Targeted Therapeutics for NF2 in a Preclinical Model
Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition syndrome caused by mutations in the NF2 gene, which codes for the protein Merlin. Patients with NF2 suffer from tumors in neural crest derived tissues, particularly vestibular schwannomas, as well as sensorineural hearing loss and challenges with balance. Currently, the frontline therapy for these tumors is surgical resection, which is complicated by these tumors’ locations proximal to the brain stem and vital functions. There are no long-term, efficacious pharmacotherapies that shrink tumors or prevent their recurrence. The overarching goal of this translational research grant is to identify novel drugs that can move forward to Phase 2 clinical trials in patients with NF2 schwannomas. Development of novel drug therapies for NF2 has been hindered by incomplete understanding of the endogenous roles of Merlin as a tumor suppressor and the lack of preclinical models that accurately recapitulate the development of tumors in NF2 patients. Our laboratory recently generated a mouse model that fills that translational gap. The resultant mice universally develop vestibular, spinal, and dermal schwannomas, as well as sensorineural hearing loss and vestibular dysfunction by 10 months of age. The mouse phenotype is well correlated with what is observed clinically in NF2 patients and makes the mice the best available model for understanding the NF2-related disease processes and running preclinical therapeutic studies. Using the preclinical model, we have discovered two key drug targets, c-MET and Pak, for which existing pipeline drugs are readily available. Studies proposed in this application will validate the respective targets and provide an experimental methodology utilized by pharma to validate drug targets as a platform to move into clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810553
Entities
People
- D. Clapp
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army