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的基因表达模式 重塑，并参与细胞身份和抑制虚假转录，包括从重复 元素在过去的20年里，在这项应用的部分研究人员领导的工作中， 被认为是癌症形成、进展和对治疗的抗性的重要驱动因素。这种认识， 沿着表观遗传学所需的生物化学修饰的可逆性质，导致了 表观遗传疗法，旨在重新编程基因表达以达到治疗效果。此字段 从DNA甲基转移酶（DNMT）抑制剂开始，已经发展到十几个表观遗传靶点， 药物临床试验。四个靶点已经获得美国FDA的批准（DNMT，组蛋白脱乙酰酶（HDAC）， EZH 2和异柠檬酸脱氢酶），每年有成千上万的癌症患者从中受益。 随着新靶点的发现和表观遗传学与敏感性和耐药性有关的认识， 到化疗和免疫治疗，表观遗传治疗的临床潜力已经开始探索， 认真的仍然存在根本性的挑战，从缺乏强有力的生物标志物的活动，以出现 以及血液恶性肿瘤和实体瘤之间反应的不明差异。 这个SPORE应用程序将解决所有这些挑战。SPORE团队由以下调查人员组成： 癌症表观遗传学和表观遗传治疗领域的先驱，并探索新的表观遗传靶点， 组合策略沿着强大的生物标志物分析管道，以识别可能应答的患者， 反应的药效学标志物。该团队利用强大的临床和翻译管道， 通过货车安德尔研究所站起来癌症表观遗传学梦之队，该研究所已经进行了14次 表观遗传疗法的临床试验在过去几年中，并完全致力于临床试验中提出的， 应用程序.这个表观遗传疗法孢子包括四个主要主题：（一）开发和测试药物 针对新的表观遗传靶点（项目1、2），（ii）免疫致敏的机制和转化研究 （三）研究可提高已知药物疗效的药物组合， 表观遗传药物（项目1-3）;和（四）生物标志物研究，以确定对表观遗传药物的敏感性和抗性 诊所治疗（所有项目）。这些主题将通过3个项目来解决： 激酶作为表观遗传治疗靶点;（ii）DNMT和EZH 1/2抑制剂之间的表观遗传协同作用;（iii） 将炎性小体信号传导的表观遗传疗法诱导与BRCAness表型的产生联系起来。这些 项目将由三个核心（行政、病理学、基因组学）支持，一个关键目标也将是 指导下一代表观遗传疗法研究人员，并通过 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.