Thursday, May 16, 2024
5/16/2024
Title: Developing humanized Nut Carcinoma mouse model for developing NUTM1 targeted therapies. Project Summary: NUT carcinoma (NC) is a highly aggressive cancer with no effective treatment (medium survival time ~6 months from diagnosis). Although considered rare, the decimal prognosis of NC call for the development of better treatment. Clinically, NC is strongly associated with chromosome translocations that lead to the formation of fusion genes between a testis-specific gene NUTM1 and various fusion partners, including BRD4 (70% of cases), and BRD3, NSD3, ZNF532, etc. (the rest 30% of cases). Functionally, knockdown of the BRD4-NUTM1 fusion gene in human NC cell lines suppresses their proliferation, suggesting a strong dependency on BRD4-NUTM1 by NC. However, because the ectopic expression of BRD4-NUTM1 in non-NC cell lines is unequivocally toxic, the oncogenic activity of the fusion gene has not been proved previously. Recently, we developed the first genetically engineered mouse model (GEMM) of NC by recapitulating the Brd4-Nutm1 forming chromosome translocation in the basal cells of epithelial tissues. The mouse model developed highly aggressive low differentiation squamous cell carcinoma, similar to human NCs. Our GEMM study provided the first functional proof of BRD4-NUTM1 as the oncogenic driver of NC. The high dependency of NC on the BRD4-NUTM1 fusion gene for both cancer initiation and development presented it as an ideal target for therapy. Moreover, the testis- specific expression profile would make therapeutic strategies targeting NUTM1 highly specific and with a high therapeutic index. Because NUTM1 is an adaptor protein that is primarily consisted of low-complexity sequences, there are no apparent target sites for small molecular inhibitors. New therapeutic modules that target its DNA (e.g., CRISPR-based gene therapy) and mRNA (antisense therapy) sequences, or the ones that target its protein by synthetic affinity agents (e.g., nanobody-directed Proteolysis Chimera (PROTAC)) would likely be needed. Due to the limited conservation in genomic DNA (~3%) and peptide sequence (66%), our NC model based on the mouse genes is not ideal for developing NUTM1-targeting therapeutics. We propose to humanize the NC GEMM by replacing the mouse Nutm1 gene component with a human NUTM1 coding sequence (Aim 1) and characterize the NC tumors generated by this humanized model (Aim 2). We expect this well-characterized humanized NC GEMM to serve as a valuable preclinical model for developing NUTM1 targeting therapies for NC. Overall Impact. This project will produce a humanized GEMM for NC. By allowing the preclinical development of human NUTM1 targeting therapies, our new model can transform the landscape of NC therapy development and benefit NC patients. More broadly, the knowledge around targeting NUTM1 that the humanized NC model will foster can provide critical clues for developing NUTM1 targeting therapies for other NUTM1 rearranged cancers such as childhood leukemia and sarcoma.
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