Identifying and Testing Molecular Therapies for Schwannoma
Abstract
Background: Neurofibromatosis Type 2 (NF2) is an autosomal dominant disorder that results in growth of multiple tumors in the nervous system. These tumors, called schwannomas because they arise from Schwann cells, can cause numbness, weakness, and chronic pain and can create pressure on vital organs, impairing their function. A hallmark tumor of NF2 is bilateral vestibular schwannoma (VS): these tumors develop on the 8th cranial nerve and lead to balance issues and deafness. Currently, there is no effective FDA-approved drug to treat schwannomas, and surgery is the main treatment. The NF2 gene encodes a tumor suppressor protein called Merlin. In 2015, the Clapp lab reported a mouse model of schwannoma in which the Merlin gene is deleted in Schwann cells and the mice develop tumors that resemble human schwannoma (Gelhausen et al., Hum Mol Gen, 2015). In 2020, the Le lab generated a different mouse schwannoma model based on deregulation of HIPPO signaling in Schwann cells (Chen et al., JCI Insight, 2020). These two unique animal models targeting different parts of the HIPPO pathway, as well as work from Dr. Read, who has an extensive biobank of human schwannoma, have revealed molecular pathways critical for schwannoma formation. In this application, we propose to use both of these preclinical schwannoma models to test new drug combination treatment strategies targeting these key pathways in schwannoma development. We will also use these models to investigate the crosstalk between key pathways involved in schwannoma development, which should lead to identification of new therapeutic targets. Finally, we will validate any new targets we find in our mouse models in human schwannoma samples. The critical resources and expertise of the collaborating PIs and the synergy of these approaches will contribute to the identification of important molecular targets with potential for clinical use in schwannoma treatment. Scientific Rationale and Objective: Certain signaling pathways have been shown in animal models and human tumor samples to be involved in schwannoma development, but whether and how these pathways interact with each other is not known. The HIPPO and the MAPK signaling pathways have been implicated in schwannoma development in NF2 mouse models; however, the interaction of these pathways downstream of NF2/Merlin has not been elucidated. Our preliminary data also show that another protein, called AXL, would be a good candidate for drug targeting. We hypothesize that combined targeting of these pathways will have a synergistic effect to block tumor growth, and that a detailed investigation of the crosstalk between these pathways could inform new treatment strategies. To this end, we propose the following aims. In Aim 1, we will use our two schwannoma mouse models to test the effectiveness of a novel treatment regimen that combines TEAD inhibitor (to block dysregulated HIPPO signaling) plus MEK inhibitor (to block MAPK signaling) for blocking schwannoma growth. Response of the tumors to drug treatment will be measured, and then treated tumors will be comprehensively analyzed to identify potential new targets. In Aim 2, we will extend our experiments to test AXL inhibitors, both alone and in combination with inhibitors of MAPK and other key pathways in schwannoma formation. In Aim 3, we will use human schwannoma samples from NF2 patients to confirm the expression of any newly identified genes arising from Aims 1 and 2. Likewise, sequencing data from these human schwannoma samples will be mined for potentially relevant genes and molecular pathways critical for schwannoma development, which will then be tested in our mouse NF2 models. Types of Patients/Clinical Benefits and Timeline: The studies proposed in this application will benefit NF2 patients as well as other patients with schwannoma. The clinical benefits of these studies will not be realized for some time, as preclinical studies must be fol
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310322
Entities
People
- David Clapp
Organizations
- Indiana University
- United States Army