The progressive growth of primary ovarian cancer and metastasis is dependent on development of anadequate blood supply (angiogenesis). Vascular endothelial growth factor (VEGF) plays a critical role inangiogenesis and consequent ovarian cancer growth and progression. VEGF blockade has shownpromise in human studies. The overall goal of this proposal is to develop new strategies for targetingblood vessels in ovarian cancers. Our pre-clinical results demonstrate that a novel approach (high-affinityVEGF decoy receptor, VEGF-Trap) for VEGF blockade is highly effective in combination with taxanechemotherapy. Recent evidence suggests that VEGF-Trap may be more potent than many other existingmodalities for targeting VEGF. Based on these encouraging preclinical results, we will conduct a Phase Iclinical trial of VEGF-Trap and docetaxel chemotherapy in patients with recurrent ovarian carcinoma inAim 1. In addition to endothelial cells, blood vessels consist of perivascular cells such as pericytes, whichare mesenchymal cells that wrap around the vessel tube. Several functions of pericytes relevant toangiogenesis have been proposed including effects on endothelial survival, deposition of matrix, andmaintenance of vessel integrity. Platelet-derived growth factor receptor (3 (PDGF-Rp) signaling is knownto 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 andassess the efficacy of combinatorial approaches for targeting both endothelial cells (VEGF-blockers) andpericytes (PDGF-blockers). Most chemotherapeutic agents are traditionally administered at maximumtolerated doses. However, recently, metronomic chemotherapy (frequent administration of chemotherapeuticagents at substantially lower doses with no prolonged drug-free breaks) has been utilized fortargeting endothelial cells of the growing vasculature of a tumor. Our preliminary data suggest thatmetronomic chemotherapy alone and in combination with other anti-vascular approaches is highlyeffective.
Aim 3 will determine the efficacy of metronomic chemotherapy in combination with VEGF andPDGF blockers. Thus, all three Aims are complementary to each other and
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