Scr as a Therapeutic Target in Prostate Cancer Bone Metastases

实例)： 目前主要针对原发肿瘤或保留骨骼的PCA治疗策略 对存活率影响不大。多年来，本实验室和合作者一直将重点放在Src 家族激酶(SFK)的激活不仅有助于小鼠模型中的PCa转移，还通过 影响肿瘤细胞、破骨细胞、成骨细胞及肿瘤细胞所需的这些细胞之间的相互作用 在骨骼中生长。该项目将检验中心假设，即使用Src的治疗策略 目前处于临床试验中的抑制剂将被证明对治疗前列腺癌转移瘤有效 骨头。支持这一假说的理由是，Src调节肿瘤细胞和肿瘤细胞中的信号通路。 它们的微环境促成了骨形成、降解和肿瘤的“恶性循环” 增长，部分是基于正在进行的L/11期转移性前列腺癌临床试验的承诺 Dasafinib(一种SFK/ABI抑制剂)和多西紫杉醇联合治疗癌症。这个项目将结合 在临床前小鼠模型系统中基于机制的策略，以检查 在使用Dasafinib的III期临床试验中，宿主和肿瘤细胞中的SRC对骨骼中的生长做出了贡献。 其具体目的是：(1)确定SFK抑制在肿瘤细胞、宿主细胞以及两者中的作用。 腓骨内注射对前列腺癌细胞生长的影响；(2)分子生物学研究 在肿瘤和宿主中与达沙替尼的有效性相关；以及(3)将这一知识与 达沙替尼联合多西紫杉醇的III期试验，用于部分去势患者的III期试验 耐药前列腺癌与骨转移相关的src和骨分子标志物的变化 保存与本病的临床病程有关。该试验将作为关联Src标记物的平台 骨转换标志物的激活、基线和系列变化(S)。因此，项目3中的实验 是新颖的，因为它们建立在一种有希望的治疗策略上，我们也认为这是反复的，我们的 增加对Src在肿瘤/骨相互作用中的作用的了解将有助于指导临床试验设计，并且 临床试验将有助于在临床前研究中改进疾病的建模。 相关性(请参阅实例)： 目前，还没有成功的疗法来治疗晚期前列腺癌(即 转移的，尤其是骨转移的)。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环境的相互作用，已有很好的应用前景。在这个项目中， 我们将使用基础科学策略来了解哪些Src功能对这一过程至关重要，以及 在III期临床试验中利用这一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.