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High-probability grants
According to our matching algorithm, Andrew J. Mhyre is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2015 — 2017 |
Mhyre, Andrew J. Olson, James M [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Identification of Small Molecule Inhibitors of Phf5a For Glioblastoma @ Fred Hutchinson Cancer Research Center
? DESCRIPTION (provided by applicant): Glioblastoma Mutiforme (GBM) causes death in 95% of patients within two years even with the current standard of care. The heterogeneity within tumors and across molecular subclasses is a major challenge and there is a significant clinical need for new therapeutic agents that target GBM cells regardless of their oncogenic drivers. We recently identified PHF5A as a target that, when perturbed, causes GBM cells from multiple molecular subclasses to die, but does not harm normal neural stem cells or astrocytes. In vivo studies revealed that targeting PHF5A in mature GBM caused tumor regression, suggesting that these cancer cells rely on PHF5A for tumor maintenance. PHF5A is a member of the spliceosome machinery involved in the recognition of uncommon C-rich sequences in 3' splice acceptor sites. Our studies revealed that normal cells can compensate for loss of PHF5A activity, but GBM cells and MYC-transformed astrocytes experience mis-splicing of many essential genes resulting in cell cycle arrest. Our long-term goal is to discover and develop drugs that effectively treat GBM. Our short-term goal is to develop assays to discover candidate therapeutics that target PHF5A. This application seeks funding to develop the appropriate assays to efficiently identify candidate PHF5A inhibitors in collaboration with the NIH National Center for Advancing Translational Science (NCATS). We will then validate the screening hits in a battery of secondary and tertiary assays eliminating false positives, compounds with DMPK liabilities, and those that broadly inhibit RNA splicing. This will be accomplished through the following specific aims/phases: Phase 1- Develop assays to identify and characterize inhibitors of PHF5A; Phase 2- Conduct an HTS campaign to identify small molecule inhibitors of PHF5A; Phase 3- Validate active molecules in secondary and tertiary assays. Innovation stems from the design of minigene reporters that induce red fluorescent protein or luciferase signal only when PHF5A- mediated mis-splicing occurs. In contrast to most splicing screens which have signals of 3-5-fold, the assay we have developed produces a signal of 80-200-fold over background. Innovative designs of secondary and tertiary screens create a clear path to effectively identify selective PHF5A inhibitors and not simply general splicing inhibitors (which we believe would have on-target toxicity and hence be unsuitable as cancer therapeutics). The significance of the proposed work is that successful identification of cell penetrating PHF5A inhibitors creates a clear path to preclinical in vivo testing and potential promotion to human clinical trials. Because MYC transformation of normal cells causes exquisite sensitivity to PHF5A inhibition, it is also likely that the molecules identified will be effective for MYC-driven cancers other than GBM, which is particularly important for PHF5A inhibitors that are effective but fail to cross the blood brain barrier. The NCATs screening program is top tier in the world and Dr. Olson's experience in discovering and developing drugs that are now in human clinical trials integrate the experience needed to be successful in such an endeavor.
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