Dissecting and Combatting Heterogeneity in NF2-Mutant Tumors
Abstract
This project brings together two PIs who have worked together for over 25 years to develop better treatment options for NF2 and schwannomatosis patients. The heterogeneity and adaptability of NF2-mutant schwannomas and meningiomas has emerged as a frustrating impediment to early clinical trials, which is surprising given that they are driven largely by mutations in the NF2 gene alone. It will be critical to understand this behavior to know why drug-based therapies do not cure tumors and learn how to improve them. It will also be critical to know whether gene therapy, an important and emerging therapeutic strategy for NF2, can overcome this heterogeneous adaptive behavior. Therefore, we worked together, taking advantage of our complementary expertise, to study how NF2-mutant tumors develop such chameleon-like behavior and to develop tools for studying how and whether drug-based or gene therapy approaches will overcome heterogeneity. Our studies suggest a completely new model of heterogeneity in NF2-mutant tumors that is based on the normal biology of the cells that give rise to each tumor, high-resolution images of the tumors themselves, and substantial preliminary data, including preliminary validation in mouse models. To map heterogeneity in tumors themselves, we enlisted the collaboration of Dr. Shannon Stott, a rising star in bioengineering; her laboratory is at the forefront of developing new imaging technology that enables the mapping of many biomarkers simultaneously in small amounts of tumor tissue from mouse models or human patients, and using artificial intelligence to extract patterns from the data that can be linked to clinical information or drug sensitivity. We propose to work together to test our new model of heterogeneity, deploy our new mouse model to determine whether gene restoration will overcome heterogeneity and reverse schwannoma and meningioma development in NF2 and schwannomatosis, and develop and deploy this state-of-the-art imaging platform for analyzing tumor heterogeneity. In the short term, the completion of these studies will identify new biomarkers of schwannoma and meningioma heterogeneity and link them to tumor response in ongoing and planned drug studies; provide the first genetic test of whether gene therapy is likely to be successful for NF2-mutant tumors; and establish and deploy an innovative platform for monitoring tumor heterogeneity. In the longer term, these will be valuable resources for the community well beyond the scope of the proposed studies, as the mechanistic model can be advanced, the mouse model used in more sophisticated ways, and the imaging platform adapted to evaluate future therapeutic strategies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110446
Entities
People
- Andrea I McClatchey
Organizations
- Massachusetts General Hospital
- United States Army