Reprogramming the Course of Precancer with Targeted Therapeutic Intervention: Lessons from Interception in Gastric Preneoplasia

Abstract Although the majority of gastric cancer research has focused on the treatment of late-stage tumor masses, intervention at precancerous stages represents a far more amenable strategy to achieve long-term prevention of cancer. In contrast with preventative strategies focusing on lifestyle changes and nutritional alterations, few efforts have evaluated the ability to use short-term therapeutic interventions to reverse precancer and thereby reduce risk for developing cancer. The distinct advantage of this approach lies in the recognition that precancerous lesions are far more homogeneous with fewer, if any, driver mutations that can lead to therapy resistance. Our recent studies have demonstrated that a limited 2- to 4-week course of MEK inhibitor in rodent models, and now in a human phase I trial, reduced intestinal metaplasia and increased normal acid-secreting parietal cells in the gastric mucosa. These findings demonstrate the efficacy of targeting the precancerous metaplasia with limited duration treatments that allow recrudescence of normal gastric lineages. Further progress to bring these approaches to clinical utility will require a major change in the outlook of pharmaceutical companies and physicians for initiatives to target precancer.