# A Hyper-Thrombotic State and Immunosuppression in GBM

> **NIH NIH F32** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $75,928

## Abstract

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...

## Key facts

- **NIH application ID:** 10994351
- **Project number:** 1F32CA287655-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Anthony Robert Sloan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,928
- **Award type:** 1
- **Project period:** 2024-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994351

## Citation

> US National Institutes of Health, RePORTER application 10994351, A Hyper-Thrombotic State and Immunosuppression in GBM (1F32CA287655-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10994351. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*