Dissecting Skp2 functions in pRb and p53 doubly deficient tumorigenesis

摘要 针对特定肿瘤的特定信号通路的癌症治疗(靶向治疗)(个性化 治疗)是目前“最先进的”，而晚期癌症的治疗和管理仍然是 整体癌症治疗成功的障碍。晚期癌症的一个共同特征是频繁的遗传 两个主要的肿瘤抑制因子pRb和p53的失活。为这些癌症寻找有效的治疗方法 依赖于找到在pRb和p53基因同时存在的情况下仍然有效的抗肿瘤机制 已停用。我们成功地阻断了pRb和p53双缺陷小鼠肿瘤的发生 删除Skp2中的模型。我们现在建议使用pRb和p53双重缺陷的前列腺癌发生 小鼠建立耐去势转移性前列腺癌(MCRPC)模型以寻找治疗前列腺癌的新方法 这种致命的癌症。前列腺癌TCGA的研究进展已证明具有统计学意义的共同作用。 RB1和TP53在mCRPC中的出现，为我们提出的研究提供了理论基础。新兴市场 癌症有机体系统已经建立了六个mCRPC有机类群的资源，我们已经建立了 小鼠前列腺癌有机化合物将我们的小鼠模型结果翻译成人类mCRPC并排在 有机平台。在本申请中，我们建议确定靶向Skp2/Cks1口袋的可能性 抑制小鼠DKO前列腺癌的发生并将研究结果翻译给人的mCRPC 免疫受损小鼠的平台和类器官细胞转移分析(特定目标1)，以及 Skp2功能在促进DKO前列腺Warburg效应中的作用及机制研究 小鼠肿瘤发生及联合抑制LDHA和Skp2/Cks1的作用 DKO前列腺癌的发生及其在器官和转移分析中对人类mCRPC的影响 (具体目标2)。

Abstract Cancer therapies targeting a specific signaling pathway (targeted therapy) in a specific tumor (personalized therapy) are the current “state-of-the-art”, while treatment and management for advanced cancer remain the barrier to overall cancer treatment success. One common feature of advanced cancer is frequent genetic inactivation of pRb and p53, the two major tumor suppressors. Finding effective treatments for these cancers depends on finding antitumor mechanisms that remain effective when both pRb and p53 are genetically inactivated. We have succeeded in blocking pRb and p53 doubly deficient tumorigenesis in mouse tumor models by deleting Skp2. We now propose to use pRb and p53 doubly deficient prostate tumorigenesis in mice to model metastatic castration resistant prostate cancer (mCRPC) in patients to identify new treatment for this lethal cancer. The advance in TCGA of prostate cancer has documented statistically significant co- occurrences of RB1 and TP53 in mCRPC, providing the rationale for our proposed studies. The emerging cancer organoids system has established a resource of six mCRPC organoid lines and we have established mouse prostate tumor organoids to translate our mouse model findings to human mCRPC side-by-side on the organoid platform. In this application, we propose to determine the potential of targeting the Skp2/Cks1 pocket to inhibit mouse DKO prostate tumorigenesis and translate the findings to human mCRPC on organoid platform followed by metastasis assay with organoid cells in immune compromised mice (Specific Aim 1), and to determine mechanism and role of Skp2 function in promoting Warburg effects in DKO prostate tumorigenesis and determine the effects of inhibiting LDHA and Skp2/Cks1 pocket in combination in mouse DKO prostate tumorigenesis and translate the finding to human mCRPC in organoids and in metastasis assays (Specific Aim 2).