Repurposing Approved Drugs for Chemoprevention: Mechanistic Insights and Clinical Prospects

Abstract

In this paper, perspectives on the use of approved, well-characterized drugs as chemopreventive agents to prevent cancer incidence among identified risk populations will be discussed. The background adds that pleiotropic agents, such as metformin, aspirin/NSAIDs, statins, selective ER modulators, bisphosphonates, and antivirals, are agents that overlap with carcinogenic pathways with tolerable doses and known safe profiles. The rationale is to combine the mechanistic evidence with trial evidence to determine what drug-risk combinations result in net benefit and how biomarkers can be used to inform it. The anticipated outcomes are identification of mechanism-based actionable mechanisms (AMPK activation, COX-2 inhibition, HMG-CoA-mevalonate pathway blockade, hormonal pathway modulation, anti-viral oncoprevention), definition of requirements to prioritize the candidates (effect size, toxicity, interaction with exposures, cost), and a description of responsive phenotypes by molecular risk markers, minimal residual disease signals, and polygenic/clinical scores. The paper envisions the proposal of adaptive trial designs, use of pragmatic endpoints (precancer regression, validated intermediate biomarkers), drug-diet synergy concepts and pharmacovigilance models that are appropriate to long-term prevention. It will map regulatory and implementation strategies with a particular focus on real-world evidence networks to promote rapid adoption in cases where benefit-risk and value are positive.