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

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。由于正常成人骨基质不利于肿瘤定植，因此人们认为前列腺癌引发的骨重塑是肿瘤细胞定植到骨的关键早期事件。一旦前列腺癌细胞转移到骨骼，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，多西他赛为基础的化疗使晚期激素难治性前列腺癌患者的中位生存期提高了近两个月，开辟了化学预防前列腺癌骨进展的可能性。前列腺癌是一种生长缓慢的异质肿瘤，需要多种治疗方法。很明显，治疗不仅应该针对肿瘤生长，还应该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)信号通过调控成骨细胞的迁移、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是一种新发现的β - pdgfr配体，它可以显著提高骨环境中肿瘤的摄取和生长速度，并介导溶骨和成骨反应，可能导致骨的净生长。这项R03申请的目的是（目的1）验证我们的动物模型的使用，该模型可以上调PDGF D/ β - pdgfr信号，用于筛选PDGF/VEGF抑制剂，并测试PDGF/VEGF抑制剂AZD2171和格列卫联合多西他赛化学预防前列腺癌骨进展的功效。（目的2）研究AZD2171和格列卫对肿瘤源性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，本研究的完成将提供具有PDGF靶向治疗价值的重要信息。这些研究还将验证我们的动物模型，该模型可以上调β - pdgfr信号，用于未来筛选PDGF/VEGF抑制剂。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。

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.