Identification of novel therapeutic combinations for NF2 schwannomas

PROJECT SUMMARY / ABSTRACT Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition syndrome characterized by germline haploinsufficiency at the NF2 locus, which encodes Merlin. NF2 patients characteristically develop bilateral vestibular schwannomas (VS) and spinal schwannomas as a result of loss of heterozygosity of NF2 in Schwann cells or Schwann cell precursors. Although these tumors are largely benign, their growth can result in significant neurological deficiencies including, but not limited to, deafness, vertigo, facial muscle weakness, chronic neuropathic pain, and death. Because of the extensive morbidity associated with surgical removal of these tumors, there is an urgent need to develop pharmaceutical approaches to halt or reverse the progression of tumor growth in these patients. To date, no long-term effective therapies exist for these highly debilitating tumors. Given the challenging clinical trial logistics in a rare tumor predisposition syndrome such as NF2, it is critical to establish a strategy linking preclinical and clinical studies for rapid translational innovation and efficiency. We have developed genetically engineered mouse models (GEMMs) of NF2 that accurately recapitulate tumor growth kinetics and histopathologic characteristics observed in NF2 patients—VS and paraspinal schwannomas with 100% incidence, combined with progressive hearing loss that occurs with VS formation. Using the Nf2 GEMM, we determined that the FDA approved multi-receptor tyrosine kinase (RTK) inhibitor brigatinib reduced schwannoma tumor size and tumor number. Brigatinib is approved to treat cancer driven by another kinase, anaplastic lymphoma kinase (ALK) and two ALK inhibitors, crizotinib and brigatinib, have both shown preclinical efficacy against NF2-associated schwannomas and are under evaluation in active clinical trials. While our findings suggest a role for FAK1 in modulating tumor progression, our understanding of the role of FAK1 as a single target for NF2 tumors or in combination with other drug targets is incomplete. We propose to build on our recent preclinical work by genetic ablation of FAK1 (Ptk2) in murine (Nf2) and human (NF2) deficient Schwann cells to establish the role of FAK1 (Ptk2) in promoting the genesis of Nf2 deficient schwannomas and associated morbidities (Aim 1). Drug synergy screening with post-IND FAK inhibitors alone and in combination with RAF, MEK, and BET bromodomain inhibitors to target cooperating Merlin-regulated pathways (Aim 2), and unbiased CRISPR-Cas9 kinome knockout screening in murine and human cells to identify FAK1-dependent kinase vulnerabilities that can be exploited therapeutically, alone or in combination (Aim 3). Our overarching goal with experiments in this application is to identify drugs or drug combinations that could expediently proceed to phase I/II clinical trials for patients with this debilitating neurological disease.