Our work on human T cell leukemia virus I (HTLV I) has revealed that the oncoprotein Tax, when introduced into p53 null cells, causes apoptosis upon exposure to UV damage, resulting in increased cell death. Tax-induced sensitization to DNA damage reveals an approach to abrogate p53 mutant tumor resistance. p53 mutant tumors remain among the most difficult to treat in human cancer because of their inherent resistance to therapy-induced apoptosis. p53 is mutated in a majority of all human cancer, including many pediatric tumors. Development of strategies to treat resistant p53 mutant tumors is one of the most important problems in clinical oncology. The long-term goal of our team is to study genomic instability in order to understand both basic mechanisms of cellular response as well as its importance to clinical problems. Dr. Kupfer is a physician-scientist whose laboratory has focused on genomic instability and DNA damage hypersensitivity utilizing the Fanconi anemia model. A major focus in Dr. Semmes'research is HTLV-1 biology and he was instrumental in demonstrating Tax-induced genomic instability as a model for development of ATL. The common interest in genomic instability has facilitated this collaboration. The objective of this application is to understand how Tax functions in chemosensitization. This will be explored by testing for the Tax effect upon sensitization in model systems with functionally distinct p53 backgrounds, probing for the mechanism of Tax- induced apoptosis in a p53 independent fashion, and defining the minimal domain necessary for such an effect. The central hypothesis for the proposed research is that Tax activates a pro- apoptotic pathway in p53 mutant cells, while promoting resistance in p53 wild type cells. The rationale for this proposal is that by uncovering the mechanism by which Tax accomplishes these functions we will reveal target molecules for the development of more effective cancer therapy. Together, we have extensive experience in translational research and a solid appreciation for moving bench observation to clinical utilization.
In Aim 1, we will determine the spectrum of DNA damage sensitivity induced by Tax in p53 mutant cells. These studies will define which types of DNA damage delineate the Tax effect. In addition we will identify which p53 mutants are susceptible to this approach as well as narrow down the specific domain of Tax responsible for its effect. Next, we will test the use of a synthesized peptide corresponding to the domain of Tax that contains the chemosensitization effect. Next, in Aim 2, we will demonstrate the use of Tax in mouse models of human cancer. First we will use Jurkat cells that inducibly express Tax as a tumor explant model to test the Tax effect in vivo. Next we will use the peptides validated in Aim 1 for use against spontaneous tumors arising in p53 -/- mice. Our work has the potential to dramatically improve the approach to treating resistant cancer.

Public Health Relevance

p53 mutations are commonly found in tumors and are a major cause of resistance to standard chemotherapy. Thus, p53 mediated chemoresistance is a major clinical oncology problem. In our work on HTLV I Tax protein, we have observed that expression of Tax in a p53 mutant resistant cell lines results in increased sensitivity to DNA damage. In our proposed work, we hypothesize that Tax could serve as a clinical tool to use as a chemosensitization agent in order to make standard chemotherapy more effective in resistant tumors. We will demonstrate the use of Tax in cell line and mouse tumor explant models as preclinical proof of principle in anticipation of working toward an eventual clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA149862-01
Application #
7872281
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$179,981
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520