Optimization of Multi-Modal Therapies in Pre-clinical models of Prostate Cancer

摘要： 治疗转移性前列腺癌(PC)的标准方法是雄激素剥夺(ADT)。ADT也是 用于治疗在初级局部治疗后复发的男性，并与放射治疗相结合，治疗局部复发的男性 晚期疾病。虽然ADT非常有效，但随着时间的推移，它总是会失败。患者ADT失败后，即一次 他们患上耐去势前列腺癌(CRPC)，治疗选择有限。化疗已经有了 对转移性CRPC患者的益处有限，一线治疗后不存在有效的二线治疗 多西紫杉醇化疗。因此，迫切需要开发更有效的治疗PC的方法。过去的事 二十年来，癌症治疗模式发生了重大变化。抗癌药物不再是 基于经验主义开发的，但现在的目标是抑制验证的目标，这些目标相对 对肿瘤细胞有特异性。然而，在个人电脑中，缺乏新的、有针对性的药物；事实上，除了抗病毒药物 在这种疾病中，雄激素、靶向治疗基本上是不存在的。临床前模型表明 雄激素敏感(AS)和雄激素非依赖性(AI)PC细胞可能从一开始就存在和/或 AI癌细胞是在ADT过程中从AS细胞中挑选出来的。由于ADT以癌细胞为靶点，所以它是 注定要失败。因此，为了最佳的疾病控制，AS和AI细胞都需要有效地靶向。在……下面 正在进行的功绩评审奖的赞助，与我们最初的假设一致，我们决定 在异种移植模型中，多西紫杉醇和ADT的序贯治疗提供了最好的结果 雄激素敏感的PC细胞。然而，即使是最理想的化学激素治疗也会随着时间的推移而失败。 模型，这表明其他靶点需要与化疗激素治疗相结合，以提高结果。 我们实验室用转基因TRAMP模型进行的其他研究已经评估了ADT和 多西紫杉醇的抗肿瘤活性和神经内分泌分化。此外，我们的初始入站 体外研究表明，在特定的条件下，PC细胞中ERK和/或Akt依赖的通路被募集 雄激素缺乏和紫杉烷暴露的条件。最后，血管生成似乎很快就会被激活 LNCaP异种移植的ADT后。综上所述，这些研究提供了额外的潜在目标 治疗性干预。我们申请续签的目的是在这项工作的基础上进行系统的研究 ADT条件下ERK和Akt依赖通路的募集机制， 雄激素耐药、多西紫杉醇处理及多西紫杉醇耐药人PC细胞的体外研究 这些通路的特定抑制剂作为单一药物以及与ADT和ADT联合使用的效果 多西他赛。我们将把这项工作扩展到体内异种移植模型，目标是优化抗肿瘤活性， 尤其是序贯化疗激素治疗的主干。我们认为这一提议的一个优点是 它具有直接的临床相关性，这一点从我们之前的临床前研究中得到了强调 已成功转化为两项针对男性激素敏感型复发性PC的临床试验。

Abstract: The standard approach for treating metastatic prostate cancer (PC) is androgen deprivation (ADT). ADT is also used to treat men relapsing after primary local therapies and, in combination with radiation, men with locally advanced disease. Although highly effective, ADT invariably fails over time. After patients fail ADT, i.e. once they develop castration resistant prostate cancer (CRPC), therapeutic options are limited. Chemotherapy has provided limited benefit in metastatic CRPC patients, and no effective second-line therapies exist after first line docetaxel chemotherapy. Thus, there is an urgent need to develop more effective treatments for PC. The past two decades have seen a major change in cancer treatment paradigms. Anti-cancer agents are no longer being developed based on empiricism, but are now being aimed to inhibit validated targets that are relatively specific for tumor cells. In PC, however, there is a paucity of novel, targeted drugs; in fact, other than anti- androgens, targeted therapies are essentially non-existent in this disease. Pre-clinical models suggest that androgen-sensitive (AS) and androgen-independent (AI) PC cells may be present from the very outset and/or AI cancer cells are selected from AS cells during the course of ADT. Since ADT targets AS cancer cells, it is destined to fail. Thus, for optimal disease control, both AS and AI cells need to be targeted effectively. Under the auspices of the ongoing Merit Review Award, consistent with our original hypothesis, we have determined that sequential treatment of docetaxel followed by ADT provides the best outcomes in xenograft models bearing androgen-sensitive PC cells. However, even the most optimal chemohormone treatments fail over time in this model, suggesting that other targets need to be integrated with chemohormone therapy to enhance outcomes. Other studies in our laboratory with the transgenic TRAMP model have evaluated the effects of ADT and docetaxel with respect to anti-tumor activity and neuroendocrine differentiation. In addition, our initial in vitro studies demonstrate recruitment of ERK- and/or Akt-dependent pathways in PC cells under certain conditions of androgen deprivation and taxane exposure. Finally, angiogenesis appears to be activated soon after ADT in LNCaP xenografts. Taken together, these studies provide additional potential targets for therapeutic intervention. Our aim in the renewal application is to build on this work and study systematically the mechanisms underlying the recruitment of ERK- and Akt-dependent pathways under conditions of ADT, androgen resistance, docetaxel treatment and docetaxel resistance in human PC cells in vitro, and to evaluate the effects of specific inhibitors of these pathways as single agents and in certain combinations with ADT and docetaxel. We will extend this work to in vivo xenograft models, with the goal to optimize anti-tumor activity, particularly of the sequential chemohormone therapy backbone. We believe a strength of this proposal is that it has direct clinical relevance, which is underscored by the fact that our previous pre-clinical studies have been successfully translated to two clinical trials in men with hormone sensitive recurrent PC.