Small Molecules and Gene Delivery in Tumor Angiogenesis

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Angiogenesis is dependent on the interaction of endothelial cells (ECs) with the remodeling extracellular matrix (ECM), an event primarily mediated by cell surface receptors termed integrins. In this renewal proposal we will explore three related applications of small molecule integrin antagonists, each designed to target and thereby inhibit the growth of angiogenic blood vessels and resulting solid tumors in animals. The first application follows our discovery that the integrin alphavbeta3 is expressed specifically on angiogenic ECs and serves as a receptor for the ECM and the cell surface protease matrix metalloproteinase 2 (MMP-2). In the initial aim, analogs of a compound that blocks MMP-2 binding to alphavbeta3 (TSRI-265, first discovered during the previous funding cycle of this proposal), will be synthesized and tested in murine tumor models for increased pharmacokinetic and therapeutic activity. In Aim 2, we will extend our recently developed nanoparticle gene delivery technology to examine specificity and efficacy of different alphavbeta3-specific targeting agents (including TSRI-265). Efficient targeting agents will be used to deliver proapoptotic genes to disrupt angiogenic blood vessels in murine tumor growth models. In the final two aims, we will develop and test inhibitors of integrin alpha3beta1, which we define here as playing a central role in EC invasion and angiogenesis. Evidence is provided that EC integrin alpha3beta1 interacts with an alternatively spliced (extra-domain B, or ED-B containing) oncofetal form of fibronectin (BFN). B-FN accumulates around angiogenic blood vessels, but to date, its role in angiogenesis has remained unclear. We will test the hypothesis that antagonists of alpha3beta1 block endothelial cell interaction with ED-B, and disrupt early stages of tumor-mediated angiogenesis. The goals of this proposal are facilitated by our continued close interactions with Drs Boger and Nicolaou, synthetic organic chemists at The Scripps Research Institute. It is anticipated that these studies will result in the development of several novel compounds that target specific EC integrins, thereby disrupting angiogenesis and tumor growth.