Retinoids in pancreatic cancer

Prognosis of advanced, unresectable pancreatic adenocarcinoma remains dismal and has not significantly improved over the past 20 years. In a broad panel of preclinical experimental settings we have therefore evaluated the effects of retinoids on human pancreatic carcinoma cells in vitro and in vivo. We found that retinoid treatment results in inhibition of growth, induction of cellular differentiation and decreased adhesion to certain components of the extracellular matrix, all features compatible with a "less malignant" phenotype. Furthermore, retinoids act synergistically antiproliferative when combined with interferon-alpha. Using transient and stable genetic transfer studies we were able to identify two retinoid receptor subtypes responsible for mediating the growth inhibitory effects as well as retinoid sensitivity. In addition we observed a crucial functional interplay between the retinoid signalling pathway and the expression of a distinct protein kinase C isoenzyme, which determines the direction of the growth regulatory effects of retinoids. Based on these encouraging preclinical results we initiated a phase II clinical trial in which patients with advanced pancreatic carcinoma were treated with retinoic acid in combination with interferon-alpha. This therapeutic regimen was well tolerated and resulted in prolonged stable disease in approximately two thirds of the patients. In summary, these studies suggest that retinoids might be beneficial in the treatment of advanced pancreatic carcinoma patients based on their pleiotropic effects on tumor cell biology.