ABSTRACT (Overall) Epigenetics refers to stable gene expression patterns mediated by DNA methylation and/or chromatin remodeling and is involved in cellular identity and repression of spurious transcription, including from repetitive elements. Over the past 20 years, in work led in part by investigators in this application, epigenetic changes were recognized as important drivers of cancer formation, progression and resistance to therapy. This recognition, along with the reversible nature of the biochemical modifications required for epigenetics led to the field of Epigenetic Therapy, which aims to reprogram gene expression to achieve a therapeutic effect. This field, which started with DNA methyltransferase (DNMT) inhibitors, has grown to a dozen epigenetic targets and over 30 drugs in clinical trials. Four targets have made it to US-FDA approval (DNMTs, Histone Deacetylases (HDACs), EZH2 and Isocitrate Dehydrogenases) and tens of thousands of cancer patients benefit from this every year. With the identification of new targets and the recognition that epigenetics is involved in sensitivity and resistance to chemotherapy and immunotherapy, the clinical potential of epigenetic therapy has begun to be explored in earnest. There remain fundamental challenges, from the lack of robust biomarkers of activity, to the emergence of resistance, and to the unexplained divide in responses between hematologic malignancies and solid tumors. This SPORE application will address all of these challenges. The SPORE team consists of investigators who are pioneers in the fields of cancer epigenetics and epigenetic therapy and explores new epigenetic targets and combination strategies along with a robust biomarker analysis pipeline to identify patients likely to respond and pharmacodynamic markers of response. The team leverages a strong clinical and translational pipeline built through the Van Andel Institute Stand Up To Cancer Epigenetics Dream Team, which has conducted 14 epigenetic therapy clinical trials in the past few years, and is fully committed to the clinical trials proposed in this application. This Epigenetic Therapy SPORE encompasses four major themes: (i) Develop and test drugs against new epigenetic targets (Projects 1, 2), (ii) Mechanistic and translational studies of immunosensitization by epigenetic therapy (projects 1-3), (iii) Studies of drug combinations that enhance the efficacy of known epigenetic drugs (projects 1-3); and (iv) Biomarker studies to define sensitivity and resistance to epigenetic therapy in the clinic (all Projects). These themes will be addressed through 3 projects: (i) Cyclin Dependent Kinases as Epigenetic Therapy Targets; (ii) Epigenetic synergy between DNMT and EZH1/2 inhibitors; (iii) Linking epigenetic-therapy induction of inflammasome signaling to generation of a BRCAness phenotype. These projects will be supported by three cores (administrative, pathology, genomics) and a key goal will also be to mentor the next generati...