A phase I/II study of bexarotene with carboplatin and weekly paclitaxel for the treatment of patients with advanced non-small cell lung cancer

Lung cancer is the leading cause of cancer-related mortality in the United States with an estimated 222,500 new cases and 155,870 deaths in 2017 (1). Despite the progress in development of targeted treatments and immunotherapy, cytotoxic chemotherapy remains the backbone of many therapeutic regimens for advanced non-small cell lung cancer. Its use is associated with improved survival and symptom control (2). Yet many patients do not respond and eventually all patient progress. Better understanding of the molecular mechanisms of lung carcinogenesis is expected to lead to improved treatment outcomes. Retinoids and rexinoids are vitamin A derivatives implicated in cell reproduction, differentiation, growth and immune function (3,4). They act by altering gene expression mediated through two families of nuclear receptors: the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Retinoids bind to RARs, and rexinoids bind to RXRs (5). Retinoids and rexinoids induce degradation of cyclin D1 by ubiquitination and proteolysis in the proteosome, resulting in inhibition of cell growth (6). These in vitro observations have been confirmed in tissue analysis of tumors of early stage NSCLC patients treated with a rexinoid before resection (7). Amplification or overexpression of cyclin D1 plays a pivotal role in the development of numerous human cancers (8). In NSCLC, high cyclin D1 protein expression has been linked to shorter overall cancer-free survival (9)