Seminar Abstract

“What do cancer and heart disease have in common? Designing therapeutic strategies by modeling angiogenesis”

Tissue does not survive without adequate vasculature; this is as true of growing tumors as it is of ischemic heart muscle. Angiogenesis (or neovascularization), the outgrowth of new vessels from the preexisting vasculature, is essential to organ development, and is involved in several physiological processes in the adult, including wound healing. Many diseases may be treated by either promoting or inhibiting the angiogenic process. In the first category, both coronary and peripheral limb ischemia may be alleviated by increasing the overall vascularization of the tissue. In the second category, tumor growth may be slowed by inhibiting angiogenesis; later stage cancers may be more effectively chemotargeted when the tumor vessels are not growing erratically; and metastatic events may be decreased by reducing the tumor’s vascular supply. Other diseases which are vasculature-dependent and can therefore be targeted with angiogenesis inhibitors include diabetic retinopathy, age-related macular degeneration and arthritis.

The principal cytokine implicated in the induction of angiogenesis is Vascular Endothelial Growth Factor (VEGF). Released by hypoxic tissue, it binds receptors on the blood vessels and guides the growth of sprouts towards the hypovascularized area. We have constructed the first molecularly-detailed models of the interactions of VEGF with its receptors and its transport through various tissues. The models, validated using all available experimental evidence, are used to predict and compare the efficacy of cell-, protein-, and gene-based therapies. In this talk, I will focus on two applications of these models. First, strategies for inhibiting VEGF signaling in tumors by targeting the VEGF co-receptor Neuropilin-1. Second, pro-angiogenic therapies for alleviating hypoxia in peripheral artery disease.