Dissecting Skp2 functions in pRb and p53 doubly deficient tumorigenesis

剖析 Skp2 在 pRb 和 p53 双缺陷肿瘤发生中的功能

• 批准号: 10023167
• 负责人: EDWARD L SCHWARTZ
• 金额: $ 38.2万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-03 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023167
• 关键词: 3-Dimensional; Acinus organ component; Advanced Malignant Neoplasm; Affect; Biological Assay; Cancer Patient; Cancer cell line; Castration; Cells; Clinical Trials; Collection; Combined Modality Therapy; Cyclin D1; DNA Sequence Alteration; DU145; Databases; Disabled Persons; Epithelial; Epithelium; Event; Genetic; Genome; Goals; Human; Immune; Joints; Knock-in; Knowledge; Life; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic to; Modeling; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Organoids; PTEN gene; Pathway interactions; Patients; Pharmacology; Play; Predictive Value; Prostate; Prostatic Neoplasms; Proteins; RB1 gene; Recurrence; Resistance; Resources; Retinoblastoma Protein; Role; Sampling; Side; Signal Pathway; Structure; System; TP53 gene; Test Result; The Cancer Genome Atlas; Therapeutic; Translating; Tumor Suppressor Proteins; Tumor-Derived; Ubiquitination; Warburg Effect; Xenograft procedure; cancer genome; cancer therapy; castration resistant prostate cancer; cohort; effective therapy; experimental study; human model; improved; inhibitor/antagonist; mouse genetics; mouse model; neoplastic cell; novel therapeutic intervention; personalized medicine; prostate cancer cell line; prostate carcinogenesis; recruit; side effect; small molecule inhibitor; success; targeted cancer therapy; targeted treatment; theories; therapeutic evaluation; therapy resistant; treatment strategy; tumor; tumorigenesis

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).

摘要 针对特定肿瘤中特定信号通路的癌症治疗（靶向治疗）（个性化） 治疗）是目前的“最先进的”，而晚期癌症的治疗和管理仍然是 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性 pRb和p53这两种主要的肿瘤抑制因子的失活。为这些癌症寻找有效的治疗方法 这取决于找到当pRb和p53基因都被抑制时仍然有效的抗肿瘤机制。 灭活我们成功地阻断了小鼠肿瘤中pRb和p53双重缺陷的肿瘤发生 通过删除Skp 2模型。我们现在建议使用pRb和p53双重缺陷的前列腺肿瘤发生， 小鼠在患者中建立转移性去势抵抗性前列腺癌（mCRPC）模型，以确定新的治疗方法， 这种致命的癌症前列腺癌TCGA的进展记录了统计学显著的共同作用， RB 1和TP 53在mCRPC中的发生率，为我们拟定的研究提供了依据。新兴 癌症类器官系统已经建立了六个mCRPC类器官系的资源，我们已经建立了 小鼠前列腺肿瘤类器官，将我们的小鼠模型结果转化为人mCRPC， 类器官平台在本申请中，我们建议确定靶向Skp 2/Cks 1口袋的潜力 抑制小鼠DKO前列腺肿瘤发生并将结果转化为类器官上的人mCRPC 平台，然后在免疫受损小鼠中用类器官细胞进行转移测定（特异性目标1），和 确定Skp 2功能在DKO前列腺中促进瓦尔堡效应的机制和作用 肿瘤发生并确定联合抑制LDHA和Skp 2/Cks 1口袋对小鼠的影响 DKO前列腺肿瘤发生，并在类器官和转移试验中将发现转化为人mCRPC （具体目标2）。