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Disintegrins as a Therapeutic and Imaging Agent for Metastatic Breast Cancer
A significant number of women with breast cancer (BC) have metastatic disease at first diagnosis. New treatment options need to be made available for these women, particularly therapies that target angiogenesis, since BC is an angiogenesis-dependent cancer and a unique target for antiangiogenic therapy. A potent inhibitor of tumor dissemination and angiogenesis, the disintegrin contortrostatin (CN), is the focus of this proposal. Tumor angiogenesis is a highly redundant process; blocking a single pathway can lead to resistance to therapy since growing tumors shift their expression profile and utilize alternate pathways. Importantly, CN simultaneously inhibits several integrin pathways. Also, CN inhibits cancer and endothelial cell adhesion and invasion, thus, it attacks tumor angiogenesis and metastasis at multiple levels. We have developed a liposomal-delivery system for CN (LCN) that shields CN from immune recognition and dramatically increases its circulatory half-life. We can now target delivery of CN to tumor cells in a breast cancer animal model and produce impressive inhibition of tumor growth, metastasis, and angiogenesis. Even though CN has been established as a promising anticancer agent, it comprises a small fraction of venom protein. Thus, its isolation from venom is difficult and prohibitively expensive. For this reason, a synthetic molecule, vicrostatin (VN), was expressed in bacteria in our lab. VN showed the same efficacy in limiting tumor growth and angiogenesis as CN following intravenous delivery of a liposomal formulation in a xenograft model of human BC in nude mice. We hypothesize that: i) VN can be expressed in sufficient levels for all preclinical studies; ii) VN will be an effective antimetastatic agent in combination with chemotherapy; and iii) VN will possess unique imaging potential for metastatic disease. Our specific aims will allow us to: 1) examine the effect of VN therapy (alone and in combination with a chemotherapeutic agent) on bone metastasis of BC; 2) separately we will examine the effect of VN therapy (alone or in combination) on lung metastasis of BC; 3) examine the use of VN as a novel imaging agent to evaluate metastatic spread of BC, as well as to visualize primary BC and evaluate effectiveness of therapy. The combination of metronomic therapy (a cytotoxic agent given chronically at low dose) with antiangiogenic therapy has proven very effective. We will demonstrate in animal models of BC bone and lung metastasis that when VN is given in combination with low doses of a cytotoxic agent there is an added therapeutic benefit, compared to the single agents, in inhibition of BC metastasis. Additionally, we will use pulsed delivery of 124I-VN and µPET during combination therapy to image primary and metastatic BC and examine the effect of therapy on metastases. Results of these studies will facilitate translation of our technology from basic research to therapeutic reality for women with metastatic BC.
Breast cancer (BC) is the 2nd most common form of cancer among women in the US with 212,920 new cases expected in 2006 and it is the second leading cause of cancer deaths in women with an anticipated 40,970 who will succumb to their disease. Spread (metastasis) of the cancer is the primary cause of death in BC patients. Despite significant improvement in the management of BC, for women with metastases the 5-year survival rate is still very poor. It is critical, that new treatment options be made available for women with metastatic BC. Angiogenesis (the growth of new blood vessels into the tumor) has been shown to play an important role in BC progression and BC has been labeled an angiogenesis-dependent cancer. Antiangiogenic therapy can produce prolonged tumor dormancy and does not kill cells, thus avoiding side effects associated with the use of cell killing (cytotoxic) chemotherapy. This proposal is focused on the translational development of contortrostatin (CN), an antiangiogenic agent with impressive anticancer activity, as a novel form of therapy for metastatic breast cancer. We have previously shown that CN has potent antitumor activity against human BC in nude mice and that the activity is enhanced by combination with a chemotherapeutic agent. The antitumor activity of CN is based on its functional disruption of a class of proteins involved in cell migration. These proteins are involved in invasion of both cancer and newly growing blood vessels. We have also shown that a liposome (lipid-like sphere) formulation can be effectively utilized to encapsulate CN (LCN) and deliver it intravenously to the cancer site in nude mice harboring human BC. This method of delivery is clinically relevant, targets CN to the cancer, and enables CN to exert its potent antitumor and antiangiogenic activity without any apparent immune response. One major obstacle to the clinical translation of CN had been the dependence on snake venom as the commercial source of the protein. To directly address this problem, we have recently produced a recombinant version of CN (that we call vicrostatin, VN), which is as active as native CN both in the test tube and in animal cancer models. We are confident that: (i) VN can be expressed in a bacterial cell line at appropriate levels for all preclinical studies; (ii) LVN can be prepared using a method appropriate for mass production; and (iii) LVN so produced will retain potent antimetastatic/antiangiogenic activity comparable to that observed for LCN. The work we propose in the present application is aimed at developing an effective therapy against spread of BC. We will examine the effect of therapy, using VN and a chemotherapeutic agent, on bone and lung metastasis of BC. We will also use VN as a novel imaging agent to evaluate metastatic spread of BC, as well as to visualize primary BC, and evaluate the effectiveness of therapy. These studies will enable us to move VN through preclinical toxicology and into clinical tria