Cancer Epigenetics Research Program

项目摘要：癌症表观遗传学研究计划 西尔维斯特综合癌症中心(西尔维斯特)癌症表观遗传学研究计划， 成立于2014年，由来自七个部门的18名调查人员组成。由Ramin Shiekhattar博士共同领导， 和Maria Figueroa医学博士，该计划旨在整合癌症领域的基础和临床研究 表观遗传学，以确定有助于癌症风险、发生、进展和治疗的表观遗传因素 考虑到西尔维斯特集水区目前的具体需求，将作出回应。要实现 这些目标，CE计划包含三个具体目标：1)阐明致癌分子 与在癌症中突变的表观遗传调节因子相关的机制；2)定义增强子和 通过异常信号转导在癌症中级联的转录重编程；以及3) 在临床前和临床中验证治疗干预和生物标记物开发的表观遗传学目标 学习。目前，计划成员每年获得550万美元的直接同行审查资金，其中包括220万美元 来自NCI的150万美元和来自NIH其他研究所的150万美元。行政长官的研究工作严重依赖西尔维斯特的共享 资源，特别是肿瘤基因组学、流式细胞术以及生物统计学和生物信息学共享 资源。CE计划促进了强大的方案内和方案间协作以及 机构协作，以利用成员在基础、翻译和 临床研究和开发创新方法以改善西尔维斯特病癌症的影响 集水区，一个由四个县组成的地区，被称为南佛罗里达州。例如，CE与 肿瘤生物学研究计划，以了解致癌信号通路和 表观遗传学在癌症中的去调控作用，并与癌症控制研究计划一起了解有多具体 环境和社会经济差异影响表观基因组并影响癌症的发生和发展 进步。这些协作努力得到了迅速扩大的同行评审产品组合的支持 提供资金，包括NCI先锋奖、多重PI R01赠款、最近授予的白血病和淋巴瘤 协会(LLS)学者奖，以及LLS专业研究中心计划项目赠款。几个 研究者发起的研究也是从CE项目发现中涌现出来的。此外，行政长官成员还 自2014年以来发表了143篇与癌症相关的论文；24%代表方案内，29%代表方案间 方案方面，77%反映了多机构合作。行政长官的部分主要贡献包括1) 分析DNA甲基化和羟甲基化在血液系统恶性肿瘤中的作用；2)靶向 AML中的组蛋白读取器、编写器和擦除器；以及3)确定BAP1和ASXL1在葡萄膜黑色素瘤中的作用 以及它们对组蛋白甲基化和泛素化的贡献；以及4)增强子RNA(ERNAs)的发现 并靶向癌症中的eRNAs，以影响致病基因的表达和细胞生长。

PROJECT SUMMARY: CANCER EPIGENETICS RESEARCH PROGRAM The Sylvester Comprehensive Cancer Center (Sylvester) Cancer Epigenetics (CE) Research Program, established in 2014, comprises 18 investigators from seven departments. Co-led by Ramin Shiekhattar, PhD, and Maria Figueroa, MD, the program aims to incorporate basic and clinical research in the field of cancer epigenetics to pinpoint epigenetic factors that contribute to cancer risk, initiation, progression, and treatment response, taking into consideration the specific needs present within Sylvester’s catchment area. To achieve these objectives, the CE program encompasses three specific aims: 1) Elucidate the oncogenic molecular mechanisms associated with epigenetic regulators that are mutated in cancer; 2) Define the enhancer and transcriptional reprogramming that is imposed through aberrant signal transduction cascades in cancer; and 3) Validate epigenetic targets for therapeutic intervention and biomarker development in pre-clinical and clinical studies. Currently, program members receive $5.5M in annual direct peer-reviewed funding, including $2.2M from the NCI and $1.5M from other NIH Institutes. CE’s research efforts rely heavily on Sylvester’s shared resources, notably the Onco-Genomics, Flow Cytometry, and Biostatistics and Bioinformatics Shared Resources. The CE program fosters robust intra- and inter-programmatic collaborations as well as inter- institutional collaborations to leverage the depth and breadth of member expertise in basic, translational, and clinical research and develop innovative approaches to ameliorate the impact of cancer in Sylvester’s catchment area, a four-county area known as South Florida. For instance, CE works collaboratively with the Tumor Biology Research Program to understand the interplay between oncogenic signaling pathways and epigenetic deregulation in cancer, and with the Cancer Control Research Program to understand how specific environmental and socio-economic disparities impact the epigenome and influence cancer initiation and progression. These collaborative efforts are supported by a rapidly expanding portfolio of peer-reviewed funding, including an NCI Pioneer Award, multi-PI R01 grants, a recently awarded Leukemia and Lymphoma Society (LLS) Scholar Award, and an LLS Specialized Center of Research program project grant. Several investigator-initiated studies are also emerging from CE program discoveries. Furthermore, CE members have published 143 cancer-relevant papers since 2014; 24% represent intra-programmatic, 29% represent inter- programmatic, and 77% reflect multi-institutional collaborations. Some of CE’s major contributions include 1) dissecting the role of DNA methylation and hydroxymethylation in the hematological malignancies; 2) targeting histone readers, writers, and erasers in AML; and 3) defining the role of BAP1 and ASXL1 in uveal melanoma and their contribution to histone methylation and ubiquitination; and 4) discovering of enhancer RNAs (eRNAs) and targeting eRNAs in cancer to affect pathogenic gene expression and cellular growth.