Project 2 is a new project that has developed from the Career Development Program of the UAB SPOREin Breast Cancer. The PI initially developed a novel anti-DR5 monoclonal antibody, TRA-8, which exhibited astrong apoptosis-inducing activity against cancer cells without hepatocyte cytotoxicity. With the support ofthe Career Development funds and in collaboration with our industrial sponsor, Sankyo Co, Ltd, TRA-8 hasbeen explored in pre-clinical studies and has moved into development as an anti-cancer candidate. Theoverall goal of this proposal for the competitive renewal is to develop an effective therapeutic strategy fortreatment of breast cancer by selectively targeting DR5 with a novel monoclonal TRA-8 in combination withchemotherapy. The central hypothesis is that breast and other cancer cells may differentially expressincreasing levels of DR5 during malignant transformation and that DR5 can be selectively targeted with anagonistic monoclonal antibody to directly induce apoptosis of cancer cells. As TRA-8 and chemotherapyagents may utilize different but complementary pathways to trigger apoptosis, the susceptibility of breastcancer cells to TRA-8-mediated apoptosis can be enhanced by chemotherapy agents. Furthermore, TRA-8may improve the efficacy of chemotherapy by preventing or reversing chemo-resistance in breast cancercells. There are four Specific Aims:
Aim 1 is to examine the efficacy of TRA-8 (anti-DR5) with and withoutchemotherapy agents in murine models of orthotopic and metastatic human breast cancer;
Aim 2 is tocharacterize the role of the DR5/DDX3 pathway in modulating sensitivity or resistance of breast cancer celllines to TRA-8 induction of apoptosis, and to characterize the DR5/DDX3 pathway in human breast cancertissue samples;
Aim 3 is to determine in vitro and in vivo synergistic mechanisms of combination therapywith TRA-8 and chemotherapy;
Aim 4 is to initiate clinical development of CS-1008 (humanized TRA-8) inbreast cancer. The proposed basic and translational studies will support the proposed clinical studies.Accomplishment of these studies will yield a new and potentially effective therapy for breast cancer. The goal of this research is to evaluate a new antibody for the treatment of breast cancer. The researchwill identify the mechanisms for maximizing the efficacy of the antibody in combination with chemotherapyand the development of biomarkers for predicting the response of patients in clinical trials.
Showing the most recent 10 out of 211 publications