Scr as a Therapeutic Target in Prostate Cancer Bone Metastases

Scr 作为前列腺癌骨转移的治疗靶点

• 批准号: 7743206
• 负责人: GARY E GALLICK
• 金额: $ 25.11万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743206
• 关键词: Affect; American; Basic Science; Binding Sites; Biological Models; Biopsy; Bone neoplasms; Bone remodeling; Cancer Center; Case Study; Cells; Cessation of life; Clinical; Clinical Course of Disease; Clinical Markers; Clinical Trials; Clinical Trials Design; Complex; Dasatinib; Data; Diagnosis; Disease model; Effectiveness; Environment; Goals; Growth; Heterogeneity; Implant; Injection of therapeutic agent; Knowledge; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular; Mus; Neoplasm Metastasis; Nude Mice; Osteoblasts; Osteoclasts; Osteogenesis; Patient Selection; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Play; Primary Neoplasm; Process; Property; RNA Interference; Reproduction spores; Research Design; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction Pathway; Staging; Stromal Cells; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; Tumor Volume; base; bone; bone cell; bone preservation; bone turnover; candidate marker; cell growth; design; docetaxel; efficacy testing; experience; improved; inhibitor/antagonist; insight; male; molecular marker; mouse model; neoplastic cell; novel; pre-clinical; preclinical study; prognostic; research study; response; src-Family Kinases; therapeutic target; tissue resource; tumor; tumor growth

Instnjctions): Current strategies for PCa treatment that target primarily the primary tumor or preserve bone have only modestly affected survival. The focus of this laboratory and collaborators for many years has been on Src family kinases (SFKs), the activation of which not only contribute to PCa metastasis in mouse models, by affecfing tumor cells, osteoclasts, osteoblasts and interacfions between these cells required for tumor cell growth in the bone. This project will test the central hypothesis that therapeutic strategies using Src inhibitors currently in clinical trial will prove efficacious in the treatment of PCa metastases in the bone. The rafionale for this hypothesis is that Src regulates signaling pathways both in tumor cells and in their microenvironment that contribute to the "vicious cycle" of bone formafion, degradation and tumor growth, and is based, in part, on the promise of an ongoing phase l/ll clinical trial for metastafic prostate cancer using the combinafion of dasafinib (an SFK/AbI inhibitor) and docetaxel. This project will combine mechanistic-based strategies in preclinical mouse model systems to examine the specific contributions of Src in the host and tumor cell contribufing to growth in the bone with a phase III clinical trial using dasafinib. The specific aims are to: (1) Determine the role of SFK inhibition in tumor cells, host cells, and both in affecting growth of PCa cells following intrafibial injecfion into nude mice; (2) Determine molecular alterafions in the tumor and host correlating with the effectiveness of dasatinib; and (3) Integrate this knowledge with a phase III trial using dasatinib in combinafion with docetaxel in a phase III trial in select pafients with castrate resistant prostate cancer and bone metastases, correlate changes in molecular markers of Src and bone preservation with clinical course of the disease. The trial will serve as a platform to associate markers of Src activation, with baseline and serial change(s) in bone turnover markers. Thus, the experiments in Project 3 are novel in that they build on a promising therapeutic strategy, which we also view as reiterative, where our increased knowledge of Src's effects in tumor/bone interacfion will help dictate clinical trial design, and the clinical trials will help refine modeling the disease in preclinical studies. RELEVANCE (See instnjctions): Currently, no successful therapies exist for the treatment of late-stage prostate cancer (i.e. cancer that has metastasized, especially to the bone). However recent early-stage clinical trials using inhibitors of Src, which affects both tumor growth and interaction of tumor with its environment, have been promising. In this project, we will employ basic science strategies to understand which Src functions are crifical to this process, and use this knowledge in a phase III clinical trial to design better treatments for prostate cancer.

指令）： 目前主要针对原发肿瘤或保留骨骼的 PCa 治疗策略仅 对生存影响不大。该实验室和合作者多年来的重点一直是 Src 家族激酶 (SFK)，其激活不仅有助于小鼠模型中的 PCa 转移， 影响肿瘤细胞、破骨细胞、成骨细胞以及肿瘤细胞所需的这些细胞之间的相互作用 骨骼中的生长。该项目将测试中心假设，即使用 Src 的治疗策略 目前正在进行临床试验的抑制剂将被证明对治疗前列腺癌转移有效 骨。这一假设的基本原理是 Src 调节肿瘤细胞和肿瘤细胞中的信号通路。 它们的微环境导致骨形成、降解和肿瘤的“恶性循环” 生长，部分基于正在进行的转移性前列腺的 l/ll 期临床试验的承诺 使用达沙非尼（一种 SFK/AbI 抑制剂）和多西紫杉醇的组合来治疗癌症。该项目将结合 临床前小鼠模型系统中基于机制的策略，以检查以下因素的具体贡献 使用达沙非尼进行的 III 期临床试验显示宿主和肿瘤细胞中的 Src 有助于骨骼中的生长。 具体目标是：（1）确定SFK抑制在肿瘤细胞、宿主细胞以及两者中的作用。 裸鼠腓骨内注射后影响PCa细胞的生长； (2) 确定分子改变 在肿瘤和宿主中与达沙替尼的有效性相关； (3) 将这些知识与 在选定的去势患者中进行的 III 期试验，使用达沙替尼联合多西紫杉醇进行的 III 期试验 耐药性前列腺癌和骨转移，Src 和骨分子标志物的变化相关 保存与临床病程有关。该试验将作为关联 Src 标记的平台 激活，骨转换标志物的基线和系列变化。因此，项目3中的实验 新颖之处在于它们建立在一种有前途的治疗策略之上，我们也认为这种策略是重复的，我们的 增加对 Src 在肿瘤/骨相互作用中的影响的了解将有助于指导临床试验设计，并且 临床试验将有助于完善临床前研究中的疾病建模。 相关性（参见说明）： 目前，尚无成功的疗法可用于治疗晚期前列腺癌（即已发生癌症的癌症） 转移，尤其是骨转移）。然而最近使用 Src 抑制剂的早期临床试验， 影响肿瘤生长以及肿瘤与其环境的相互作用，这一点很有希望。在这个项目中， 我们将采用基本科学策略来了解哪些 Src 函数对此过程至关重要，并且 在 III 期临床试验中利用这些知识来设计更好的前列腺癌治疗方法。