PROJECT SUMMARY This fellowship proposal describes a three-year research and training plan designed to prepare Dr. Matthew McCord, a clinical fellow in neuropathology at Northwestern University, for a career as a physician-scientist. Dr. McCord’s long term goal is to become an expert diagnostic neuropathologist and independently-funded brain tumor research scientist. The research plan is focused on better understanding temozolomide (TMZ) resistance and TMZ-driven hypermutation in glioblastoma (GBM). Chemotherapy with temozolomide (TMZ) is standard-of-care for GBM, and temporarily extends survival. However, tumors universally recur and develop TMZ resistance, and are almost uniformly fatal. Defects in DNA mismatch repair (MMR) enzymes, most commonly Msh6, have been linked to TMZ resistance in recurrent GBM. A subset of post-TMZ recurrent GBMs develop extremely high tumor mutation burden (TMB), also known as a “hypermutated” phenotype, which has also been linked to MMR defects, like Msh6. However, a clear causal relationship between impaired Msh6 and hypermutation in response to TMZ has not yet been experimentally proven. Certain types of hypermutated cancer arising elsewhere in the body have proven responsive to immune checkpoint inhibition (ICI), but in clinical trials of hypermutated GBMs, ICI responsiveness has been uneven, for reasons that are not entirely clear. Previously published data, from Dr. McCord and others, suggest that Msh6 impairment and hypermutation may be heterogeneous, occurring only in subclones of GBM that, via global genomic assays, appear to be hypermutated. This could help explain the inconsistent effects of ICI in trials thus far. The central hypothesis of the proposal is that MMR defects facilitate hypermutation in the presence of temozolomide and ICI responsiveness, but that sub-clonal variation in these defects contributes to variable ICI efficacy. Specific Aims to test this hypothesis are as follows: (1) prove a causative role for MSH6 in TMZ-driven hypermutation and TMZ resistance, through MSH6 gene knockout experiments in glioma cells; (2) demonstrate the intratumoral heterogeneity of Msh6 impairment and hypermutation, via single cell whole genome sequencing, in post-TMZ patient-derived gliomas and TMZ-resistant patient-derived xenografts (PDX); (3) evaluate the in vivo sensitivity of hypermutated versus non-hypermutated tumor subclones to TMZ and ICI by creating orthotopic intracranial GBMs with varying proportions of each cell type, then treating with both TMZ and ICI. The training plan for Dr. McCord is tailored to the proposed research, with focused mentoring, workshops, and coursework on bioinformatics, immunology, and glioma models, as well as addressing specific issues relevant for nascent physician-scientists. This fellowship will provide support for Dr. McCord at a critical juncture in his career, will enable him to eventually compete for both K- and R-level funding, and will also advance understanding of why GBMs develop resistance to both TMZ and ICI therapy.
|Effective start/end date||9/26/22 → 9/25/25|
- National Institutes of Health (NOT SPECIFIED)
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