Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma
About This Grant
Project Summary/Abstract Glioblastoma, IDH-wildtype (GBM; WHO grade 4), the most malignant primary brain tumor, has well-defined pre-necrotic, necrotic and recurrent growth phases. Transition to the necrotic phase in primary and recurrent states involves a massive restructuring of the tumor microenvironment (TME), in which there is a dramatic increase in tumor- associated macrophages (TAMs) that are polarized to an immunosuppressive state. TAMs emerge from the perivascular niche and aggregate in high density with hypoxic glioma cells within the peri-necrotic niche (PN) with remarkable temporal similarity. We hypothesize that the spatial arrangement of TAMs and glioma cells within the highly hypoxic PN represents a biologic engine that serves as a sustainable source of TAM immunosuppression and is reliant on their synergistic interdependencies. We propose investigations to better understand mechanisms underlying these events using patient- derived, molecularly characterized GBM neurosphere cultures and RCAS-tv-a mouse model that allows study of the evolution of TME events following necrosis in real-time in vivo and with advanced spatial transcriptomics. We focus on specific signaling events within the PN that cause polarization of TAMs and have preliminary data indicating that the hypoxic expression of podoplanin (PDPN) by glioma cells activates CLEC5A on TAMs, causing an immunosuppressive phenotype through Syk/STAT3 signaling. We also suggest that the direct effects of hypoxia and TGFβ1 activate Hippo signaling and PDPN expression within this niche. Pharmacologic inhibition of Syk as a single agent prolongs survival and enhances the presence of CD8+ T cells in the RCAS/tv-a model of GBM. We hypothesize that therapeutic targeting of CLEC5A signaling by using Syk inhibitors in addition to standard of care chemoradiation, with or without checkpoint inhibitors, will diminish immunosuppression, enhance immunity and prolong survival in preclinical models of primary and recurrent GBM.
Grant Summary
Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma is a NCI - National Cancer Institute grant providing up to $496K for university, nonprofit, healthcare org. Applications are due 2031-03-31 (open). Check eligibility and apply with FindGrants.
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How to Apply
Up to $496K
2031-03-31
- 1Confirm your organization is eligible for Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma from NCI - National Cancer Institute, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NCI - National Cancer Institute before the deadline.
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Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma: Frequently Asked Questions
Who is eligible for the Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma?
Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma is offered by NCI - National Cancer Institute and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma provide?
Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma provides up to $496K per award from NCI - National Cancer Institute. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma deadline?
Applications for Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma are due 2031-03-31 (open). Because deadlines can change, verify the date with the funder, NCI - National Cancer Institute, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma?
To apply for Disrupting the Peri-necrotic Engine of Immunosuppression in Glioblastoma, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NCI - National Cancer Institute.