A phase I trial of erlotinib and bexarotene as a targeted combination therapy for aerodigestive tract cancers
2005
7093 Background: We previously reported the overexpression of the epidermal growth factor receptor (EGFR) and cyclin D1 as early events in lung carcinogenesis. All-trans-retinoic acid (RA) suppressed EGFR expression through a transcriptional mechanism and cyclin D1 through proteasome-dependent proteolysis. Non-classical retinoids such as the rexinoid, bexarotene (B), repress both cyclin D1 and EGFR expression but signal independent of RAR-beta, which is often deregulated in lung carcinogenesis. Combining an EGFR tyrosine kinase inhibitor, erlotinib (E), with B induced at least additive suppression of growth and cyclin D1 expression in RA-resistant human bronchial epithelial cells which had silenced RAR beta and in some lung cancer cell lines. Methods: A phase I trial of E and B was conducted in patients (pts) with advanced aerodigestive tract cancers. Primary objective - maximum tolerated dose. Secondary objectives - toxicities, efficacy, and surrogate markers of response (cyclin D1) in buccal swabs from ...
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