Project Leaders


Albert F. LoBuglio, M.D.,
Co-Leader

Tong Zhou, M.D., Co-Leader

Objectives

Project 5 is a new project being initiated in the competitive renewal, which has developed from the Career Development Program. With the support of the Career Development funds and in collaboration with our industrial sponsor, Sankyo Co, Ltd, A novel anti-DR5 antibody, TRA-8, has been explored in pre-clinical studies and has moved into development as an anti-cancer candidate. The overall goal is to develop an effective therapeutic strategy for treatment of ovarian cancer by selectively targeting DR5 with TRA-8 in combination with chemotherapy. The central hypothesis of this proposal is that ovarian cancer cells express elevated levels of DR5 expression and enhanced DR5 mediated apoptosis resulting in TRA-8 mediated anti-tumor efficacy as a single agent or in combination with chemotherapy. The key apoptosis regulatory proteins around the death domain of DR5 determine the susceptibility of tumor cells to TRA-8-mediated apoptosis, which may be used as a biomarker for selection of patients likely to benefit from hTRA-8 therapy and served as the molecular targets of chemotherapy for further enhancing the apoptosis-inducing efficacy of TRA-8. There are four Specific Aims: AIM 1: To determine expression levels of DR5 and TRA-8 apoptosis-inducing cytotoxicity in primary ovarian carcinoma tissues. AIM 2: To determine the correlation of the DR5/DDX3-associated IAPs with the susceptibility to TRA-8-mediated apoptosis of ovarian cancer cell lines and patient ovarian cancer tissues as a putative biomarker for predicting tumor cell response to TRA-8. AIM 3: To determine how modulation of DDX3 effects TRA-8 mediated apoptosis and how chemotherapeutic agents which enhance TRA-8-mediated apoptosis affect the DR5/DDX3 protein complex in human ovarian cancer cell lines both in vitro and in vivo . AIM 4: To initiate clinical development of TRA-8, including Phase I dose escalation trial of huTRA-8 in patients with treatment resistant metastatic cancer and Phase I/II trial of huTRA-8 plus chemotherapy in patients with relapsed/resistant ovarian carcinoma. This project addresses several critical issues to support the clinical development of huTRA-8 in ovarian cancer patients. Accomplishment of this project will certainly increase our understanding of death receptor-mediated apoptosis, may well provide identification of biomarkers to select ovarian cancer patients most likely to benefit from therapy and could yield a novel and effective therapy for treatment of ovarian cancer.