Therapeutic Targeting of Centrosome Abnormalities in NF2-Mutant Tumors
Abstract
The goals of this proposal are to determine how the NF2 protein Merlin controls key aspects of the cell division machinery, and, consequently, to test the hypothesis that defects in the integrity of the cell division machinery render NF2-mutant cells exquisitely sensitive to a panel of drugs that target different aspects of this machinery. Proposed experiments will examine the sensitivity of a large panel of NF2-mutant cells to these drugs and then bring the best-performing drug or drug combination forward and test it in an established mouse model of NF2- mutant tumorigenesis. These studies will yield new basic insight into the molecular function of Merlin/ERMs and test a completely novel therapeutic avenue for NF2-mutant tumors. Our studies will focus on multiple types of NF2-mutant tumors, including schwannomas and meningiomas, the hallmarks of NF2, as well as sporadic NF2-mutant mesothelioma and renal carcinoma. Preliminary data provided in the proposal revealed cell division machinery defects in all four types of NF2-mutant tumors. We believe that the analysis of multiple tumor types will be advantageous for several reasons: (1) Comparing molecular and drug sensitivity studies across multiple cell types will provide the strongest predictive insight into which tumors will be most sensitive to this therapeutic strategy and why; thus, insight from studying a particularly sensitive cell type will inform modifications to improve drug sensitivity in another cell type. (2) The inclusion of multiple tumor types will leverage our ability to acquire additional drugs and funding for this important NF2-specific avenue of investigation. If successful, these studies will therefore identify new drugs that could be advanced into clinical trials for the treatment of both major tumors that impact NF2 patients (schwannomas and meningioma) and for two key sporadic NF2-mutant tumor types (mesothelioma and renal carcinoma).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610222
Entities
People
- Andrea I McClatchey
Organizations
- Massachusetts General Hospital
- United States Army