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Dissertation
Identifying new targets and drug combinations in neurofibromatosis type 2
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2024
DOI:
https://doi.org/10.17918/00010718
Abstract
Neurofibromatosis type-2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas that cause progressive hearing loss as well as balance issues and brain stem compression. Treatment for this condition remains insufficient. Surgery to ameliorate the symptoms is invasive and radiation-based treatment is risky for patients with germline tumor suppressor mutations. There are several pharmacotherapies in clinical trials with varying success, but so far, there are no FDA-approved treatments for these patients. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. PAK1 and PAK2 directly bind to, and are inhibited by wild-type Merlin, but transmit proliferation and survival signals when Merlin is mutated or absent. However, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. Here we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. We also demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines. In a second study, we also identify the DNA damage repair pathway as a potential vulnerability for NF2-deficient schwannomas. Compared to WT schwannoma cells, The NF2-deficient cells are more sensitive to DNA damaging agents. Specifically, inhibition of CHK1, a cell cycle checkpoint kinase that is involved in the sensing and repair of DNA damage, can inhibit growth of NF2-deficient cells. These findings uncover a better understanding of NF2 biology and identify future targets for therapeutic treatments.
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Details
- Title
- Identifying new targets and drug combinations in neurofibromatosis type 2
- Creators
- Dorothy Benton
- Contributors
- Jonathan Chernoff (Advisor)Todd Strochlic (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 100 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991021901914404721