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Develop a human pluripotent stem cell-derived preclinical model for NUT Carcinoma

NCI - National Cancer Institute

Title: Develop a human pluripotent stem cell-derived preclinical model for NUT Carcinoma Project Summary: NUT Carcinoma (NC) is a devastating cancer with no effective treatment. A deeper understanding of its oncogenesis mechanism is vital for developing treatments that improve its prognosis. Although NC cases are strongly associated with Nuclear Protein in Testis (NUTM1) fusion genes, predominantly BRD4::NUTM1 (70% of cases), their oncogenic functions have been under debate. Using one of the first two NC genetically engineered mouse models we created, we demonstrated that inducing an endogenous chromosome translocation that forms the Brd4::Nutm1 fusion gene in progenitor cells in tissues as distinctive as oral mucosa, thyroids, lungs, and pancreas can induce carcinomas recapitulating human NC. Our results provided the long-awaited proof of NUTM1 fusion genes as the oncogenes for NC. Our new GEMM provided a critical tool to deepen our understanding of the molecular mechanisms of NC oncogenesis and develop effective treatments. However, the 90 million years’ evolution distance between humans and mice posed two significant challenges for translational studies of NC using the mouse model: · Due to the evolutionary divergence of protein and sequence structure, targeting agents including CRISPR-CAS9-based gene therapy agents and NUTM1-degrading molecular glues cannot be effectively tested using mouse model. · Due to the relatively loose evolution constraints on regulatory sequences, the genetic regulatory network (GRN) controlled by the NUTM1 fusion genes could differ between the two species. This could hamper the effective identification of BRD4::NUTM1 targets for future therapeutic development. To overcome these challenges, we propose to develop a human pluripotent stem cell (hPSC) derived NC model. We will use a genetic design demonstrated in our GEMM to build human PSC cell lines for modeling NC. To gain access to the progenitor cells of respiratory epithelial tissues, from which lung NCs that account for more than 50% of reported human cases likely originate, we will use human PSC-derived teratoma in immunocompromised mice as the platform to generate NCs. We will first create and characterize the human PSC-NC model (Aim 1) and then use this model to demonstrate the BRD4::NUTM1 dependency and thus the proof-of-principle of the effectiveness of NUTM1-targeted therapy for NC. (Aim 2). Overall Impact. Our project will provide a critical human-relevant in vivo preclinical model for studying NC. It will provide a proof-of-principle demonstration of NUTM1-targeted therapy. Our study will also provide a novel generalized road plan for developing in vivo human-relevant models for fusion gene-driven cancers.

Up to $157K

2028-05-31

health research

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Develop a human pluripotent stem cell-derived preclinical model for NUT Carcinoma

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Develop a human pluripotent stem cell-derived preclinical model for NUT Carcinoma

Develop a novel multi-approach dynamic Spot Scanning Proton Arc optimization framework

Develop a Regional Bike and Pedestrian Plan for the Southeastern Connecticut Planning Region.

Develop a Regional Complete Streets Policy and Action Plan.

Develop a study comparing alternative routes for the HouBike Trail between Kent and the Cornwall Bridge.

Develop a study to establish an official route for a 7-mile gap in the Naugatuck River Greenway between the Thomaston Dam and Bogue Road in Torrington.

Develop a study to identify potential options for water and wastewater infrastructure within the West Cornwall village center.

Develop a technology for whole-genome sequencing of RNA-DNA triplexes

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Develop Grazing Guidelines for the Ash Mountain Pasture in Sequoia and Kings Canyon National Parks

Develop Indy Economic Development Grants

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