靶向泛素连接酶Skp2抑制高侵袭性前列腺癌的研究

Treatment for the most aggressive late/end stage cancer with multi-drug resistance remains a critical barrier to overall cancer care success. The Cancer Genome Atlas revealed Arf-p53, Ink4a-pRb and RTK-RAS-PI3K as the three pathways most frequently disrupted, and disrupted dramatically more frequently in metastatic over primary cancers, which explains in large part why late/end stage aggressive cancers are difficult to treat. We thus propose to establish a new mouse prostate tumor model with pRb/p53 double deficiency and oncogenic KRAS activation to mimic the clinically frequent and aggressive late/end stage prostate cancers. In previous studies, we showed that Skp2 deletion induced mitotic block in pRb/p53DKO tumor cells, and further cleared them via apoptosis. In this study, we will study by Skp2 targeting, (a) whether we could block the tumorigenesis and tumor progression in established pRb/p53/KRas(G12D) highly aggressive mouse prostate tumor model; (b) and determine the underlying mechanism of this blocking with cell and organoid model. Together, we expect to identify novel targets and strategies for treating aggressive late/end stage cancer.

晚/末期、高侵袭性肿瘤对靶点药物产生广泛的耐药性，对其继续治疗是肿瘤临床治疗中难以逾越的最大障碍。癌症基因组测试数据揭示，Ink4a-pRb、Arf-p53和RTK-Ras通路基因突变率与癌症的进展及转移呈显著的正相关，或为末期肿瘤难以治疗的潜在原因。本课题拟构建pRb/p53/KRas(G12D)三突变的高恶性、高侵袭性的小鼠前列腺肿瘤模型，分析该模型与病患晚期前列腺肿瘤在病理学、生物学各方面的相似性。在肿瘤抑制靶点方面，前期研究揭示靶向抑制泛素连接酶Skp2，有效阻断pRb/p53双突变细胞的有丝分裂，进一步通过凋亡将其清除。我们将研究(1)以Skp2为靶点对pRb/p53/KRas(G12D)三突变小鼠前列腺肿瘤发生、进展与转移的抑制及其程度；(2)并通过细胞模型、organoid模型进一步明确对其抑制的内在分子机制。希望通过本项目研究，找到晚/末期、耐药性肿瘤新的治疗策略及靶点。

晚/末期、高侵袭性肿瘤对靶点药物产生广泛的耐药性。癌症基因组测试数据揭示，Ink4a-pRb、Arf-p53和RTK-Ras通路基因突变率与癌症的进展及转移呈显著的正相关，或为末期肿瘤难以治疗的潜在原因。本课题构建pRb/p53/KRasG12D三突变高恶性、侵袭性的前列腺癌细胞模型，类器官模型和小鼠移植瘤模型，探究以Skp2为靶点对高恶性前列腺癌的抑制及其分子机制。通过本项目研究，（1）我们揭示Skp2可作为临床高恶性前列腺癌的潜在治疗靶点，靶向Skp2可与pRb/p53抑癌基因缺失形成“组合致死”效应，通过将E2F1从“促增殖”转换为“促凋亡”，抑制晚期阶段多基因突变、多耐药性的前列腺癌。（2）在此基础上，我们设计开发出一种以Skp2为靶点的纳米核酸药物，实现siRNA的“零载体”递送和“协同增效”。该纳米核酸能够在动物肿瘤模型和ex vivo类器官模型上实现对高恶性前列腺癌的抑制效果（3）我们从金线莲内生真菌次生代谢产物中筛选到一个靶向Skp2蛋白的天然小分子药物E2A1，并通过深入的分子药理研究揭示，该小分子可作为APC/C泛素E3连接酶的激动剂，促进其底物Skp2蛋白降解，进而抑制前列腺癌移植瘤生长。以上研究成果在科学意义上揭示了Skp2可作为临床高恶性前列腺癌治疗的潜在靶点，明确了其作用的分子机制；同时以Skp2为靶点设计开发的纳米核酸药物与天然小分子活性药物具有一定的临床应用前景和价值。

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