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A Hyper-Thrombotic State and Immunosuppression in GBM

Award Number: F32CA287655
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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A Hyper-Thrombotic State and Immunosuppression in GBM - Project Abstract: Cancer-related thrombosis is the second leading cause of death for cancer patients. Glioblastoma (GBM), the most common primary malignant brain tumor, is associated with a 30% risk of venous thromboembolism (VTE). High platelet counts and a hyper-thrombotic state have been associated with poor clinical outcome in many cancers, and while platelets are known to promote progression of other tumors, the mechanisms by which this hyper-thrombotic state drives GBM progression has not been explored. Moreover, sex-biases are well established in GBM with men being 1.6 times more likely to develop GBM and have a poorer prognosis than females. Despite this, no work has explored how sex-biases contribute to the hyper-thrombotic state in GBM. New preliminary data suggests that GBM patient platelets have an increase in PAR4 receptor mediated platelet activation. PAR receptor expression is found on platelets and T cells setting the stage for platelet – T cell interaction in the GBM TME. Our laboratory has previously shown that specific immune cell populations in the tumor microenvironment function in a sex dependent manner. Pharmacologically targeting the thrombin-PAR4 axis in murine models of GBM results in prolonged survival in females but not males and preliminary data suggest this sex-bias may be due to the platelet T-cell interaction. Aim 1 will test the hypothesis that GBM results in platelet hyperactivity leading to enhanced tumor growth. Aim 1a I will expand on my initial observations and interrogate the function of PAR1 and PAR4 receptor signal transduction using flow cytometry, confocal microscopy, and aggregometry in GBM patient and mouse bearing tumors platelets in the context of six differences. In Aim 1B, I will build on my initial observations and deplete platelets in multiple orthotopic pre- clinical models and assess overall survival and changes in the immune landscape. Aim 2 will test the hypothesis that that the thrombin-PAR4 signaling axis in GBM regulates T cell function to enhances the immunosuppressive tumor microenvironment in a sex-dependent manner. I will intracranially inject murine GBM cells into wild-type mice and treat with a PAR4 followed by subsequent immune profiling using flow cytometry and histology. Bone marrow chimera experiments will be performed to determine the relative contribution of biological sex of the immune cells versus the host on survival and to the tumor associated immune landscape. In parallel, we will assess platelet and T cell depletion studies to determine how the thrombin-PAR4 signaling axis regulates T cell function. The proposed research will provide me with a foundation in new areas including platelet biology, GBM immunology and cancer associated thrombosis. Expertise in neurobiology, platelet biology, clinical neuro- oncology, and cancer associated thrombosis from my mentors, postdoctoral advisory committee, and my lab members at the Cleveland Clinic will aid in successful completion of this proposal.


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 = $79,480 )
2026	2026	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	000	2	12/10/2025	NON-COMPETING CONTINUATION	$78,220
2026	2026	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	001	2	4/16/2026	NON-COMPETING CONTINUATION	$1,260
														Subtotal = $79,480

Issue Date FY: 2024 ( Subtotal = $75,928 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	001	1	6/24/2024	NEW	$0
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Research Manpower	000	1	6/24/2024	NEW	$75,928
														Subtotal = $75,928

Grand Total All Awards = $155,408

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A Hyper-Thrombotic State and Immunosuppression in GBM

Award Number: F32CA287655

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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