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: 8597341
• 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/8597341
• 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 Targeting; 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; castration resistant prostate cancer; chemotherapy; clinically relevant; deprivation; disorder control; docetaxel; effective therapy; improved; in vivo; inhibitor/antagonist; men; neoplastic cell; novel; novel strategies; preclinical study; prostate cancer cell; 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.

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 用于治疗原发性局部治疗后复发的男性，并与放射联合治疗局部 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 他们发展为去势抵抗性前列腺癌（CRPC），治疗选择是有限的。化疗已 在转移性CRPC患者中获益有限，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。抗癌药物不再是 开发的基础上，抗生素，但现在的目的是抑制验证的目标， 对肿瘤细胞有特异性。然而，在PC中，缺乏新的靶向药物;事实上，除了抗- 雄激素，靶向治疗基本上不存在于这种疾病。 临床前模型表明， 雄激素敏感性（AS）和雄激素非依赖性（AI）PC细胞可以从一开始就存在，和/或 AI癌细胞在ADT过程中从AS细胞中选择。 由于ADT靶向AS癌细胞， 注定要失败 因此，为了最佳的疾病控制，AS和AI细胞都需要被有效地靶向。下 正在进行的优秀评审奖的赞助，与我们最初的假设一致，我们已经确定 多西他赛序贯治疗后ADT在异种移植模型中提供了最佳结局， 雄激素敏感PC细胞。然而，即使是最佳的化学激素治疗也会随着时间的推移而失败， 模型，这表明其他目标需要与化学激素治疗相结合，以提高结果。 我们实验室中使用转基因TRAMP模型的其他研究已经评估了ADT的作用， 多西他赛的抗肿瘤活性和神经内分泌分化。 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，血管生成似乎很快被激活， 在LNCaP异种移植物中ADT后。 总之，这些研究提供了额外的潜在目标， 治疗干预我们在更新申请中的目的是在这项工作的基础上系统地研究 ADT条件下ERK和Akt依赖性通路募集的潜在机制， 雄激素抵抗，多西他赛治疗和多西他赛耐药的人PC细胞在体外，并评估 这些途径的特异性抑制剂作为单一药物以及与ADT的某些组合的作用， 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， 特别是序贯化学激素治疗的基础。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，我们以前的临床前研究强调了这一点， 已成功转化为两个临床试验的男性激素敏感性复发性PC。