Pathological epigenetic hyper-plasticity promotes acquisition of pro-tumor states in cancer

项目摘要 这个K22 NCI过渡职业发展奖的候选人是博士后William Flavahan博士 他是马萨诸塞州总医院和布罗德研究所的研究员。这个奖项的重点是弗拉瓦汉博士的长期- 长期目标是成为一名研究癌症表观遗传学的独立研究者。表观遗传学是 控制细胞身份、执行转录程序和驱动细胞表型的机制。 表观遗传过程在癌症中经常改变，并且可以作为肿瘤形成的起始事件， 导致细胞身份的恶性转化。表观遗传过程是严格校准的， 转换沿着设置细胞身份程序的过程，如细胞分化或响应， 外部刺激。在弗拉瓦汉博士以前工作的基础上，所附申请试图检验这一假设 癌症特异性表观遗传超可塑性形成了肿瘤特异性调节机制的基础， 逃避和转化。本申请提出测试的生物环境是琥珀酸盐的生物环境 脱氢酶（SDH）缺陷型胃肠道间质瘤（GIST）。虽然大多数GIST存在 作为癌基因KIT的突变，并且在临床上对KIT抑制具有高度反应性，SDH缺陷型GIST是 对大多数治疗都有抵抗力本申请提供的初步数据表明， 肿瘤转化的机制与Flavahan博士先前描述的肿瘤细胞丢失的范例相同。 表观遗传隔离保护癌基因免受强有力的管家超级增强剂的影响。这些数据显示 在缺乏SDH的GIST中，绝缘子的丢失激活FGF配体基因，并且患者来源的异种移植物 这种疾病的模型对FGFR靶向治疗高度响应。本申请旨在首先测试 假设表观遗传可塑性是负责这些肿瘤的转化和脆弱性， FGFR抑制，并且它可能导致对相同治疗的耐药性。其次，该申请旨在深入研究 表观遗传损伤的基础，以证明，使用表观遗传和等位基因的模型， 临床患者切除术的具体询问，绝缘损失发生在肿瘤开始时， SDH缺陷GIST背后的驱动病变。该应用程序将利用尖端的表观遗传分析， 以及先进的细胞培养工程和异种移植疾病模型。该应用程序的主要重点是 去了解基本的表观遗传过程，使癌细胞能够驱动疾病， 创造洞察力，这将允许治疗靶向和治疗。作为潜在的表观遗传状态， 造成这种病变（DNA超甲基化）是常见的癌症，从这些项目的结果可能有 超越GIST的重要性。

PROJECT SUMMARY The candidate for this K22 NCI Transition Career Development Award is Dr. William Flavahan, a postdoctoral fellow at Massachusetts General Hospital and the Broad Institute. This award focuses on Dr. Flavahan’s long- term goal of becoming an independent investigator studying cancer epigenetics. Epigenetics are the fundamental mechanisms that control cell identity, enforcing the transcriptional programs and driving cellular phenotypes. Epigenetic processes are frequently altered in cancer, and may serve as initiating events for tumor formation, driving malignant transformation of the cellular identity. Epigenetic processes are tightly calibrated, allowing transitions along set cellular identity programs for processes such as cellular differentiation or response to external stimuli. Building on Dr. Flavahan’s previous work, the enclosed application seeks to test the hypothesis that cancer-specific epigenetic hyperplasticity forms the basis of a tumor-specific mechanism of regulatory evasion and transformation. The biological setting this application proposes to test is that of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST). While the majority of GIST present with a mutation in the oncogene KIT and are highly clinically responsive to KIT inhibition, SDH-deficient GIST are resistant to most forms of therapy. This application presents preliminary data showing that the primary mechanism of tumor transformation is identical to Dr. Flavahan’s previously described paradigm of loss of epigenetic insulation protecting an oncogene from a potent housekeeping superenhancer. These data show that in SDH-deficient GIST, loss of an insulator activates FGF ligand genes, and a patient-derived xenograft model of this disease is highly responsive to FGFR-targeted therapy. This application seeks to first test the hypothesis that epigenetic plasticity is responsible for the transformation and vulnerability of these tumors to FGFR inhibition and that it may drive resistance to the same treatment. Second, this application seeks to delve into the underpinnings of the epigenetic lesion to demonstrate, using models of epigenetic inheritance and allele- specific interrogation of clinical patient resection, that the loss of insulation occurs at tumor initiation and may be the driver lesion behind SDH-deficient GIST. The application will leverage cutting edge epigenetic assays as well as advanced cell culture engineering and xenograft models of disease. The main focus of this application is to understand the fundamental epigenetic processes that enable cancer cells to drive the disease and hopefully create insight that will allow for therapeutic targeting and treatment. As the underlying epigenetic state that creates this lesion (DNA hypermethylation) is commonplace in cancer, the results from these projects may have great relevance beyond GIST.