Evaluating a Novel Strategy to Target Trop2 in Prostate Cancer

患有晚期前列腺癌的男性接受激素治疗，这导致了最初的反应，这种反应不可避免地以称为去势抵抗性前列腺癌（CRPC）的致命形式复发。虽然雄激素信号传导轴是该领域治疗的主要靶点，但需要鉴定独立于AR轴的促进存活和增殖的途径以用于有效的组合治疗策略。重要的是，旨在消耗干/祖细胞机制（如自我更新）的疗法尚未得到充分探索。我们最近发现，干细胞标志物Trop 2是前列腺自我更新和增殖的新调节因子，与去势抵抗状态密切相关。我们已经定义了Trop 2通过调节蛋白水解的作用机制，导致细胞内结构域的释放，类似于Notch的激活。由于Trop 2标记和调节干细胞，并与去势抵抗相关，我们建议阻断Trop 2蛋白水解/激活将抑制干细胞样能力，包括自我更新和增殖，并防止疾病复发。在这项提案中，我们将利用临床标本，原发性再生肿瘤和已建立的癌症异种移植物来评估Trop 2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的目标是通过测量前列腺癌受试者中的Trop 2、其蛋白水解产物和下游效应物来验证Trop 2作为临床前列腺癌样本中的靶标。AIM 2的目标是确定Trop 2在人前列腺自我更新和肿瘤发生中的作用，使用解离的细胞组织重组策略来评估Trop 2+细胞和Trop 2本身在体内遗传定义的原发性肿瘤中的作用。AIM 3的目标是在临床前研究中研究靶向Trop 2的机制。这些实验将利用遗传和化学方法来确定Trop 2调节蛋白水解的作用，并评估单克隆抗体干扰Trop 2加工和肿瘤生长的能力。

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.