Pathological epigenetic hyper-plasticity promotes acquisition of pro-tumor states in cancer

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PROJECT SUMMARY The candidate for this K22 NCI Transition Career Development Award is Dr. William Flavahan, a postdoctoral fellow at Massachusetts General Hospital and the Broad Institute. This award focuses on Dr. Flavahan’s long- term goal of becoming an independent investigator studying cancer epigenetics. Epigenetics are the fundamental mechanisms that control cell identity, enforcing the transcriptional programs and driving cellular phenotypes. Epigenetic processes are frequently altered in cancer, and may serve as initiating events for tumor formation, driving malignant transformation of the cellular identity. Epigenetic processes are tightly calibrated, allowing transitions along set cellular identity programs for processes such as cellular differentiation or response to external stimuli. Building on Dr. Flavahan’s previous work, the enclosed application seeks to test the hypothesis that cancer-specific epigenetic hyperplasticity forms the basis of a tumor-specific mechanism of regulatory evasion and transformation. The biological setting this application proposes to test is that of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST). While the majority of GIST present with a mutation in the oncogene KIT and are highly clinically responsive to KIT inhibition, SDH-deficient GIST are resistant to most forms of therapy. This application presents preliminary data showing that the primary mechanism of tumor transformation is identical to Dr. Flavahan’s previously described paradigm of loss of epigenetic insulation protecting an oncogene from a potent housekeeping superenhancer. These data show that in SDH-deficient GIST, loss of an insulator activates FGF ligand genes, and a patient-derived xenograft model of this disease is highly responsive to FGFR-targeted therapy. This application seeks to first test the hypothesis that epigenetic plasticity is responsible for the transformation and vulnerability of these tumors to FGFR inhibition and that it may drive resistance to the same treatment. Second, this application seeks to delve into the underpinnings of the epigenetic lesion to demonstrate, using models of epigenetic inheritance and allele- specific interrogation of clinical patient resection, that the loss of insulation occurs at tumor initiation and may be the driver lesion behind SDH-deficient GIST. The application will leverage cutting edge epigenetic assays as well as advanced cell culture engineering and xenograft models of disease. The main focus of this application is to understand the fundamental epigenetic processes that enable cancer cells to drive the disease and hopefully create insight that will allow for therapeutic targeting and treatment. As the underlying epigenetic state that creates this lesion (DNA hypermethylation) is commonplace in cancer, the results from these projects may have great relevance beyond GIST.