The number of cases of malignant cutaneous melanoma has been rising at an alarming rate over the last decades, at about 4% per year, and it has been estimated that up to 1 in 80 Americans will develop melanoma. Despite years of research, there are no viable treatment modalities for advanced melanoma, and mortality rates remain exceptionally high. This saddening fact emphasizes the urgent need for new effective drugs, not only to treat existing tumors, but also to inhibit occurrence of second primary cancers after convential treatment modalities, or prevent further transformation of premalignant cells in high-risk patients. This application aims to address these issues by assessing the chemopreventive activity of a promising selection of drugs in a novel, inducible murine melanoma model. This uniquely suitable model is the only one to allow synchronization of the onset of development of cutaneous melanoma on a genetic background, which accurately mimics that of human disease. By adding doxycyclin (Dox) to the drinking water, expression of H-RASV12G is induced in melanocytes on a p16INK4A-ARF null background. This cooperativity then results in development of largely non-metastatic, cutaneous melanomas in 25% of mice with an average latency of 60 26 days. The mouse model itself has already been thoroughly analyzed in terms of tumor pathology, which closely resembles that of human disease, and the essential role for H-Ras in maintaining tumor growth. However, these mice have never been used to develop new chemoprevention protocols. We will test the efficacy of the following drugs: suberohydroxamic acid (SHA), celecoxib, retinoic acid (RA) and lovastatin. These drugs were selected because they i) are non-toxic (except for RA, but 13-cisRA provides a less toxic clinical alternative), ii) are widely used already, iii) affect different biochemical pathways, iv) have shown promise as chemopreventive agents in other studies, and v) have shown potential to enhance each other's activity when combined. Our working hypothesis is that these drugs will inhibit tumor growth to some degree, but that the combination of at least some of these drugs will inhibit proliferation of premalignant melanoma cells to a much larger extent than any drug alone can achieve, without significantly increasing toxicity. We propose to induce 4-week old animals drugs, and determine chemopreventive antitumor efficacy by monitoring size, number and location of skin tumors.
Specific Aim I proposes to establish an optimal chemoprevention drug protocol to suppress tumor development.
Specific Aim II proposes to establish expression of key cell cycle regulatory genes in control, drug-responsive and non-responsive transgenic tumors to determine whether expression is associated with tumor growth and responsiveness to therapy. The results of these experiments in this inducible melanoma model will allow us to assess whether our protocol should be considered for use in phase I trials in high risk patients, which is the long term goal of this application.
