FDA-approved iron oxide nanoparticles. We hypothesize that our TNPs will be converted to an active therapeutic agent only within MMP-14-expressing tumors, releasing the therapeutic drug azademethylcolchicine and causing significant antitumor effects. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with magnetic resonance imaging (MRI). In aim 1, we will evaluate whether TNP dose and VDA payload affect VDA mediated vascular disruption, blood brain barrier (BBB) breakdown and cancer-specific toxicity. In aim 2, we will investigate the link between VDA-mediated tumor microvessel disruption, microvascular endothelial cell death and GIC death. TNPs hold the potential to substantially improving therapeutic efficacy whilst simultaneously reducing dose-limiting toxicities. Realizing our goal will uncover new targets and mechanisms for successful GBM therapy, eliminate or substantially reduce off-target toxicities and provide children with brain cancers with a much needed new treatment option.


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 = $0 )
2026	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	5	11/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $645,938 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	5	4/15/2025	NON-COMPETING CONTINUATION	$64,594
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	5	1/15/2025	NON-COMPETING CONTINUATION	$581,344
														Subtotal = $645,938

Issue Date FY: 2024 ( Subtotal = $646,803 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	4	6/13/2024	NON-COMPETING CONTINUATION	$58,799
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	4	2/12/2024	NON-COMPETING CONTINUATION	$588,004
														Subtotal = $646,803

Issue Date FY: 2023 ( Subtotal = $661,242 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	3	2/2/2023	NON-COMPETING CONTINUATION	$661,242
														Subtotal = $661,242

Issue Date FY: 2022 ( Subtotal = $668,562 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	2	2/23/2022	NON-COMPETING CONTINUATION	$601,702
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	2	5/27/2022	NON-COMPETING CONTINUATION	$66,860
														Subtotal = $668,562

Issue Date FY: 2021 ( Subtotal = $676,775 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	000	1	4/15/2021	NEW	$677,761
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Child Health and Human Development Extramural Research	001	1	4/16/2021	NEW	-$986
														Subtotal = $676,775

Grand Total All Awards = $3,299,320

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Theranostics for Pediatric Brain Cancer

Award Number: R01HD103638

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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