A small molecule that targets MiT/TFE dysregulated sarcomas
Dysregulation of MiT/TFE transcription factors (TFE3, TFEB, TFEC, and MITF) drive a subset of rare solid tumors across lineages, including alveolar soft part sarcoma (ASPS), and clear cell sarcoma (CCS). In ASPS, the defining genetic alteration is a gene fusion involving a MiT/TFE gene. In CCS, the EWS-ATF1 fusion binds to and directly activates the MITF gene, and these cancers are dependent on the MITF pathway. Collectively, MiT/TFE-dysregulated sarcomas are aggressive cancers without defined molecular targets that represent major unmet needs. We recently found that MITF-dependent melanomas are defined by activation of the nuclear factor erythroid-derived-2-like 2 (NFE2L2, or commonly, NRF2) pathway, a master regulator of the cellular response to xenobiotics and oxidative stress. In additional preliminary studies, we have developed a small molecule that is selectively cytotoxic to cancer cells with dysregulation of the NRF2 signaling pathway. We hypothesize that MiT/TFE-dysregulated sarcomas share a feature of elevated NRF2 pathway activity. The objectives of this project are to: (1) comprehensively assess the extent and mechanism of NRF2 pathway activation in ASPS and CCS; and (2) test whether a novel cytotoxic small molecule is active in MiT/TFE-dysregulated sarcomas. The identification of shared biology between these rare cancers could provide the basis for better diagnostics (through detection of p62/ NRF2 pathway dysregulation) and could lead to the development of common treatments for these diseases. We will advance preclinical validation of a novel small molecule that may ultimately be developed for clinical studies in MiT/TFE-dysregulated cancers. This project is conceptually innovative in that it seeks to unify the diagnosis and treatment of two rare sarcomas, both of which represent unmet medical needs. This work characterizes a novel small molecule that we have developed that selectively targets the NRF2 pathway in tumor cells. Based on our mechanistic studies, this compound may have promising activity in these sarcomas, thereby offering the potential for rationally-based therapeutics for patients who have limited treatment options.