Pilot Testing of VEGF/PDGF inhibitors for chemoprevention of bone metastasis

VEGF/PDGF 抑制剂化学预防骨转移的中试

• 批准号: 7214549
• 负责人: Hyeong-Reh Choi Kim
• 金额: $ 7.53万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214549
• 关键词: bone; chemoprevention; metastasis; neoplasm /cancer; paclitaxel; prostate neoplasms

DESCRIPTION (provided by applicant): A vast majority of prostate cancer patients die with metastases and almost 90% of prostate cancer metastases occur at skeletal sites. It is thought that prostate carcinoma-initiated bone remodeling is a critical early event for tumor cell colonization to the bone, since the normal adult bone matrix is not conducive to tumor colonization. Once prostate cancer cells metastasize to bone, there is no effective therapy to offer a survival advantage. Importantly, recent clinical studies showed that docetaxel-based chemotherapy improves median survival by nearly two months in patients with advanced hormone-refractory prostate cancer, opening up the possibility of chemoprevention of prostate cancer progression in bone. Prostate cancer is a slow- growing, heterogeneous tumor that requires multimodality therapy. It becomes clear that therapy should target not only tumor growth but also tumor-mediated stromal responses. Studies suggest that platelet- derived growth factor receptor-beta (beta-PDGFR) signaling promotes prostate bone metastasis via its regulation of osteoprogenitor cell migration, proliferation and differentiation. Our recent study has revealed that prostate tumor-produced PDGF D, a newly discovered ligand for beta-PDGFR, drastically enhances tumor-take and growth rate in the bone environment and mediates both osteolytic and osteoblastic responses, possibly leading to net growth of bone. The objectives of this R03 application are (Aim 1) to validate the use of our animal model engineered to upregulate PDGF D/ beta-PDGFR signaling for screening of PDGF/VEGF inhibitors and test the efficacy of PDGF/VEGF inhibitors, AZD2171 and Gleevec, combined with docetaxel for chemoprevention of prostate cancer progression in bone, and (Aim 2) to investigate the effects of AZD2171 and Gleevec on tumor-derived PDGF D-induced signal transduction and gene expression in bone stromal cells in vitro. Considering that beta-PDGFR is highly upregulated in both bone metastases and primary prostate cancer specimens, the completion of the proposed study will provide important information with therapeutic value of PDGF targeting. Theses studies will also validate our animal model engineered to upregulate beta-PDGFR signaling for screening of PDGF/VEGF inhibitors in the future. This information will be useful in designing more rational therapeutic interventions aimed at modulating the PDGF/VEGF signaling pathways.

描述（由申请人提供）：绝大多数前列腺癌患者死于转移，几乎90%的前列腺癌转移发生在骨骼部位。认为前列腺癌引发的骨重建是肿瘤细胞定植到骨的关键早期事件，因为正常成人骨基质不利于肿瘤定植。一旦前列腺癌细胞转移到骨，就没有有效的治疗方法来提供生存优势。重要的是，最近的临床研究表明，以紫杉醇为基础的化疗使晚期难治性前列腺癌患者的中位生存期延长了近两个月，这为骨中前列腺癌进展的化学预防开辟了可能性。前列腺癌是一种生长缓慢的异质性肿瘤，需要综合治疗.很明显，治疗不仅要针对肿瘤生长，还要针对肿瘤介导的基质反应。研究表明，血小板衍生生长因子受体-β（β-PDGFR）信号传导通过其调节骨祖细胞迁移、增殖和分化促进前列腺骨转移。我们最近的研究表明，前列腺肿瘤产生的PDGF D，一种新发现的β-PDGFR配体，大大提高了骨环境中的肿瘤摄取和生长速率，并介导溶骨性和成骨细胞反应，可能导致骨的净生长。该R 03申请的目的是（Aim 1）验证我们的动物模型的使用，该动物模型被工程化以上调PDGF D/β-PDGFR信号传导，用于筛选PDGF/VEGF抑制剂，并测试PDGF/VEGF抑制剂AZD 2171和Gleevec与多西他赛组合用于化学预防骨中前列腺癌进展的功效，目的2研究AZD 2171和Gleevec对肿瘤源性PDGF D诱导的骨基质细胞信号转导和基因表达的影响。考虑到β-PDGFR在骨转移和原发性前列腺癌标本中均高度上调，完成拟定研究将提供PDGF靶向治疗价值的重要信息。这些研究也将验证我们的动物模型工程上调β-PDGFR信号转导的PDGF/VEGF抑制剂的筛选在未来。这些信息将有助于设计更合理的治疗干预措施，旨在调节PDGF/VEGF信号通路。