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

前列腺癌临床前模型中多模式治疗的优化

• 批准号: 7792273
• 负责人: Arif Hussain
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792273
• 关键词: Address; Aging; Androgen Antagonists; Androgens; Antineoplastic Agents; Apoptosis; Apoptotic; Award; Behavior; Biological; Cancer Patient; Castration; Cell Culture Techniques; Cell Line; Cells; Clinical; Clinical Trials; Cytotoxic Chemotherapy; DU145; Development; Disease; Drug Delivery Systems; Empiricism; General Population; Goals; Growth Factor; Healthcare; Hormones; Human; Immune; In Vitro; Knowledge; LAPC4; LNCaP; Laboratories; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Metastatic/Recurrent; Mission; Modeling; Mus; Neurosecretory Systems; Outcome; PC3 cell line; Pathway interactions; Patients; Population; Pre-Clinical Model; Procedures; Prostate Cancer therapy; Radiation; Recruitment Activity; Recurrence; Regimen; Relapse; Resistance; Sequential Treatment; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Structure of base of prostate; Taxane Compound; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; Translating; Treatment Effectiveness; Treatment Protocols; Tumor Tissue; Vertebral column; Veterans; Work; Xenograft Model; Xenograft procedure; advanced disease; androgen independent prostate cancer; angiogenesis; base; cancer cell; cancer therapy; chemotherapy; clinically relevant; deprivation; disorder control; docetaxel; effective therapy; hormone therapy; improved; in vivo; inhibitor/antagonist; men; mouse model; neoplastic cell; novel; novel strategies; preclinical study; public health relevance; response; response marker; standard care; taxane; therapy outcome; tumor; tumor progression

DESCRIPTION (provided by applicant): 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 chemo-hormone 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. PUBLIC HEALTH RELEVANCE: The leading cancer in men in the U.S. is prostate cancer. It is also a leading cancer in our aging Veteran population. To date, there are no curative treatments for advanced stages of prostate cancer, including recurrent and metastatic disease. Although hormone therapy and chemotherapy can palliate prostate cancer, they are generally not curative. This proposal will analyze systematically how to improve the treatment of prostate cancer by targeting additional pathways activated in this disease in specific combinations with chemotherapy and hormone therapy. Both cell culture and mouse models will be used. These studies will provide novel information on how to develop more effective treatment regimens for prostate cancer. Thus, the proposal is highly relevant to the healthcare mission of the Department of Veterans Affairs as well as the healthcare of the general population.

描述(由申请人提供)： 治疗转移性前列腺癌(PC)的标准方法是雄激素剥夺(ADT)。ADT还用于治疗在接受初级局部治疗后复发的男性，以及与放射治疗相结合的局部晚期疾病男性。虽然ADT非常有效，但随着时间的推移，它总是会失败。在患者ADT失败后，即一旦他们患上耐去势前列腺癌(CRPC)，治疗选择就有限了。化疗对转移性CRPC患者的益处有限，在一线多西紫杉醇化疗后没有有效的二线治疗方法。因此，迫切需要开发更有效的治疗PC的方法。在过去的二十年里，癌症治疗模式发生了重大变化。抗癌药物的开发不再基于经验论，而是现在的目标是抑制对肿瘤细胞相对特异的有效靶点。然而，在PC中，缺乏新的靶向药物；事实上，除了抗雄激素外，这种疾病基本上不存在靶向治疗。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，它注定要失败。因此，为了最佳的疾病控制，AS和AI细胞都需要有效地靶向。在正在进行的功绩评审奖的支持下，与我们最初的假设一致，我们确定在携带雄激素敏感的PC细胞的异种移植模型中，多西紫杉醇和ADT的序贯治疗提供了最佳结果。然而，在这个模型中，即使是最理想的化疗激素治疗也会随着时间的推移而失败，这表明需要将其他靶点与化疗激素治疗结合起来，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和多西紫杉醇在抗肿瘤活性和神经内分泌分化方面的效果。此外，我们的初步体外研究表明，在某些雄激素剥夺和紫杉烷暴露的条件下，依赖ERK和/或Akt的通路在PC细胞中招募。最后，血管生成似乎在ADT后不久在LNCaP异种移植中被激活。综上所述，这些研究为治疗干预提供了额外的潜在靶点。我们更新应用的目的是在这项工作的基础上，系统地研究在ADT、雄激素耐药、多西紫杉醇治疗和多西紫杉醇耐药条件下，ERK和Akt依赖的通路在体外人PC细胞中招募的机制，并评价这些通路的特定抑制剂作为单一药物以及与ADT和多西紫杉醇联合使用的效果。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，特别是序贯化疗激素治疗的主干。我们认为这项建议的一个优点是它具有直接的临床相关性，这一点得到了强调，因为我们之前的临床前研究已经成功地转化为两项针对激素敏感型复发性PC男性的临床试验。 公共卫生相关性： 在美国，男性的主要癌症是前列腺癌。在我们老龄化的退伍军人中，它也是一种主要的癌症。到目前为止，还没有针对晚期前列腺癌的根治方法，包括复发和转移性疾病。虽然激素治疗和化疗可以缓解前列腺癌，但它们通常不能治愈。这项提案将系统地分析如何通过将前列腺癌中激活的额外通路与化疗和激素治疗结合起来，来改善前列腺癌的治疗。将同时使用细胞培养和小鼠模型。这些研究将为如何开发更有效的前列腺癌治疗方案提供新的信息。因此，该提案与退伍军人事务部的医疗保健任务以及普通民众的医疗保健高度相关。