Novel therapeutic strategies targeting the enhancer landscape in high-risk T-cell lymphomas.

Abstract public domain (NIH RePORTER)

Project Summary T-cell lymphomas (TCL), particularly those for which the transcription factor GATA-3 is oncogenic, are rarely cured with existing therapies and remain an area of unmet medical need. The first line gstandard of careh among GATA-3 driven TCL is futile, and those with relapsed/refractory disease do not fare better, as a median overall survival <6 months is anticipated, rivaling that observed in metastatic pancreatic cancer. Like many transcription factors, GATA-3 lacks an obvious small molecule binding domain and is a challenging therapeutic target. However, elucidation of novel mechanisms regulating GATA-3 dependent transcriptional programs in these TCL may unveil novel therapeutic strategies. We have topographically and epigenetically characterized the enhancer landscape in these TCL and have performed an unbiased CRISPR/Cas9 vulnerability screen using >10,000 gRNA targeting potential neo-enhancers regulating GATA-3 and an oncogenic GATA-3 target gene (i.e. c-Myc). This approach has unveiled novel enhancers that are essential for GATA-3 expression and regulate oncogenic and GATA-3-dependent transcriptional programs. The histone acetyltransferases p300 and CBP promote H3K27 histone acetylation required for enhancer activation, and selective inhibitors of the p300/CBP bromodomain impair enhancer activation. Our preliminary data demonstrates that antagonism of the p300/CBP bromodomain disrupts the enhancer landscape and impairs the expression of both GATA-3 and many (.50%) of its target genes, including c-myc, and is thus a novel therapeutic strategy in these challenging and treatment refractory TCL. Therefore, we will investigate the enhancer landscape as a therapeutically exploitable dependency in high-risk TCL in three aims: 1) We will utilize orthogonal and complementary strategies, including the use of primary TCL specimens, to characterize a novel GATA-3 enhancer and investigate its role in the evolution of chemorefractory TCL variants; 2) We will utilize unbiased approaches to identify GATA-3 dependent neo-enhancers driving oncogenic (including c-myc) transcriptional programs, and will further define their role in TCL evolution from a pre-malignant state using genetically diverse, but clinically representative, GEM models; 3) We will utilize a novel therapeutic strategy to disrupt the GATA-3-dependent enhancer landscape in PDX models. Immunodeficient (NSG) mice have been selected given their ability to support the growth of xenogeneic patient-derived lymphomas and alternative model systems fail to fully recapitulate the transcriptional and genetic characteristics of the original lymphoma, as required for the scientifically rigorous pre-clinical studies proposed here. We believe the work proposed will provide the foundation required for the development of future gnon-chemotherapyh regimens targeting addiction to oncogenic transcriptional programs in these chemotherapy refractory TCL. Consequently, we believe the translational impact of the work proposed is high.

Public health relevance public domain (NIH RePORTER)

Project Narrative The T-cell lymphomas are aggressive lymphomas associated with dismal outcomes as current therapeutic strategies are rarely associated with complete or durable responses. As novel therapeutic strategies are needed, we will investigate the extent to which the enhancer landscape regulates key oncogenic transcriptional programs and is a therapeutic dependency in high-risk and treatment refractory T-cell lymphomas. A novel and clinically translatable p300/CBP bromodomain inhibitor, alone and in combination with rationally selected targeted agents, will be investigated in pre-clinical models.