Examining the EYA2/MYC axis in Group 3 Medulloblastoma

项目总结： 髓母细胞瘤是儿童最常见的恶性脑肿瘤。对甲基溴的治疗包括 手术、放疗和化疗。不幸的是，长期的发病率，包括终身认知 缺陷，内分泌功能障碍，神经缺陷，情感和社会问题，以及继发性 肿瘤与目前的治疗方法有关。这种治疗相关的副作用尤其明显。 在儿童中，因为他们的大脑还在发育，而且他们可以在治疗后存活很多年。MB是一种 至少识别了12个不同亚组的异质性疾病。MYC高表达MB的患者 (25%-30%的病例；称为第3组)预后最差(5年存活率为41.9% 3个γ亚型)，并且已知MYC是该MB亚型的主要驱动因素。因此，对于组3 MB，有一个 迫切需要开发新的靶向疗法，赋予有限的毒性。然而，MYC一直保持着 “无法下药”。为了在高表达MYC的MBS中寻找新的治疗靶点，我们已经开始研究 EYA2转录辅助因子和双磷酸酶(酪氨酸和丝氨酸/苏氨酸在可分离结构域中)在血管紧张素转换酶中的作用 MB进度。有趣的是，EYA2已被证明在转录和转录后都控制着MYC。 翻译过来就是，在胚胎发育期间，但通常在发育完成后下调。 我们的初步数据显示，与正常小脑相比，EYA2在第3组MB中高表达 MB的其他子类型，它控制着第3 MB组的MYC水平，以及EYA2的KO 显著降低Group3MB的体内生长。我们在这项建议中的主要目标是确定小说 第3组MB中的可用药靶点；被抑制时不会导致显著副作用的靶点 与目前的甲基溴疗法有关。为此，我们将测试SIX1/EYA2的假设 转录复合体和/或EYA2磷酸酶通过以下途径在第3组MB进展中发挥关键作用 转录激活和/或稳定MYC，以及靶向MYC活性的新型抑制剂 EYA2可以减缓疾病的进展，同时产生有限的副作用。要解决这个问题 假设，我们将实现三个目标：1)确定EYA2调节MYC的哪些活动并参与 第3组MBS的侵略性，2)决定了是否需要EYA2对MYC进行监管才能对其产生影响 MB生长和进展，3)确定EYA2抑制是否从遗传或药物角度(使用 靶向SIX1转录活性或酪氨酸磷酸酶活性的新型小分子抑制剂 活性)，将提供一种独特的方法来抑制关键的癌基因myc，防止MB在体内的进展。 如果我们的假设是正确的，并且EYA2是MYC的关键、可用药的调节器，我们将识别出阿喀琉斯 HELL不仅适用于Group3MB，而且可能适用于许多其他依赖MYC的肿瘤。瞄准MYC 仍然是癌症研究的“圣杯”，我们的研究试图通过一种新的方法来做到这一点，预计 毒性有限，因为发育完全后，EYA2在正常组织中的表达很少。

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.