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。人们认为前列腺癌引起的骨重塑是肿瘤细胞定植到骨骼的关键早期事件，因为正常的成年骨基质不利于肿瘤定植。一旦前列腺癌细胞转移到骨骼，就无法提供有效的疗法来提供生存优势。重要的是，最近的临床研究表明，基于多西他赛的化学疗法可在晚期荷尔蒙 - 难治性前列腺癌患者中提高近两个月的生存率，从而开放了骨骼中前列腺癌进展的化学预防的可能性。前列腺癌是一种缓慢增长的异质性肿瘤，需要多模式治疗。很明显，治疗不仅应针对肿瘤生长，还应针对肿瘤介导的基质反应。研究表明，血小板衍生的生长因子受体β（beta-pDGFR）信号传导通过调节骨源性细胞迁移，增殖和分化来促进前列腺转移。我们最近的研究表明，前列腺肿瘤产生的PDGF D是一种新发现的β-PDGFR配体，大大提高了骨环境中的肿瘤摄取和生长速率，并介导了骨质和骨细胞的反应，可能导致骨骼的净生长。该R03应用程序的目标是（AIM 1）验证我们设计的动物模型的使用，以上调PDGF D/beta-PDGFR信号传导，以筛选PDGF/VEGF抑制剂并测试PDGF/VEGF抑制剂，AZD2171和Gleevec，AZD2171和Gleevec，AZD2171和Gleevec的功效结合多西他赛在骨骼中进行化学预防的化学预防，（AIM 2）研究AZD2171和Gleevec对肿瘤衍生的PDGF D诱导的信号转导和基因表达的影响。考虑到Beta-PDGFR在骨转移和原发性前列腺癌标本中都高度上调，因此拟议的研究的完成将提供重要信息，并具有PDGF靶向的治疗价值。这些研究还将验证我们设计的动物模型，以上调beta-pDGFR信号传导，以筛选PDGF/VEGF抑制剂。该信息将有助于设计旨在调节PDGF/VEGF信号通路的更合理的治疗干预措施。