Lung cancer chemoprevention: current status and future prospects

Abstract

Lung cancer is the leading cause of cancer death worldwide, making it an attractive disease for chemoprevention. Although avoidance of tobacco use and smoking cessation will have the greatest impact on lung cancer development, chemoprevention could prove to be very effective, particularly in former smokers. Chemoprevention is the use of agents to reverse or inhibit carcinogenesis and has been successfully applied to other common malignancies. Despite prior studies in lung cancer chemoprevention failing to identify effective agents, we now have the ability to identify high-risk populations, and our understanding of lung tumour and premalignant biology continues to advance. There are distinct histological lesions that can be reproducibly graded as precursors of non-small-cell lung cancer and similar precursor lesions exist for adenocarcinoma. These premalignant lesions are being targeted by chemopreventive agents in current trials and will continue to be studied in the future. In addition, biomarkers that predict risk and response to targeted agents are being investigated and validated. In this Review, we discuss the principles of chemoprevention, data from preclinical models, completed clinical trials and observational studies, and describe new treatments for novel targeted pathways and future chemopreventive efforts.

Figure 1

Potential tobacco smoke induced carcinogenic processes for chemopreventive intervention. Hallmarks in the development of squamous-cell lung cancer as the bronchial epithelium proceeds through pathological stages in the progression to CIS. Tobacco cessation and chemopreventive agents can promote repair and block progression. Abbreviation: CIS, carcinoma in situ.

Figure 2

Schematic pathway of the cyclooxygenase pathway showing conversion of arachidonic acid to prostanoids. The fatty acid arachidonic acid is released from the membrane phospholipids by several forms of phospholipase A₂, which have previously been activated by one of a range of stimuli. The free arachidonic acid is converted to the cyclic endoperoxides prostaglandin G₂ and prostaglandin H₂ by the sequential COX and HOX actions of PGHS-1 or PGHS-2; these isoforms both have dual COX and HOX activity. Aspirin inhibits the conversion of free arachidonic acid to prostaglandin G₂ by inhibiting the COX activity of PGHS-1 or PGHS-2. Prostaglandin H₂ is converted into a range of prostanoids by tissue-specific isomerases; therefore, the inhibition of this pathway prevents (or reduces) the downstream activation of a superfamily of G-protein-coupled receptors by these prostanoids. Prostacyclin binds to both a transmembrane G-protein coupled receptor and to PPARγ, a nuclear receptor. Abbreviations: ASA, acetylsalicylic acid; COX, cyclooxygenase; HOX, hydroperoxidase; NSAIDs, nonsteroidal anti-inflammatory drugs; PGHS, prostaglandin H synthase; PPARγ, peroxisome proliferator-activated receptor γ.