Development of Novel Therapeutic Approaches for NF1 Deficient Peripheral Nerve Sheath Tumors

Abstract

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) associated with Neurofibromatosis Type 1 (NF1) pose a significant clinical challenge due to their aggressive nature and limited treatment options. This thesis endeavors to address this challenge by developing innovative therapeutic approaches for NF1-deficient PNSTs. The first objective of this research focused on the development of oncolytic adenovirus therapy specifically tailored for MPNSTs. Through the utilization of conditionally replicating adenoviruses (CRAds), we aimed to elucidate their cytotoxic and anti-tumor properties against MPNSTs. Our findings revealed that these adenoviruses exhibit a remarkable affinity for MPNST cells, leading to preferential replication and cell death compared to non-tumor control cells. Moreover, intratumoral injection of CRAds in murine models resulted in improved survival rates. In immunocompetent murine models, an increased intratumoral CD8+ T cell infiltrate was observed, promising a potential immunotherapeutic dimension to this approach. These results collectively underscore the feasibility of oncolytic virotherapy development as a novel strategy for combating MPNSTs. The second key objective of this study involved the identification of synthetic lethal targets specific to MPNSTs through a genome-wide CRISPR/Cas9 synthetic lethal screen. Our screening process unveiled a multitude of potential synthetic lethal interactors in the context of NF1-null and NF1/SUZ12-null Schwann cells and MPNST cells. Furthermore, the initial validation of these candidate interactors yielded promising results, substantiating the need for additional development and investigation. These findings hold significant promise for the use of genetic screens to identify and develop novel therapeutic interventions targeting MPNSTs.