Examining the EYA2/MYC axis in Group 3 Medulloblastoma

项目摘要： 髓母细胞瘤是儿童最常见的恶性脑肿瘤。MB的治疗包括 手术放疗化疗不幸的是，长期的发病率，包括终身的认知障碍， 缺陷，内分泌功能障碍，神经缺陷，情绪和社会问题，以及继发性 肿瘤与目前的治疗有关。这种治疗相关的副作用特别明显 在儿童中，由于他们的大脑仍在生长，他们可以在治疗后存活多年。MB是一个 至少有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（第3组的5年生存率为41.9%）。 3γ亚型），并且已知MYC是该MB亚型的主要驱动因子。因此，对于组3 MB，存在 迫切需要开发具有有限毒性的新型靶向疗法。然而，MYC仍然 “无法抗拒”为了在高表达MYC的MB中鉴定新的治疗靶点，我们已经开始研究 EYA 2转录辅因子和双磷酸酶（可分离结构域中的Tyr和Ser/Thr）在 MB进展。有趣的是，EYA 2已被证明可以控制MYC，无论是转录还是转录后。 在胚胎发育过程中，通常是下调的，但在发育完成后通常是下调的。 我们的初步数据显示，与正常小脑相比，EYA 2在Group 3 MB中过表达， MB的其他亚型，其在组3 MB的背景下控制MYC水平，并且EYA 2的KO 显著减少组3 MB的体内生长。我们的主要目标是确定新的 第3组MB中的可药物靶点;抑制时不会导致显著副作用的靶点 与当前MB治疗相关。为此，我们将测试SIX 1/EYA 2 转录复合物和/或EYA 2磷酸酶在组3 MB进展中起关键作用， 转录激活和/或稳定MYC，以及靶向MYC活性新抑制剂 EYA 2可以减少疾病进展，同时产生有限的副作用。为了解决这个 假设，我们将实现三个目标：1）确定EYA 2的哪些活性调节MYC并有助于 第3组MB的侵袭性，2）确定是否需要EYA 2调节MYC以影响 MB生长和进展，3）确定EYA 2抑制是否是遗传性的或非遗传性的（使用 靶向SIX 1转录活性或Tyr磷酸酶的新型小分子抑制剂 活性），将提供一种独特的手段来抑制关键的致癌基因MYC，防止体内MB进展。 如果我们的假设是正确的，并且EYA 2是MYC的一个关键的、可药用的调节因子，我们将确定一个致命弱点。 不仅对第3组MB，而且对许多其他MYC依赖性肿瘤也有可能。针对MYC 仍然是癌症研究中的“圣杯”，我们的研究试图通过一种新的手段来实现这一目标， 由于发育完成后正常组织中EYA 2表达的缺乏，毒性有限。

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.