Therapeutic Targeting of Schwannoma Heterogeneity
Abstract
This proposal brings together two investigators who have devoted over 40 years of combined effort to understanding the molecular function of the NF2 protein and the underlying causes of schwannoma with the goal of developing new therapies for NF2/schwannoma patients. The present proposal addresses three areas of emphasis of the FY15 NFRP: (1) Heterogeneity of neurofibromas and other NF-related tumors. (2) Novel disease markers for NF using genomics, epigenetics, system biology, metabolomics, or other similar approaches. (3) Target identification and drug discovery for the treatment of NF. Our most recent work suggests that schwannomas have a unique ability to adapt to a changing environment as they grow and that this adaptability affects both their growth behavior and response to potential therapies. We believe that this adaptability underlies the devastating and unpredictable clinical and symptomatic behavior of vestibular and other schwannomas. Our preliminary work also suggests that this adaptability has a major impact on the sensitivity of schwannoma cells to pharmacologic drugs, including some that are being used in ongoing or planned clinical trials. Therefore, an understanding of the mechanisms by which schwannoma cells adapt to their surroundings and the identification of signatures of the "adapted" state are essential for designing and interpreting clinical trials. The goal of this proposal is to work together to test this hypothesis using an unprecedented panel of tools and novel animal models that we have developed. This work is focused on schwannomas, and particularly vestibular schwannomas, and therefore will help virtually all NF2 patients and individuals who develop sporadic vestibular or spinal schwannomas, common tumors that are virtually all caused by NF2 mutation. For NF2 patients, our studies will guide the design and interpretation of ongoing and future clinical trials, yield biomarkers that may allow appropriate drug-tumor matching, and test new drug candidates based on our hypothesis-driven preliminary studies. These studies could impact the design and interpretation of ongoing clinical trials and therefore have an impact on patients in the relatively short term; longer-term benefits will come from the identification of biomarkers and testing of new drugs. We believe that these studies will also yield novel insight into the cellular consequences of NF2 mutation that will apply to other types of NF2-mutant tumors. Overall, by identifying the magnitude and underlying causes of tumor heterogeneity, these studies will have a broad and critical impact on the field of NF2 research and patient care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610086
Entities
People
- Marco Giovannini
Organizations
- United States Army
- University of California, Los Angeles