NSAIDs for PI3K-altered head and neck cancer: a biomarker-driven therapeutic opportunity

Non-steroidal anti-inflammatory drugs (NSAIDs), primarily aspirin, have long been studied for their anti-cancer properties. Epidemiologic studies have reported diminished rates of several cancers in regular NSAID users. NSAIDs inhibit cyclooxygenase (COX) enzymes, thus decreasing the production of pro-inflammatory prostaglandins, which are known to stimulate tumor growth. Efforts to characterize the molecular features of human cancer, such as The Cancer Genome Atlas (TCGA), have revealed the presence of genetic alterations that activate the Phosphoinositide 3-kinase (PI3K) signaling pathway in a large subset of cancers, including head and neck squamous cell carcinoma (HNSCC). Mutation or amplification of the PIK3CA oncogene, or decreased expression of the tumor suppressor protein phosphatase and tensin homolog (PTEN), is found in one-third of HNSCCs. Cumulative evidence from retrospective clinical analyses and preclinical laboratory studies has demonstrated the anti-tumor effects of NSAIDs, including aspirin, in PI3K-altered HNSCC. In a recent trial, daily aspirin significantly decreased disease recurrence in PI3K-altered colorectal cancer, thus providing a compelling justification for a prospective trial of aspirin in HNSCC. Given the prevalence of PI3K alterations in HNSCC, aspirin has potential to benefit nearly 1 million patients with HNSCC annually worldwide.