Squamous cell carcinoma of the head and neck (SCCHN), including that of the oral cavity, has a significant level of mortality and a high rate of recurrence. A significant portion of these clinical failures result from tumor cell radiation resistance (RR). Thus, the development of an effective method for sensitizing head and neck tumors to radiotherapy would have a profound effect on the treatment of this disease. Wild-type (wt) p53 plays a crucial role in apoptotic pathways leading to tumor cell death. The lack of functional p53 in many SCCHN tumor cells is thought to be responsible for their RR. The restoration of wtp53 function may restore the p53-mediated apoptotic pathway resulting in more efficient treatment. A combination of wtp53 gene therapy and radiation will be used to restore radiation sensitivity to RR SCCHN. A long-standing goal in gene therapy for cancer is a systemic delivery system that selectively targets tumor cells, including metastases. This application proposes to optimize a folate-linked liposome systemic delivery system for wtp53 to improve the efficacy of conventional radiotherapy. Preliminary in vivo results have proved in principle that restoration of wtp53 function enhances radiation induced apoptosis, leading to long term total tumor regression. In collaboration with a pharmaceutical partner, we will obtain GMP grade reagent, perform toxicology and pharmacokinetic studies to obtain IRB, IBC and FDA approval. Once approvals are obtained we will use this combination therapy in a Phase I clinical trial in an effort to translate this new and potentially more effective treatment modality into the clinic for head and neck cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013151-04
Application #
6523872
Study Section
Special Emphasis Panel (ZDE1-GH (03))
Program Officer
Shirazi, Yasaman
Project Start
1999-09-01
Project End
2007-08-31
Budget Start
2002-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$591,665
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Yu, W; Pirollo, K F; Rait, A et al. (2004) A sterically stabilized immunolipoplex for systemic administration of a therapeutic gene. Gene Ther 11:1434-40
Yu, Wei; Pirollo, Kathleen F; Yu, Bin et al. (2004) Enhanced transfection efficiency of a systemically delivered tumor-targeting immunolipoplex by inclusion of a pH-sensitive histidylated oligolysine peptide. Nucleic Acids Res 32:e48
Xu, Liang; Frederik, Peter; Pirollo, Kathleen F et al. (2002) Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. Hum Gene Ther 13:469-81
Pirollo, K F; Xu, L; Chang, E H (2000) Non-viral gene delivery for p53. Curr Opin Mol Ther 2:168-75