Treatment of Breast Cancer With Antibodies Against DR4 and DR5 Receptors in Combination With Chemotherapy

摘要

The overall goal of this proposal is to determine the therapeutic potential of apoptosis-inducing anti-human DR5 and DR4 antibodies, alone or together, in combination with chemotherapeutic drugs with activity against breast cancer, for the treatment of metastatic breast cancer. Aim I was to determine the expression profile in human breast cancer cell lines of DR5 and DR4 before and after treatment with anti-DR5 and -DR4 MAb alone, together, and in combination with chemotherapy drugs. Aim 2 was to determine the expression profile of DR5 and DR4 during the progression of breast cancer. Aim 3 was to determine the cytotoxicity of anti-DR5 and -DR4 antibodies against human breast cancer cells alone, together, and in combination with adriamycin or paclitaxel. Aim 4 was to determine the therapeutic efficacy and toxicity of anti-DR5 and - DR4 antibodies against human breast cancer xenografts alone, together, and combined with adriamycin or paclitaxel. We investigated mTRA-8 anti-DR5 antibody cytotoxicity alone and in combination with several chemotherapy and biomodulating drugs and identified which combinations resulted in synergistic cytotoxicity. These combination treatments were then tested in nude mice with subcutaneous breast cancer xenografts. We also showed that bioluminescence imaging can be used to evaluate tumor response in mammary fat pad and disseminated breast cancer models. Mechanistic studies of combination treatment were carried out both in vitro and in vivo. Expression of DR5 was determined by immunohistochemistry to be present in human biopsy specimens of breast cancer and in adjacent normal breast epithelium.