Scr as a Therapeutic Target in Prostate Cancer Bone Metastases

说明）： 目前主要针对原发性肿瘤或保留骨的PCa治疗策略仅 适度影响生存。多年来，该实验室和合作者的重点一直是Src 家族激酶（SFKs），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 生长在骨头里。该项目将测试中心假设，使用Src的治疗策略 目前在临床试验中的抑制剂将证明在治疗前列腺癌转移中有效。 骨头这一假设的理论基础是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，并且部分基于正在进行的转移性前列腺I/II期临床试验的前景。 使用达沙替尼（SFK/AbI抑制剂）和多西他赛的组合治疗癌症。这个项目将联合收割机 在临床前小鼠模型系统中采用基于机制的策略， 宿主和肿瘤细胞中的Src有助于骨生长，使用dasafinib进行III期临床试验。 具体目的是：（1）确定SFK抑制在肿瘤细胞、宿主细胞以及两者中的作用， （2）检测PCa细胞在裸鼠皮下注射后对PCa细胞生长的影响 在肿瘤和宿主中与达沙替尼的有效性相关;以及（3）将这些知识与 在选定去势患者中使用达沙替尼联合多西他赛的III期试验 耐药前列腺癌和骨转移，Src和骨的分子标记物的相关变化 保存与疾病的临床过程。该试验将作为一个平台， 活化，骨转换标志物的基线和系列变化。因此，项目3中的实验 是新颖的，因为他们建立在一个有前途的治疗策略，我们也认为这是一种替代性的， 增加对Src在肿瘤/骨相互作用中作用的了解将有助于指导临床试验设计， 临床试验将有助于完善临床前研究中的疾病模型。 相关性（参见说明）： 目前，不存在用于治疗晚期前列腺癌（即，具有前列腺增生的癌症）的成功疗法。 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， 影响肿瘤生长和肿瘤与其环境的相互作用。在这个项目中， 我们将采用基本的科学策略来理解Src的哪些功能对这一过程至关重要， 在III期临床试验中使用这些知识来设计更好的前列腺癌治疗方法。

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.