Target MDM2/MDMX for reducing normal tissue toxicity induced by chemotherapy

摘要 尽管靶向治疗改变了医学肿瘤学，但传统的 细胞毒性化疗仍然是癌症的主要治疗方法之一。对人体的毒性 正常组织，特别是可再生组织继续构成重大挑战 在诊所里。迫切需要有效的正常组织保护策略 减少副作用，从而提高癌症患者的生活质量。我们最近 揭示了一种新的机制，即P53调控的MDM2与 MDMX通过靶向EZH2降解来控制DNA损伤敏感性。作为一名 组蛋白甲基转移酶EZH2促进H3K27me3，从而促进染色质 压实以保护DNA。我们证明了干扰之间的联系 MDM2和MDMX可以稳定EZH2，从而保护再生组织 来自DNA损伤剂引起的急性损伤。根据这些研究结果，我们建议 测试MDM2/MDMX复合体可以靶向EZH2的假设 稳定，从而为正常的组织化疗保护。的交付成果 该建议旨在建立一种针对MDM2/MDMX调节的EZH2的新策略 有选择地保护正常细胞。此外，该提案还将发展 这是一种药理学方法，已经确定了先导化合物。因此， 我们建议的研究的成功将为以MDM2/MDMX为目标铺平道路- 调控的EZH2用于临床化疗保护，有望获得巨大潜力 增强化疗疗效，改善患者生活质量。

Summary Although targeted therapies have transformed medical oncology, traditional cytotoxic chemotherapeutics remain one of the primary cancer treatments. Toxicity to normal tissues, the renewable tissue in particular continues to represent major challenge in the clinic. Effective strategies of normal tissue protection are in great need for reducing the side effects and thus improving cancer patient’s quality of life. We recently uncovered a novel mechanism by which p53-regulated MDM2 functions together with MDMX to govern DNA damage sensitivity by targeting EZH2 for degradation. As a histone methyltransferase, EZH2 promotes H3K27me3 and therefore chromatin compaction to protect DNA. We showed that interference of the association between MDM2 and MDMX could stabilize EZH2, resulting in protection of renewable tissues from DNA damage agents-induced acute injury. Based on these findings, we propose to test the hypothesis that the MDM2/MDMX complex can be targeted for EZH2 stabilization and thereby for normal tissue chemotherapy protection. The deliverable of this proposal is to establish a novel strategy of targeting MDM2/MDMX-regulated EZH2 to selectively protect normal cells. Additionally, the proposal will develop the pharmacological approach and has already identified lead compounds. Therefore the success of our proposed studies would pave the way of targeting MDM2/MDMX- regulated EZH2 for chemotherapy protection to the clinic, promising a great potential to enhance the efficacy of chemotherapy and to improve patient quality of life.