Classical retinoids prevent in vitro transformation of human bronchial epithelial (HBE) cells and repress cyclin D1 and EGFR expression after tobacco carcinogen exposure. Clinical activity of classical retinoids is limited by the frequent silencing of the critical retinoic acid receptor, RAR-beta. Certain non-classical retinoids also repress cyclin D1 and EGFR expression but signal independent of RAR-beta, suggesting non-classical retinoids could by-pass clinical retinoid resistance. EGFR tyrosine kinase inhibitors (TKIs) are active in lung cancer therapy, and selectively repress cyclin D1 expression in vitro.
In order to extend our in vitro findings, we performed a proof-of-principle trial with erlotinib (OSI-774), in patients with aerodigestive tract (ADT) tumors. Tumor tissue and plasma pharmacokinetics were performed along with pre- and post-treatment biopsies and immunohistochemical analyses. We also combined a non-classical retinoid, bexarotene, and erlotinib in vitro to determine effects on growth and cyclin D1 expression. Based on the in vitro findings, a phase I/II trial with bexarotene and erlotinib in advanced ADT tumors resistant to chemotherapy was performed. The objectives were to determine the maximum tolerated dose of the combination, toxicity, efficacy, and surrogate markers of response in buccal epithelial cells.
In the proof-of-principle trial, 4 patients were evaluable, 2 had pathologic responses. Cyclin D1 and Ki-67 expression decreased in these responding cases. In contrast, non-responding cases did not exhibit these changes and had much lower tissue erlotinib levels than did responders. These findings confirmed cyclin D1 repression as an EGFR-TKI therapeutic target. Combining bexarotene and erlotinib in vitro induced additive repression of growth and cyclin D1 expression. The phase I/II trial of this combination revealed that the combination is well tolerated. To date, one partial response for more than 1 year, 1 minor response, and 4 patients with stable disease were observed. Updated results will be presented.
Preliminary results indicate that the combination of bexarotene and erlotinib is well-tolerated and active.
Further studies of this combination are warranted in lung cancer therapy or chemoprevention.
W.J. Petty, OSI Pharmaceuticals, Ligand Pharmaceuticals