Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges

Area of Science:

• Oncology
• Nutritional Biochemistry
• Chemoprevention Research

Background:

• Phase III trials of selenomethionine (SeMet) and SeMet-rich selenized yeast (Se-yeast) for prostate cancer and non-small cell lung cancer (NSCLC) prevention showed negative efficacy outcomes in North America.
• These results led to the rejection of SeMet/Se-yeast for cancer prevention in selenium-adequate populations, highlighting issues with trial design and agent selection.

Purpose of the Study:

• To analyze the lessons learned from failed selenium-based cancer chemoprevention trials.
• To propose next-generation selenium (Se) forms as potentially more effective agents for cancer chemoprevention.
• To outline the necessary steps for future research and development of selenium chemoprevention strategies.

Main Methods:

• Review and analysis of outcomes from Phase III clinical trials involving SeMet and Se-yeast.
• Identification of key deficiencies in the "antioxidant hypothesis" application and agent selection processes.
• Proposal of a new research paradigm focusing on mechanism-based preclinical assessments and next-generation Se agents.

Main Results:

• The "antioxidant hypothesis" for cancer prevention was likely tested in inappropriate patient populations.
• The selection of SeMet and Se-yeast lacked sufficient preclinical efficacy validation, a standard practice in drug development.
• Next-generation Se forms, like methylselenol precursors, present a promising but challenging avenue for cancer chemoprevention.

Conclusions:

• Selenium (Se) chemoprevention requires a paradigm shift, moving beyond the "antioxidant hypothesis" in Se-adequate populations.
• Next-generation Se agents necessitate robust, mechanism-based preclinical efficacy and safety evaluations before human trials.
• Smaller, mechanism-driven Phase I/II trials are crucial to guide future definitive Phase III chemoprevention studies with novel Se compounds.