Cell-specific Targeting of Ovarian Cancer Vasculature

点击翻译按钮获取中文摘要

The progressive growth of primary ovarian cancer and metastasis is dependent on development of an adequate blood supply (angiogenesis). Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and consequent ovarian cancer growth and progression. VEGF blockade has shown promise in human studies. The overall goal of this proposal is to develop new strategies for targeting blood vessels in ovarian cancers. Our pre-clinical results demonstrate that a novel approach (high-affinity VEGF decoy receptor, VEGF-Trap) for VEGF blockade is highly effective in combination with taxane chemotherapy. Recent evidence suggests that VEGF-Trap may be more potent than many other existing modalities for targeting VEGF. Based on these encouraging preclinical results, we will conduct a Phase I clinical trial of VEGF-Trap and docetaxel chemotherapy in patients with recurrent ovarian carcinoma in Aim 1. In addition to endothelial cells, blood vessels consist of perivascular cells such as pericytes, which are mesenchymal cells that wrap around the vessel tube. Several functions of pericytes relevant to angiogenesis have been proposed including effects on endothelial survival, deposition of matrix, and maintenance of vessel integrity. Platelet-derived growth factor receptor (3 (PDGF-Rp) signaling is known to play a functionally significant role in pericyte development and recruitment by endothelial cells. Aim 2 will examine the mechanisms by which pericytes provide a survival advantage for endothelial cells and assess the efficacy of combinatorial approaches for targeting both endothelial cells (VEGF-blockers) and pericytes (PDGF-blockers). Most chemotherapeutic agents are traditionally administered at maximum tolerated doses. However, recently, metronomic chemotherapy (frequent administration of chemotherapeutic agents at substantially lower doses with no prolonged drug-free breaks) has been utilized for targeting endothelial cells of the growing vasculature of a tumor. Our preliminary data suggest that metronomic chemotherapy alone and in combination with other anti-vascular approaches is highly effective. Aim 3 will determine the efficacy of metronomic chemotherapy in combination with VEGF and PDGF blockers. Thus, all three Aims are complementary to each other and