The Convergent Development of Molecular-Targeted Drugs for Cancer Treatment and Prevention

Abstract

Advances in our understanding of multistep and field carcinogenesis are erasing the clear demarcation of intraepithelial neoplasia from invasive neoplasia.The growing ability to define a very high risk of cancer is forging important commonalities between prevention and therapy, such as in potential prognostic/predictive markers, agents, and side effects that patients would be willing to tolerate, and the logistics of definitive trials. The emergence of promising new moleculartargeted agents and new technologies for screening and early detection provides new opportunities for applying clinical trial designs that integrate therapy and prevention end points. Such trials may be used to facilitate targeted drug development and help identify strategies for both cancer prevention and advanced cancer therapy. These several advances are creating a convergence of cancer therapy with cancer prevention that promises to streamline the development of targeted drugs and improve the control of major cancers.Advances in the molecular biology of carcinogenesis are gradually erasing any clear demarcation between preinvasive and invasive neoplasia and are bringing about a convergence between cancer therapy and prevention research. Several models of multistep and field carcinogenesis reflect the convergence of precancer and cancer biology. The growing ability to define very high risk of cancer is further bridging the gap between therapy and prevention. The final piece of the convergence puzzle is molecular-targeted drug development, which is already providing settings for the convergent development of targeted therapy and prevention drugs (1, 2).

Cancer Prevention: Epigenetics Steps Up to the Plate

“…Investigators showed that methylation markers in the sputum of chronic smokers were associated with a high risk of lung cancer (35). This study raises the intriguing potential for designing a feasible clinical epigenetic strategy for these patients, whose high lung-cancer risk may allow the use of current (rather toxic) agents and certainly would help reduce trial size and duration (36). New, less toxic epigenetic-altering agents also could be tested, potentially targeting the same methylation markers that denote elevated risk in these patients and which could serve as biomarkers of drug activity.…”

Update on Cancer Prevention Research in the United States and China: The 2009 China—U.S. Forum on Frontiers of Cancer Research

“…He indicated that early treatment will involve molecular tumor profiling to identify successfully treated patients who are at highest risk of reoccurrence, whereas late cancer prevention involves molecular profiling to identify microneoplasia/intraepithelial neoplasia (IEN) patients at highest risk of primary cancer. New molecular targeted agents combined with new technologies for screening provide unique opportunities for developing clinical trials that integrate treatment with prevention end points thus creating a convergence of prevention and therapy (30). This sharing of molecular targets provides a platform for convergent (treatment and prevention) drug development, which promises to accelerate the reduction of cancer burden (30).…”

“…New molecular targeted agents combined with new technologies for screening provide unique opportunities for developing clinical trials that integrate treatment with prevention end points thus creating a convergence of prevention and therapy (30). This sharing of molecular targets provides a platform for convergent (treatment and prevention) drug development, which promises to accelerate the reduction of cancer burden (30). Dr. Peng Huang (Johns Hopkins University) discussed the advantages of designing clinical trials with multiple end points as opposed to single outcomes and introduced the idea of a new measure, the global treatment effect (GTE), to summarize a treatment's efficacy from multiple primary outcomes (31).…”

Assessing Efficacy in Early-Phase Cancer Prevention Trials: The Case of Oral Premalignancy

“…The only published data on this question from a prospective clinical trial showed a nonsignificant association between oral premalignant lesion response and cancer development (23). An ongoing phase III clinical trial using erlotinib in subjects with high-risk oral leukoplakia will assess both leukoplakia response and cancer incidence within the same study (24). The relationship between oral premalignant lesion response and cancer development may differ significantly between high-risk and low-risk lesions (21,25).…”