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: 8321883
• 负责人: GARY E GALLICK
• 金额: $ 24.97万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8321883
• 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; Regimen; Research Design; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction Pathway; Staging; Stromal Cells; Testing; Therapeutic; Time; Toxic effect; 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; phase 3 study; 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.

Instnjctions）： 主要针对主要肿瘤或保留骨的PCA治疗的当前策略仅具有 适度影响生存。这个实验室和合作者的重点已经多年了 家族激酶（SFK），其激活不仅有助于小鼠模型中的PCA转移 肿瘤细胞，破骨细胞，成骨细胞和肿瘤细胞所需细胞之间的间隔 骨骼的生长。该项目将检验使用SRC治疗策略的中心假设 目前正在临床试验中的抑制剂将证明有效地治疗PCA转移 骨。该假设的大礼是SRC调节肿瘤细胞和中的信号通路 它们的微环境有助于骨形造成骨形成，降解和肿瘤的“恶性循环” 生长，部分基于持续的阶段L/LL临床试验的承诺 使用Dasafinib（SFK/ABI抑制剂）和多西他赛的组合进行癌症。这个项目将结合在一起 临床前小鼠模型系统中基于机械的策略，以检查 使用dasafinib进行的III期临床试验，宿主和肿瘤细胞中的SRC在骨骼中有助于生长。 具体目的是：（1）确定SFK抑制在肿瘤细胞，宿主细胞中以及在 在裸鼠肠内损伤后影响PCA细胞的生长； （2）确定分子替代品 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 第三阶段试验在与castrate的精选水平的第三阶段试验中使用dasatinib与多西他赛的组合 耐药性前列腺癌和骨转移，与SRC和骨的分子标记的变化相关 保存疾病的临床过程。该试验将作为与SRC的标记相关标记的平台 激活，骨转换标记中的基线和串行变化。因此，项目3中的实验 这是新颖的，因为它们以有希望的治疗策略为基础，我们也将其视为重复性，我们 对SRC在肿瘤/骨间的影响的知识增加将有助于决定临床试验设计，并有助于 临床试验将有助于完善临床前研究中的疾病建模。 相关性（请参阅Instnjctions）： 目前，尚无用于治疗晚期前列腺癌的成功疗法（即患有的癌症 转移，特别是对骨头）。但是最近使用SRC抑制剂的最新早期临床试验， 影响肿瘤的生长和肿瘤与环境的相互作用，这是有希望的。在这个项目中， 我们将采用基础科学策略来了解哪些SRC功能对此过程很重要，并且 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。