Epigenetic Therapies - New Approaches

摘要（总体） 表观遗传学是指由 DNA 甲基化和/或染色质介导的稳定基因表达模式 重塑并参与细胞身份和虚假转录的抑制，包括来自重复的转录 元素。在过去的 20 年里，在本申请的研究人员部分领导的工作中，表观遗传变化 被认为是癌症形成、进展和治疗耐药的重要驱动因素。这种认可， 随着表观遗传学所需的生化修饰的可逆性，导致了以下领域： 表观遗传疗法，旨在重新编程基因表达以达到治疗效果。这个领域，哪个 从 DNA 甲基转移酶 (DNMT) 抑制剂开始，现已发展到十几个表观遗传靶点和 30 多个 临床试验中的药物。四个目标已获得美国 FDA 批准（DNMT、组蛋白脱乙酰酶 (HDAC)、 EZH2 和异柠檬酸脱氢酶）和数以万计的癌症患者每年都从中受益。 随着新靶标的确定以及表观遗传学与敏感性和耐药性相关的认识 相对于化疗和免疫疗法，表观遗传疗法的临床潜力已开始在以下领域被探索： 认真的。从缺乏强有力的活性生物标志物到出现 耐药性，以及血液系统恶性肿瘤和实体瘤之间无法解释的反应差异。 这个 SPORE 应用程序将解决所有这些挑战。 SPORE 团队由以下调查员组成 癌症表观遗传学和表观遗传学治疗领域的先驱，并探索新的表观遗传学靶点和 组合策略以及强大的生物标志物分析流程，以确定可能有反应的患者和 反应的药效学标志物。该团队利用强大的临床和转化管道 通过 Van Andel Institute Stand Up To Cancer 表观遗传学梦想团队，该团队已进行了 14 过去几年进行过表观遗传疗法的临床试验，并全力致力于本次提出的临床试验 应用程序。该表观遗传疗法 SPORE 涵盖四大主题： (i) 开发和测试药物 针对新的表观遗传目标（项目 1、2），(ii) 免疫敏化的机制和转化研究 通过表观遗传疗法（项目 1-3），(iii) 研究增强已知药物疗效的药物组合 表观遗传药物（项目1-3）； (iv) 生物标志物研究，以确定对表观遗传的敏感性和抗性 诊所治疗（所有项目）。这些主题将通过 3 个项目来解决：(i) 细胞周期依赖性 激酶作为表观遗传治疗靶点； (ii) DN​​MT 和 EZH1/2 抑制剂之间的表观遗传协同作用； (三) 将表观遗传疗法诱导炎症体信号转导与 BRCAness 表型的产生联系起来。这些 项目将得到三个核心（行政、病理学、基因组学）的支持，一个关键目标也是 指导下一代表观遗传治疗研究人员并通过以下方式支持尖端科学 职业提升和发展研究计划。

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.