; This proposal is a continuation of Project 2 in the original SPORE grant. Pertinent to this proposal, we have developed an anti-DRS monoclonal antibody therapy for pancreatic cancer through in vitro studies, animal model efficacy and with an industry partner (Daiichi Sankyo), Phase I and recently completed Phase II trials in pancreatic cancer. We have also discovered a novel molecule (DDX3) which appears to play a major role in regulation of anti-DRS mediated apoptosis. In this proposal, we will explore two strategies to enhance the efficacy of anti-DRS monoclonal therapy especially in pancreatic tumor cell lines which are intermediate or resistant to anti-DRS. The two strategies are to evaluate the addition of a monoclonal anti-DR4 reagent or the addition of small molecule modulators ofthe apoptosis cascade. The two apoptosis modulators to be evaluated are AT-101, a Bcl-2 family inhibitor, and AT-406, an lAP family inhibitor. These two strategies will be studied using in vitro analysis and orthotopic and metastatic xenogeneic pancreatic cancer models leading to a Phase I trial of the best strategy. In addition, we will continue studies of DDX3 and the DRS/DDX3 complex as a putative biomarker for tumor cell sensitivity/resistance to death receptor mediated anti-tumor efficacy and as the target of enhancement strategies for anti-DR mediated anti-tumor effects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA101955-06A2
Application #
7962128
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M1))
Project Start
2010-03-01
Project End
2015-02-28
Budget Start
2010-03-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$183,608
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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