. Oral cancer affects around 30,000 persons/year in the USA and leads to around 15,000 deaths, yet no new forms of treatment have been introduced for many decades. One form of gene therapy for oral cancer could consist of introducing the HSV gene for TK into the tumor, followed by administration of the prodrug ganciclovir. Unfortunately there are no ways of limiting the expression of any such gene to the tumor cells. The applicant proposes to develop ways of maximizing the expression of the TK gene in oral cancer cells, while minimizing expression in non-cancer cells. This will be done by developing new gene promoter/enhancer elements that will be preferentially active in oral cancer cells.
In Specific Aim 1, new gene promoters will be developed which show higher activity in oral cancer cells than in other cells. This will be done by linking a promoter which shows some of the desired qualities to a selectable marker gene - the constructs will the undergo random mutations in oral cancer cells and the improved promoters will be recovered from the surviving cells.
In Specific Aim 2, the new promoters will be compared to known promoters for strength, specificity and spectrum of action. This will be done by linking the promoters to reporter genes and introducing them into a large panel of cell lines.
In Specific Aim 3, the applicant will use the promoters with the most specific activity and broadest spectrum of action to induce expression of the TK gene in cells, so as to obtain selective killing of oral cancer cells by ganciclovir. If the project succeeds in obtaining selective killing of oral cancer cells it will be extended in the future to more extensive experiments in animal models, and possibly to trials in human patients.
