M08-04: Retinoids and rexinoids in lung cancer biology and therapy

Abstract

Retinoids are natural or synthetic vitamin A derivatives that have long been implicated in an important role in cancer biology and prevention. Studies show that vitamin A deprivation can lead to an increased carcinogenesis in the lung and upper aerodigestive tract. Early trials by Hong et al of a high dose synthetic retinoid, isotretinoin, showed that this agent could reverse early to intermediate head and neck premalignancy, and that high doses of isotretinoin given for one year in 8 patients treated definitively for an advanced head and neck primary tumors prevented second primary tumors (SPTs) for a period of two to three years after cessation of retinoid therapy. However, high doses of isotretinoin were intolerable to most patients, and a larger randomized trial of isotretinoin in head and neck squamous cell cancer failed to reproduce the earlier data, with no evidence of reduction in SPTs. Moreover, this agent was ineffective at tolerable doses in preventing SPTs in patients treated for early stage non-small cell lung cancer (NSCLC). Both retinoids and rexinoids, and in fact, all synthetic vitamin A compounds function by binding to cograte retinoid nuclear receptors, the retinoic acid receptors (RARs), and retinoid X receptors (RXRs). Synthetic rexinoids were first synthesized in the early 1990s, given the diverse binding partners (RAR/RXR or LXR/RXR heterodimers, for example or RXR/RXR homodimers) that these compounds can bind to. The rexinoid, bexarotene, was introduced into clinical trials in the early 1990s and was shown to produce prolonged stabilization in patients with NSCLC. Subsequent combinations with standard front line chemotherapy for NSCLC appeared promising with longer than expected median survivals in the absence of more pronounced responses. Two phase III trials of bexarotene with front line chemotherapy failed to show superiority over the standard chemotherapy arms. However, in those patients who had grade 3 hypertriglyceridemia due to bexarotene, median survival appeared to be meaningfully better than in those patients treated with chemotherapy alone. The biological mechanisms underpinning these surprising results are unclear at this time and are currently under investigation. Given the broad biological effects of rexinoids and retinoids, continued investigation of these agents in lung and aerodigestive tract cancers is imperative for the advancement of this important class of differentiating agents.