Cancer prevention and therapy: The molecular interface

Proc Amer Assoc Cancer Res, Volume 46, 2005 SY25-4 Cancer prevention and therapy are beginning to share an important interface within molecular-targeted drug development. Major advances in our molecular understanding of premalignant and malignant neoplasia, cancer risk and prognosis, the mechanisms of action of molecular-targeted drugs having profiles with less toxicity and more cytostatic activity, and technology such as molecular imaging can be applied both in preventing and treating cancer. An excellent example of the early interface of cancer prevention and therapy is molecular and early clinical research in oral neoplasia, including intraepithelial neoplasia (IEN) and cancer. Oral cancer is a major worldwide cancer accompanied by high morbidity and mortality rates that have resisted improvement for decades despite intensive standard therapy and prevention (mainly smoking cessation) approaches. Tobacco smoking is the major overall risk factor of oral cancer development, which is a multistep, multifocal process over a wide field and involving intraepithelial clonal spread. Smoking, however, does not accurately measure an individual smoker’s risk of oral cancer; therefore, intense efforts to identify precise molecular markers of cancer risk are a major focus of research in oral carcinogenesis. These efforts have identified two molecular biomarkers of genomic instability, aneuploidy and allelic imbalance, that can accurately measure the risk of oral cancer associated with oral IEN. Oral IEN with aneuploidy has such an extremely high risk of cancer development and mortality that this setting has been viewed as tantamount to a therapy setting, further highlighting the molecular interface between cancer prevention and therapy. Retinoid studies in the oral IEN model have pioneered molecular methodologies with applications to cancer prevention and therapy. These studies have elucidated aspects of the roles of retinoic acid receptor-beta, p53 , genomic instability, allelic imbalance, and cyclin D1 in oral neoplasia, thus advancing the overall understanding of the biology of intraepithelial and invasive carcinogenesis and of molecular mechanisms and targets for potential preventive and therapeutic agents. Such advances are important for monitoring preventive and therapeutic interventions and for assessing cancer risk, pharmacogenomics and prognosis. Clinical management of oral IEN varies from watchful waiting to complete resection, which frequently does not prevent oral cancer in high-risk patients. Molecular approaches are helping to identify the most suitable patients for resection (e.g., diploid oral IEN patients) or new preventive approaches (e.g., aneuploid oral IEN patients). New approaches, such as combinatorial chemoprevention, under development for molecularly defined high-risk oral IEN patients as well as for head-and-neck cancer patients represent molecular advances that highlight the interface developing between cancer prevention and therapy. This interface is in promising early phases, such as designing therapy trials with imbedded prevention endpoints, that should continue to mature so as to help prevention and therapy fulfill their respective promises for reducing the burden of major worldwide cancers.