Our investigative team has developed a novel anti-DR5 monoclonal antibody (TRA-8) which triggers apoptosis and cytotoxicity to a variety of tumor cell lines including ovarian cancer. The TRA-8 mediated cytotoxicity and in vivo anti-tumor efficacy in murine xenograft models is markedly enhanced in combination with chemotherapy drugs (Adriamycin, Taxol, Carboplatin, Camptostar, etc.). In collaboration with our industry partner (Sankyo Co., Ltd.), a humanized construct of TRA-8 has been generated (CS-1008). The central hypothesis of this proposal is that ovarian cancer tumor cells from patients express elevated levels of DR5 expression and enhanced anti-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 huTRA-8 therapy. These apoptosis regulatory proteins may serve as targets of chemotherapy for further enhancement of TRA-8 efficacy. There are four Specific Aims:
Aim 1 : To determine TRA-8-induced cytotoxicity and its correlation with expression of apoptosis-associated proteins in primary ovarian carcinoma tissues.
Aim 2 : To determine the correlation of the DR5/DDX3-associated clAP1 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 affects 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 carry out a phase I/II protocol of huTRA-8 (CS-1008) plus combination chemotherapy in Stage Illc and IV ovarian cancer patients. This trial will correlate TRA-8 and drug cytotoxicity assays (tissue slice technique), apoptotic protein profile and DR5/DDX3 complex analysis with clinical efficacy as well as provide a reasonable estimate of therapeutic efficacy. ? ? ?
|Bevis, Kerri S; McNally, Lacey R; Sellers, Jeffery C et al. (2011) Anti-tumor activity of an anti-DR5 monoclonal antibody, TRA-8, in combination with taxane/platinum-based chemotherapy in an ovarian cancer model. Gynecol Oncol 121:193-9|