Epigenetic Therapies - New Approaches

表观遗传疗法 - 新方法

• 批准号: 10269639
• 负责人: STEPHEN B. BAYLIN
• 金额: $ 226.97万
• 依托单位: CORIELL INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10269639
• 关键词: Address; Biochemical; Biological Markers; Cancer Patient; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cultured Cells; Cyclin-Dependent Kinases; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Modification Methylases; DNA Repair; DNA methyltransferase inhibition; Development; Dreams; Drug Combinations; EZH2 gene; Ensure; Enzymes; Epigenetic Process; Funding; Gene Expression; Gene Expression Profile; Generations; Genetic Transcription; Genomics; Goals; Hematologic Neoplasms; Histone Deacetylase; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunologic Monitoring; Immunotherapy; Inflammasome; Institutes; Interferons; Isocitrate Dehydrogenase; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mentors; Modification; Molecular; Mus; Nature; Neoadjuvant Therapy; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phase I Clinical Trials; Phase I/II Trial; Phenotype; Regulation; Repetitive Sequence; Repression; Research; Research Personnel; Research Project Grants; Resistance; Running; Science; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Therapeutic Effect; Therapy Clinical Trials; Tissues; Translational Research; Work; analysis pipeline; cancer cell; cancer therapy; cancer type; career; chemotherapy; chromatin remodeling; clinical application; drug action; drug testing; epigenetic drug; epigenetic regulation; epigenetic silencing; epigenetic therapy; improved; inhibitor/antagonist; malignant breast neoplasm; next generation; novel; novel therapeutic intervention; pharmacodynamic biomarker; preclinical study; programs; response; response biomarker; synergism; targeted treatment; therapy design; therapy resistant; translational pipeline; translational study; tumor; tumor growth

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 generation of Epigenetic Therapy investigators and support cutting-edge science through the Career Enhancement and Developmental Research Programs.

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