Project 4: Transcriptional Coactivators and Enhancers in Human Cancer

项目总结-项目4

PROJECT SUMMARY - PROJECT 4 Emerging evidence has implicated transcriptional coactivators and enhancer elements as having a central role in the pathogenesis of human cancer. The research outlined in Project 4 will develop transcriptional coactivators as proteins that support the aberrant capabilities of cancer cells, thus revealing a novel class of epigenetic drug targets in oncology. This research will explore the role of SWI/SNF and TFIID coactivator complexes in the pathogenesis of Acute Myeloid Leukemia (AML) and will identify novel roles for coactivators in supporting the progression of late-stage Pancreatic Ductal Adenocarcinoma (PDA). The first Aim of this proposal will analyze the anti-leukemia effects of chemical inhibitors of the bromodomain of BRD9, which are novel compounds we generated in collaboration with Boehringer-Ingelheim. The major objective of this research will be to develop drug combinations that augment the therapeutic effects of BRD9 inhibition in AML. This will include use of CRISPR-scanning and domain-focused CRISPR screening, which are recently developed genetic tools to allow deep mechanistic investigation of endogenous protein complexes and to reveal opportunities for drug repurposing. This research has a direct potential to motivate clinical studies of novel drug combinations in AML patient populations. The second Aim will develop the TAF12/TFIID complex as a novel dependency in AML and reveal its underlying mechanism in supporting oncogene-mediated leukemic transformation. This will also include identifying suitable routes for direct chemical inhibition of this complex, an objective that has yet to be achieved in the cancer epigenetics field, largely owing to our incomplete understanding about how TFIID supports cancer pathogenesis. The third Aim of Project 4 will be to understand how modulation of nucleosome structure by writers, readers, and erasers of post-translational histone marks might endow PDA cells with the capacity to undergo metastasis. This will include domain- focused CRISPR screening to interrogate chromatin regulators that allow distal metastasis in mouse models of PDA. Since early metastasis is a major contributor to the high mortality of PDA patients, this research may significantly impact our basic understanding of the lethal form of this disease, and carries the potential for revealing epigenetic drug targets for this malignancy. Importantly, the research outlined in Project 4 will provide a deep mechanistic investigation of transcriptional mechanisms that support AML and PDA, which will rely on extensive use of epigenomic tools (e.g. ChIP-seq-based measurement of enhancer activity), and biochemical approaches. Project 4 will also feature extensive collaborations with the other Projects and Cores to evaluate molecular mechanisms and in vivo biology of malignant cells. This basic research will reveal novel vulnerabilities in lethal malignancies, which could provide new routes for therapy.