Title |
Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer
|
Institution |
UNIVERSITY OF ALABAMA AT BIRMINGHAM, BIRMINGHAM, AL
|
Principal Investigator |
ZHOU, TONG
|
NCI Program Director |
William Timmer
|
Cancer Activity |
Clinical Oncology
|
Division |
DCTD
|
Funded Amount |
$339,209
|
Project Dates |
04/20/2007 - 01/31/2012
|
Fiscal Year |
2007
|
Project Type |
Grant
|
Research Topics w/ Percent Relevance |
Cancer Types w/ Percent Relevance |
Chemotherapy (50.0%)
MOAB (50.0%)
Orphan Drug Research (100.0%)
|
Ovarian Cancer (100.0%)
|
Research Type |
Systemic Therapies - Clinical Applications
|
Abstract |
DESCRIPTION (provided by applicant): 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. |