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Bi-specific Endothelin Receptor Antagonists for Breast Cancer Therapy
Tumor Cell Biology I
Background: Endothelins (ET) and their receptors are expressed in a broad range of tumors, and play an important role in tumor growth, progression, inhibition of apoptosis and metastases. In breast carcinomas, ET-1, ET receptor A (ETAR) and B (ETBR), are overexpressed on cell lines and in vivo overexpression of ET-1, ETBR and especially of ETAR is associated with reduced overall survival. Recently, ET antagonists have been development in potential therapeutic agents for hypertension, heart failure and renal diseases. However, clinical data with these antagonists has been disappointing and did not reflect the highly promising data obtained in animal disease models. Because ET receptors are widely expressed, there is concern that inhibition of the ET network will cause serious adverse side effects. Objective/Hypothesis: It is proposed that synergizing of ET antagonists with an apoptosis inducing antibody therapy will reduce the side effects associated with ET antagonist administration. Furthermore, the proposed novel strategy for tumor-specific targeting of ET antagonists with the single –chain antibody method will enable us to test the hypothesis that the targeting of systemically administered ET antagonists will markedly enhance their efficacy and reduce the risk of side effects on homeostatic mechanisms. Specific Aims: (1) To determine the role of ET receptor on human breast cancer with ET antagonists. (2) To investigate the therapeutic feasibility of enhancing cell death signaling of breast tumor cells in vitro and vivo using the ET antagonist together with an apoptosis inducing anti-Her-2 antibody therapy. (3) To examine the feasibility of bi-specific ET receptor antagonists constructs that will target to tumor cells and block the function of ET receptor. Study Design: The peptide antagonist against ET receptors will be searched with a special computer program “ANTIS”. ET antagonists will be assessed using human breast tumor cell lines and their effect on cell proliferation determined in vitro and in vivo. Recombinant bi-specific antagonist constructs will have specificity for a breast tumor antigen (Her-2 or MUC1) and an ET antagonist. Bi-specific ET antagonist constructs are predicted to effect of act only breast cancer cells. Potential Outcomes and Benefits of the Research: These studies will contribute to our understanding of the mechanism of ET axis on breast cancer cells. Furthermore, the studies proposed have direct relevance to the therapy of breast cancer. ET receptor antagonists have been shown to have effect cancer cell proliferation and metastases, and there are clear advantages to targeting tumor cells for inhibition of the ET axis due to toxicity associated with systemic administration. In additional, the targeted or non-targeted ET receptor antagonists with anti-Her-2 antibody therapy have synergistic potential and may be effective for patients with poor prognosis.
Endothelins and their receptors are important for maintaining normal vascular tone via vasoconstrictor and vasodilator mechanisms. The involvement of endothelins in proliferation as well as in a wide range of pathological conditions, such as hypertension, ischemia, acute renal failure or ever in Alzheimer’s disease prompted an intensive search for an appropriate antagonist to endothelin receptors. Recently, it has also been shown that the endothelin network plays a role on the growth and progression of sundry cancers. In breast carcinomas, ET-1, endothelin receptor A (ETAR) and B (ETBR) are overexpressed in vitro and in vivo. The overexpression of endothelin on breast cancer has also been shown to reduce overall survival and has been associated with increased VEGF expression and higher vascularity. Furthermore, increased expression of ETAR in breast carcinomas is associated with resistance to chemotherapy. On recent reports, atrasentan, which is an ETAR antagonist, improved the time to clinical progression in prostate cancer patients. Endothelin receptor antagonists have been widely studied because of their therapeutic potential in disorders including hypertension, heart failure and renal diseases. However, despite highly promising results in animal disease models, their clinical potential has not been fully realized mainly because endothelin receptors are expressed widely in the body and the inhibition of the endothelin axis generally increases the risk of potential side effects. Our laboratory has generated data establishing the development of a unique functional protein with molecular biology methods as well as the regulation of the anti-tumor immune response using the complement system with anti-tumor antibodies. These findings have enabled us to propose a very innovative and unique approach to target only tumor cells and inhibit the endothelin system to specifically eliminate breast cancer cells. The plan consists of engineering modified antibodies containing two different function regions. The first functional portion acts as targeting to the malignant breast cancer cell via surface molecules (Her-2 and MUC1). The second one exerts the inhibition of endothelin system. These strategies would not only work to reduce the tumor cell proliferation, but would spare normal cells since normal cells either do not express the tumor specific antigen or express the antigen at much lower levels. Further studies will investigate the hypothesis that the blocking of the endothelin axis at a tumor cell surface may also facilitate the outcome of immunotherapies using antitumor antibodies via a synergistic effect. If the proposed studies are successful, they will provide convincing evidence for the biological role of the endothelin network in the proliferation and invasiveness of tumor cells, and may lay the foundation for novel and effective immunotherapies of human breast cancer.