The study proposed here seeks to develop efficacious new therapeutic agents for the treatment of cancer. An increased understanding of molecular targets associated with tumor angiogenesis that supports cancer growth, receptors involved in cancer metastasis, and molecular targets associated with tumor cells themselves, provide novel opportunities for effective targeting of cancer at multiple levels. The promise of targeting antibodies to both the tumors vasculature and the tumor itself is a new and effective therapy for a variety of cancers. We hypothesize that the integrins avb3 and avb5 might fulfill some of these criteria. In preliminary studies, we have prepared a novel chemically programmed antibody that targets the integrins avb3 and avb5 and demonstrated the efficacy of this immunotherapeutic in animal models of Kaposi's sarcoma, melanoma, and colon cancer. Additionally, we have identified ligands that target several other tumor associated markers that can complement the integrin markers in providing a concerted molecular therapy for cancer. We hypothesize that antibodies that target tumor associated antigens as well as angiogenic receptors wilt be more potent and broadly applicable therapeutic agents. We will attempt to further validate the utility of our chemically programmed antibody approach and the dual compartment targeting hypothesis in animal models of cancer. Given the relevance of integrins avb3 and avb5 in melanoma, ovarian, and cervical cancers and in angiogenesis in general, success using these molecular targets and the chemically programmed antibody approach proposed herein may have many benefits. With chemically-programmed antibodies, we will address the therapeutic potential and mechanism of treating melanoma, breast, and ovarian cancer in animal models with single antibodies that target 1,2, or 3 defined receptors while addressing the question of whether there is a synergistic or additive advantage of combining anti-angiogenic and tumor targeted immunotherapies in cancer. It is anticipated that the results of this work will provide a promising new approach to the treatment of cancer.
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