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: 7910721
• 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/7910721
• 关键词: Address; Androgen Antagonists; Androgens; Antineoplastic Agents; Apoptosis; Apoptotic; Award; Behavior; Biological; Cancer Patient; Castration; Cell Line; Cells; Clinical; Clinical Trials; Cytotoxic Chemotherapy; DU145; Development; Disease; Drug Delivery Systems; Empiricism; Goals; Growth Factor; Hormones; Human; Immune; In Vitro; Knowledge; LAPC4; LNCaP; Laboratories; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Mus; Neurosecretory Systems; Outcome; PC3 cell line; Pathway interactions; Patients; 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; Work; Xenograft Model; Xenograft procedure; abstracting; advanced disease; androgen independent prostate cancer; angiogenesis; base; cancer cell; cancer therapy; chemotherapy; clinically relevant; deprivation; disorder control; docetaxel; effective therapy; improved; in vivo; inhibitor/antagonist; men; neoplastic cell; novel; novel strategies; preclinical study; response; response marker; standard care; taxane; therapy outcome; tumor; tumor progression

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.

抽象的： 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 用于治疗在主要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 疾病晚期。尽管 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 他们患上去势抵抗性前列腺癌（CRPC），治疗选择有限。化疗有 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 多西他赛化疗。因此，迫切需要开发更有效的 PC 治疗方法。过去 二十年来，癌症治疗模式发生了重大变化。抗癌药不再是 是基于经验主义而开发的，但现在的目的是抑制相对而言有效的目标 对肿瘤细胞有特异性。然而，在 PC 方面，缺乏新颖的靶向药物。事实上，除了反 雄激素、靶向治疗对于这种疾病基本上是不存在的。 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细胞中选出的。 由于 ADT 的目标是 AS 癌细胞，因此 注定会失败。 因此，为了实现最佳的疾病控制，AS 和 AI 细胞都需要有效地靶向。在下面 在正在进行的优秀评审奖的主持下，与我们最初的假设一致，我们确定 多西紫杉醇继之以 ADT 的序贯治疗在异种移植模型轴承中提供了最佳结果 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，表明其他靶点需要与化学激素治疗相结合以提高疗效。 我们实验室使用转基因 TRAMP 模型进行的其他研究评估了 ADT 和 多西紫杉醇具有抗肿瘤活性和神经内分泌分化作用。 此外，我们最初在 体外研究表明，在某些条件下，PC 细胞中 ERK 和/或 Akt 依赖性途径的募集 雄激素剥夺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 异种移植物中 ADT 后。 总而言之，这些研究提供了额外的潜在目标 治疗干预。我们续展申请的目的是在这项工作的基础上进行系统的研究 ADT 条件下招募 ERK 和 Akt 依赖性途径的潜在机制， 体外人 PC 细胞的雄激素抵抗、多西他赛治疗和多西他赛抵抗，并进行评估 这些途径的特定抑制剂作为单一药物以及与 ADT 的某些组合的效果 多西紫杉醇。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， 特别是序贯化学激素治疗的支柱。我们认为该提案的优势在于 它具有直接的临床相关性，我们之前的临床前研究强调了这一点 已成功转化为两项针对激素敏感性复发性 PC 男性的临床试验。