新型MDM2-p53抑制剂激活p53募集TLE3抑制GR信号通路克服CRPC恩杂鲁胺耐药的作用和机制研究

前列腺癌是我国男性中发病率增长最快的恶性肿瘤，药物耐药严重制约着去势抵抗前列腺癌（CRPC）临床治疗效果。糖皮质激素受体（GR）高表达是导致CRPC对第二代抗雄激素药物恩杂鲁胺耐药的重要原因。临床对通过药物下调GR蛋白水平从而在体内外高效克服CRPC恩杂鲁胺耐药存在迫切需求。申请人前期发现使用课题组设计合成的新型MDM2-p53抑制剂激活野生型p53，能够抑制GR信号通路，促进细胞凋亡。我们推测，MDM2-p53抑制剂能够通过激活野生型p53，募集TLE3作用于GR基因转录元件区域，进而抑制GR信号通路功能，克服GR高表达导致的CRPC恩杂鲁胺耐药。本课题拟利用已构建好的CRPC耐药模型与PDX模型，在动物、细胞和分子水平阐明新型MDM2-p53抑制剂通过抑制GR信号通路，克服CRPC恩杂鲁胺耐药的作用与分子机制。为临床上第二代抗雄激素药物耐药问题的解决提供理论基础和潜在的药物治疗方案。

Prostate cancer is the fastest-expanding malignant tumor in males in China. The high expression of the glucocorticoid receptor (GR) plays an essential role in the resistance of CRPC (castration-resistant prostate cancer, CRPC) to the second-generation anti-androgen drug enzalutamide, which severely restricts the clinical treatment effect of advanced castration-resistant prostate cancer (CRPC).The applicant reported for the first time that simultaneous antagonism of AR and GR functions could inhibit the proliferation activity of GR high-expressing enzalutamide-resistant CRPC cells at the cellular level. However, how to down-regulate GR protein lever to overcome enzalutamide-resistance in CRPC in vivo and in vitro effectively still needs more exploration. We found in the previous work that wild-type p53 can down-regulate GR protein levels in CRPC cells in a TLE3-dependent manner. Our group designed and synthesized a new MDM2-p53 inhibitor that can activate wild-type p53, inhibit the GR signaling pathway, and promote cell apoptosis. We speculate that MDM2-p53 inhibitors can recruit TLE3 to interact with the GR transcription element region by activating wild-type p53, thereby inhibiting the function of the GR signaling pathway and overcoming enzalutamide resistance of CRPC caused by the high expression of GR. The aim of this project is 1) use the established CRPC resistance model and PDX model to elucidate the role and molecular mechanism of novel MDM2-p53 inhibitors to overcome CRPC enzalutamide resistance by inhibiting GR signaling pathway at the animal model, cellular and molecular levels; 2) Provide a theoretical basis and potential drug treatment method for overcoming the second-generation anti-androgen drug resistance in the clinic.