HER2-mediated immunoregulation and therapy resistance in glioblastoma
Active Project Grant Awarded Last action
- Award ID
- F31CA318007
- Recipient
-
Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University UEI M5QFLTCTSQN6
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $39,622
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Place of performance
- Cleveland, OH 44195, USA
Award details come from USAspending.gov.
Description
- Abstract
- Glioblastoma (GBM) remains the most aggressive primary brain tumor, with limited treatment options and a median survival of approximately 10 months. Although erbb/her-family signaling has been extensively studied in other cancers, the functional and immunologic consequences of HER2 signaling specifically in GBM remain poorly defined. My preliminary data and published datasets indicate that HER2-expressing GBM tumors display distinct cellular states, enhanced invasion, and altered immune interactions, suggesting that HER2 may regulate both mesenchymal-like tumor cell plasticity and immune evasion. However, the specific mechanistic pathways through which HER2 shapes transcriptional programs and suppresses anti-tumor immunity in GBM are unknown. Preliminary findings show that HER2-positive GBM models exhibit gene expression changes consistent with mesenchymal-like glioblastoma stem cells (MGSCS), the therapy-resistant population responsible for recurrence. HER2 expression strongly correlates with MES-like transcriptional signatures, EMT-associated signaling, and impaired antigen presentation, positioning HER2 as a biomarker for this treatment-refractory cell state. In addition, HER2 upregulates immune checkpoint pathways, including PD-L1, suggesting that HER2 actively contributes to immune evasion in GBM. Given that HER2 is an extracellular receptor with available FDA-approved, brain-penetrant inhibitors such as tucatinib, HER2 represents a clinically actionable vulnerability in recurrent, treatment-resistant GBM. This fellowship will use crispr-engineered GBM models and immune-competent syngeneic mouse systems to dissect how HER2 shapes tumor cell-state transitions and anti-tumor immunity. Aim 1: define how HER2 drives tumor cell transcriptional state shifts and signaling pathway activation using single-cell and bulk transcriptomic profiling, signaling analysis, and functional assays of invasion, self-renewal, and treatment resistance. Determine how HER2 inhibition with tucatinib alters these processes. Aim 2: determine how HER2 regulates immune evasion using immune-competent GBM models, flow cytometry, and combinatorial HER2 and checkpoint inhibition to define HER2-dependent changes in immune- cell recruitment, checkpoint ligand expression, and antigen presentation. The results of this work will reveal how HER2 promotes GBM plasticity and immune suppression, identify HER2 as a biomarker for treatment-resistant states in recurrence, and define therapeutic strategies that combine HER2-targeted agents with immunomodulatory approaches. Ultimately, this research will advance efforts to improve outcomes for individuals with this universally fatal cancer by informing precision therapeutic strategies for recurrence.
Quick answers
Who received award F31CA318007?
F31CA318007 was awarded to Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University by National Cancer Institute (National Institutes of Health) on February 11, 2027.
How much is award F31CA318007 worth?
$39,622 has been obligated on F31CA318007.
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