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

总结 尽管靶向治疗已经改变了医学肿瘤学，但传统的 细胞毒性化疗剂仍然是主要的癌症治疗方法之一。毒性 对于正常组织，特别是可再生组织， 在诊所里有效的正常组织保护策略是非常需要的， 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，通过这种机制，p53调节的MDM 2与 MDMX通过靶向EZH 2降解来控制DNA损伤敏感性。作为 组蛋白甲基转移酶，EZH 2促进H3 K27 me 3，从而促进染色质 压缩以保护DNA。我们发现， MDM 2和MDMX可以稳定EZH 2，从而保护可再生组织 DNA损伤剂引起的急性损伤基于这些发现，我们建议 测试MDM 2/MDMX复合物可以靶向EZH 2的假设 稳定，从而用于正常组织化疗保护。的可交付成果 该建议是建立一种靶向MDM 2/MDMX调节的EZH 2的新策略， 选择性地保护正常细胞。此外，该提案还将制定 药理学方法，并已经确定了先导化合物。因此 我们建议的研究的成功将为MDM 2/MDMX目标铺平道路- 调节EZH 2用于临床化疗保护，有希望成为一个巨大的潜力， 提高化疗疗效，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.