Evaluating a Novel Strategy to Target Trop2 in Prostate Cancer

评估针对前列腺癌中 Trop2 的新策略

• 批准号: 9131627
• 负责人: OWEN N. WITTE
• 金额: $ 24.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9131627
• 关键词: Androgens; Antibodies; Binding; Biological Markers; Blood Circulation; Bypass; Castration; Cells; Clinical; Clinical Trials; Disease; Disease Outcome; Future; Genetic; Goals; Growth; Human; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Molecular; Molecular Profiling; Monoclonal Antibodies; Mus; Natural regeneration; Neoplasm Circulating Cells; Pathway interactions; Patients; Phosphotransferases; Primary Neoplasm; Process; Prostate; Proteolysis; Proteolytic Processing; Radical Prostatectomy; Recurrence; Resistance; Role; Signal Transduction; Specificity; Specimen; Stem cells; Therapeutic; Tissue Microarray; Tissue Recombination; Tissues; Xenograft procedure; advanced disease; animal imaging; castration resistant prostate cancer; chemical genetics; combat; combinatorial; defined contribution; extracellular; gamma secretase; hormone therapy; in vivo; men; mutant; notch protein; novel strategies; preclinical study; prevent; progenitor; prostate cancer cell; research study; resistance mechanism; response; self-renewal; small molecule; stem; targeted treatment; therapeutic target; tumor; tumor growth; tumor progression; tumorigenesis

Men with advanced prostate cancer are treated with hormonal therapy, which leads to an initial response that inevitably recurs in the lethal form of the disease termed castration-resistant prostate cancer (CRPC). While the androgen-signaling axis is the predominant target for therapy in the field, pathways promoting survival and proliferation that are independent of the AR axis need to be identified for potent combinatorial therapeutic strategies. Importantly, therapies aimed at depleting stem/progenitor cell mechanisms, such as self-renewal, have not been adequately explored. We have recently discovered that the stem cell marker Trop2 is a new regulator of self-renewal and proliferation in the prostate and is strongly associated with a castration-resistant state. We have defined a mechanism of action for Trop2 through regulated proteolysis, leading to release of an intracellular domain, similar to activation of Notch. As Trop2 marks and regulates stem cells and is associated with castration-resistance, we propose that blocking Trop2 proteolysis/ activation will inhibit stem-like capacities including self-renewal and proliferation and prevent disease-recurrence. In this proposal, we will utilize clinical specimens, primary regenerated tumors and established cancer xenografts to evaluate Trop2 proteolytic processing as a therapeutic target for future clinical trials in prostate cancer. The goal of AIM 1 is to validate Trop2 as a target in clinical prostate cancer specimens by measuring Trop2, its proteolytic products and downstream effectors in prostate cancer subjects. The goal of AIM 2 is to determine the role of Trop2 in human prostate self-renewal and tumorigenesis, using a dissociated cell tissue recombination strategy to evaluate Trop2+ cells and Trop2 itself in genetically defined primary tumors in vivo. The goal of AIM 3 is to investigate mechanisms to target Trop2 in pre-clinical studies. These experiments will utilize genetic and chemical approaches to establish the role of Trop2 regulated proteolysis, and assess monoclonal antibodies for their ability to interfere with Trop2 processing and tumor growth.

患有晚期前列腺癌的男性接受了荷尔蒙治疗治疗，这导致最初的反应，不可避免地会以称为cast割的前列腺癌（CRPC）的疾病的致命形式复发。虽然雄激素信号轴是该领域治疗的主要靶标，但需要确定促进与AR轴无关的生存和增殖的途径，需要确定有效的组合治疗策略。重要的是，旨在耗尽茎/祖细胞机制（例如自我更新）的疗法尚未得到充分探索。我们最近发现，干细胞标记物trop2是前列腺中自我更新和增殖的新调节剂，并且与cast割耐药性状态密切相关。我们通过调节的蛋白水解定义了Trop2的作用机理，导致细胞内结构域的释放，类似于Notch的激活。随着Trop2标记并调节干细胞，并与cast割抗性有关，我们建议阻止Trop2蛋白水解/激活将抑制类似茎样能力，包括自我更新和增殖，并预防疾病疾病。在此提案中，我们将利用临床标本，原发性再生肿瘤和确定的癌症异种移植物来评估Trop2蛋白水解加工作为前列腺癌未来临床试验的治疗靶点。 AIM 1的目的是通过测量Trop2，其蛋白水解产物和前列腺癌受试者的下游效应子来验证Trop2作为临床前列腺癌标本的靶标。目标2的目的是使用解离的细胞组织重组策略来确定trop2在人前列腺自我更新和肿瘤发生中的作用，以评估trop2+细胞和trop2本身在体内遗传定义的原发性肿瘤中。目标3的目的是研究临床前研究中靶向trop2的机制。这些实验将利用遗传和化学方法来确定Trop2调节的蛋白水解的作用，并评估单克隆抗体的能力，以干扰Trop2加工和肿瘤生长。