J. Silvio Gutkind, Ph.D., Chief
Molecular mechanisms involved in squamous cell carcinogenesis
Carcinogenesis is a multistep process involving the activation of cellular protooncogenes and inactivation of tumor suppressor genes. In spite of the high frequency of oral cancers, little is known about the molecular events which contribute to disease initiation and progression. Recently, it has been found that 40-50% of squamous cell carcinomas harbor inactivating mutations in the p53 tumor suppressor gene. However, there is limited information on tumor-causing genes expressed in oral cancers. Current efforts to identify oncogenic sequences expressed in squamous carcinoma cells will contribute to the understanding of the basic mechanisms of neoplastic conversion in oral cancer, and will provide useful new biomarkers of disease progression.
Development of animal models for squamous carcinogenesis
One of the major limitations in the area of oral cancer research is the lack of suitable animal models to test the validity of current genetic models of tumorigenesis, and to explore the effectiveness of treatment modalities or chemopreventive approaches. The final goal of this project is the development of oral models (for example, rat oral squamous cell carcinoma models, transgenic mice targeting oncogenes to oral mucosa, HPV transgenics treated with oral carcinogens, animal and human oral cell lines) to generate tumor tissues at various stages of neoplastic progression for evaluating marker expression, biochemical changes, and treatment strategies. This may allow us to recapitulate in animal models all the molecular events believed to lead to squamous cell carcinomas in humans, and will facilitate the search for alternative oral cancer treatments.
Oral cancers result from progressive genetic changes leading to malignancy in a multistep process. If molecular markers representing early and late events can be defined, it would be possible to identify persons at high risk of oral cancer, namely, those with lesions progressing through the premalignant state. Such biochemical markers heralding malignancy would facilitate the monitoring of recurrence and expedite the evaluation of chemopreventing agents, a number of which are ready for testing in clinical trials. Current efforts to identify molecular and cellular markers of oral tumorigenesis focus on the analyzing markers of proliferation, squamous differentiation, and genetic changes in genes believed to play a role in the carcinogenic process. Additional approaches involve the study of molecules whose levels of expression change during tumor progression, using cellular RNAs derived from normal, dysplastic, and malignant keratinocytes. The identity of the differentially expressed transcripts will then be established using the nucleotide information generated by the Human Genome Project and by private efforts. This work is expected to help identify gene products that determine the transformed and/or the metastatic phenotype, as well as additional molecules that, without playing an obvious role in the neoplastic process, can nevertheless be used as clinically useful markers of squamous carcinogenesis.
Development of new therapeutic approaches
The ultimate goal of this project is to develop novel therapies aimed at improving the quality of life and life expectancy of oral cancer patients. The recent use of high throughput screening procedures followed by computer assisted molecular modeling and chemical synthesis of lead compounds has tremendously accelerated the discovery of small molecule inhibitors of signaling and cell cycle controlling proteins. Several such drug candidates are now becoming available. These drugs will be evaluated for activity, efficacy and toxicity in biologically relevant in vitro and in vivo models of squamous cell carcinogenesis. Cell systems and animal models described above are expected to be of significant importance for this drug evaluation, aimed at the launching of a clinical oral cancer program. The use of gene transfer approaches to prevent neoplastic conversion of premalignant lesions and to treat oral cancer will also be explored, with emphasis on the evaluation of new genetically engineered viruses and viral vectors for their ability to express genes in oral tissues and for their therapeutic potential in squamous cell carcinoma.