Examining the EYA2/MYC axis in Group 3 Medulloblastoma

检查第 3 组髓母细胞瘤中的 EYA2/MYC 轴

• 批准号: 9753388
• 负责人: Heide L. Ford
• 金额: $ 42.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753388
• 关键词: Address; Aftercare; Binding; Biochemical; Biological Models; Brain; C-terminal; CRISPR/Cas technology; Cell Nucleus; Cells; Cerebellum; Child; Clinical; Cognitive; Complex; Coupled; DNA Methylation; Data; Defect; Development; Disease; Disease Progression; Embryonic Development; Emotional; Endocrine; Family; Family member; Foundations; Functional disorder; Future; Gene Expression; Genetic Transcription; Growth; Homeodomain Proteins; Human; In Vitro; Individual; Knock-out; Lead; Link; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mediator of activation protein; Molecular; Morbidity - disease rate; Mus; N-terminal; Nature; Neoplasm Metastasis; Neurologic; Normal tissue morphology; Oncogenes; Operative Surgical Procedures; Output; Pathway interactions; Patients; Pediatric Neoplasm; Pharmacology; Phosphoric Monoester Hydrolases; Play; Point Mutation; Population; Post-Translational Regulation; Proteins; Radiation; Regulation; Role; SHH gene; Sampling; Social Problems; Stem cells; Subgroup; Testing; Toxic effect; Transcription Alteration; Transcriptional Regulation; Xenograft Model; anticancer research; base; c-myc Genes; chemotherapy; clinically relevant; cofactor; effective therapy; embryonic protein; genome-wide; in vivo; inhibitor/antagonist; innovation; interest; medulloblastoma; neoplastic cell; new therapeutic target; novel; novel strategies; organ growth; outcome forecast; overexpression; phosphatase inhibitor; pre-clinical; prevent; protein complex; restoration; side effect; small molecule inhibitor; therapeutic target; transcription factor; tumor; tumor growth; tumor progression

Project Summary: Medulloblastoma (MB) is the most common malignant brain tumor in children. Treatment for MB includes surgery, radiation and chemotherapy. Unfortunately, long-term morbidity, including lifelong cognitive deficiencies, endocrine dysfunction, neurological defects, emotional and social problems, and secondary tumors are associated with current treatments. Such treatment associated side effects are particularly evident in children, as their brains are still growing, and they can survive many years after treatment. MB is a heterogeneous disease with at least 12 different subgroups identified. Patients with high MYC expressing MB (25-30% of cases; referred to as Group3) have the worst prognosis (survival at 5 years is 41.9% in the Group 3γ subtype), and MYC is known to be a major driver of this MB subtype. Thus, for Group 3 MB there is a pressing need to develop novel targeted therapies that confer limited toxicities. However, MYC has remained “undruggable”. To identify novel therapeutic targets in high MYC expressing MBs, we have begun to examine the role of the EYA2 transcriptional co-factor and dual phosphatase (Tyr and Ser/Thr in separable domains) in MB progression. Intriguingly, EYA2 has been shown to control MYC, both transcriptionally and post- translationally, during embryonic development, but is normally downregulated after development is complete. Our preliminary data show that EYA2 is overexpressed in Group3 MB compared to normal cerebellum and other subtypes of MB, that it controls MYC levels in the context of Group3 MB, and that KO of EYA2 dramatically diminishes in vivo growth of Group3 MB. Our main objective in this proposal is to identify novel druggable targets in Group 3 MB; targets that when inhibited will not lead to the significant side effects associated with current MB therapies. To this end, we will test the hypothesis that the SIX1/EYA2 transcriptional complex and/or EYA2 phosphatase plays a critical role in Group 3 MB progression via transcriptionally activating and/or stabilizing MYC, and that novel inhibitors targeting the activity of EYA2 can diminish disease progression while conferring limited side effects. To address this hypothesis, we will carry out three aims: 1) Determine which activity of EYA2 regulates MYC and contributes to the aggressive nature of Group 3 MBs, 2) Determine if regulation of MYC by EYA2 is required for its effects on MB growth and progression, 3) Determine whether EYA2 inhibition, genetically or pharmacologically (using novel small molecule inhibitors targeting either its transcriptional activity with SIX1 or its Tyr phosphatase activity), will provide a unique means to inhibit the critical oncogene, MYC, preventing MB progression in vivo. If our hypothesis is correct, and EYA2 is a key, druggable regulator of MYC, we will have identified an achilles heel not only for Group3 MB, but potentially for the many other MYC-dependent tumors. Targeting MYC remains a “holy grail” in cancer research, and our studies seek to do so via a novel means anticipated to have limited toxicity due to the paucity of EYA2 expression in normal tissues after development is complete.

项目概要： 髓母细胞瘤 (MB) 是儿童中最常见的恶性脑肿瘤。MB 的治疗包括。 不幸的是，手术、放疗和化疗会导致长期发病，包括终生认知障碍。 缺陷、内分泌功能障碍、神经系统缺陷、情绪和社交问题以及继发性问题 肿瘤与当前治疗相关的副作用尤其明显。 对于儿童来说，他们的大脑仍在发育，治疗后他们可以存活很多年。 具有高 MYC 表达 MB 的患者具有至少 12 个不同亚组的异质性疾病。 （25-30% 的病例；称为第 3 组）预后最差（该组的 5 年生存率为 41.9%） 3γ 亚型），并且已知 MYC 是该 MB 亚型的主要驱动因素，因此，对于第 3 组 MB 来说，存在一个。 迫切需要开发具有有限毒性的新型靶向疗法，但 MYC 仍然存在。 为了确定高 MYC 表达 MB 的新治疗靶点，我们已经开始研究。 EYA2 转录辅助因子和双磷酸酶（Tyr 和 Ser/Thr 在可分离结构域中）的作用 有趣的是，EYA2 已被证明可以在转录和后期控制 M​​YC。 翻译上，在胚胎发育期间，但通常在发育完成后下调。 我们的初步数据表明，与正常小脑相比，EYA2 在第 3 组 MB 中过度表达， MB 的其他亚型，它在 Group3 MB 的背景下控制 MYC 水平，并且 EYA2 的 KO 显着减少 Group3 MB 的体内生长 我们本提案的主要目标是新的鉴定。 第 3 组 MB 中的可药物靶标；被抑制时不会导致显着副作用的靶标 为此，我们将检验 SIX1/EYA2 的假设。 转录复合物和/或 EYA2 磷酸酶在第 3 组 MB 进展中发挥关键作用 转录激活和/或稳定 MYC，以及针对 MYC 活性的新型抑制剂 EYA2 可以减少疾病进展，同时产生有限的副作用。 假设，我们将实现三个目标：1）确定 EYA2 的哪些活性调节 MYC 并有助于 第 3 组 MB 的攻击性，2) 确定 EYA2 是否需要对 MYC 进行调节以达到其对 MB 的生长和进展，3) 确定 EYA2 是否受到遗传或药理学抑制（使用 新型小分子抑制剂，针对 SIX1 或其酪氨酸磷酸酶的转录活性 活性），将提供一种独特的方法来抑制关键的癌基因 MYC，从而防止体内 MB 的进展。 如果我们的假设是正确的，并且 EYA2 是 MYC 的一个关键的、可药物调节的，那么我们将识别出跟腱 不仅适用于 Group3 MB，还可能适用于许多其他 MYC 依赖性肿瘤。 仍然是癌症研究中的“圣杯”，我们的研究试图通过一种新的方法来实现这一目标 由于发育完成后正常组织中 EYA2 表达很少，因此毒性有限。