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Targeting the MAP4K4 pathway to inhibit pediatric high-grade glioma invasion

Award Number: K08NS140556
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Targeting the MAP4K4 pathway to inhibit pediatric high-grade glioma invasion - Project Summary Hemispheric high-grade gliomas (HGGs) in children are fast-growing and become rapidly widespread; the median survival rates for these diagnoses are measured in months, not years. It is therefore critical to discover more about the pathophysiology of pediatric HGGs (pHGGs), particularly their highly invasive nature. Investigating this characteristic to identify drug targets that would slow the speed of tumor invasion would significantly benefit our patients. MAP4K4 is a kinase with diverse biochemical and physiological roles in normal cell physiology. Previous data have suggested the MAP4K4 pathway may be a cornerstone in tumor invasiveness in multiple central nervous system and peripheral cancer types. We hypothesize that changes in function and expression of MAP4K4 play a significant role in the invasive ability of pHGGs. To determine whether MAP4K4 is altered in specific subtypes of hemispheric pHGG specimens from Stanford/Lucile Packard Children’s Hospital, our team will perform high- throughput methylation in combination with genomic sequencing to test for variants of MAP4K4 (and associated genes) (Aim 1). To determine whether MAP4K4 is necessary for pHGGs invasion, we will use pharmacological inhibition of (PF-06260933) and genetic (CRISPR/Cas9) silencing of MAP4K4 and downstream targets to regulate function and assess invasion in spheroid invasion assays (Aim 2). To evaluate whether inhibiting MAP4K4 reduces tumor cell invasion in vivo and prolongs survival, we will use MAP4K4 drug inhibitors in a pHGGs-luciferase orthotopic mouse model, and image the tumors at defined time points. We will also identify the cellular specificity of the MAP4K4 inhibitor in vivo with clearing-assisted tissue click chemistry (Aim 3). In conjunction with the Prolo laboratory, our team includes experts in CRISPR/Cas9 technology to probe molecular pathways genetically (Michael Bassik, PhD), leaders in neuro-oncology and xenograft mouse modeling of high-grade gliomas (Michelle Monje, MD, PhD), genomic and methylomic profiling of tumors (Matija Snuderl, MD) and click-chemistry (Li Ye, PhD). Analyzing these results will help to inform us of the molecular mechanisms underlying pHGG invasion. By creating a database detailing the profiles of our pHGG cohort, which will be published and made widely available for the broader scientific community, we hope to accelerate translational research to design treatments for this devastating cancer.


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 = $209,177 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/29/2026	NEW	$209,177
														Subtotal = $209,177

Grand Total All Awards = $209,177

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Targeting the MAP4K4 pathway to inhibit pediatric high-grade glioma invasion

Award Number: K08NS140556

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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