Abstract ED05-03: Rexinoid nuclear receptors and cancer prevention

Abstract

Abstract This session will present on the use of retinoid X receptor (RXR) agonists (rexinoids) for cancer prevention. Several areas will be highlighted. Using lung cancer as a model, both preclinical and clinical evidence for use of RXR-selective ligands in cancer prevention will be discussed. Emphasis will be placed on the pharmacology of newer rexinoids. Lung cancer is the most common cause of cancer death for men and women. Innovative ways to combat lung cancer are needed. A previously unrecognized antineoplastic pathway that triggers proteasomal degradation of different cyclins was found. Both retinoic acid receptor (RAR) and RXR agonists (among other agents) cause degradation of cyclins. This confers check point arrest and repair of carcinogenic damage of DNA in bronchial epithelial cells. Mechanisms responsible for this induced proteasomal degradation will be presented. The critical receptor that confers cyclin destabilization is RARβ. Yet, silencing of RARβ and of the novel isoform RARβ1' likely accounts for clinical resistance to classical retinoids in lung carcinogenesis. It was explored whether RXR/RAR heterodimer complex activation with a rexinoid triggers G1 cyclin destabilization. This was found and this result implied that the same pathway would be engaged in vivo. To establish if this occurred in the lung, transgenic mice were independently engineered with human surfactant C-driven wild-type cyclin E or a proteasome-degradation resistant cyclin E species. This was done because human pre-malignant and malignant lung lesions deregulate cyclin expression. Intriguingly, these mice recapitulated frequent features of lung carcinogenesis found in patients. These changes were enhanced by the expression of degradation-resistant cyclin E species. This finding was built upon by showing that a rexinoid can chemoprevent lung cancers in vinyl carbamate-induced lung tumors within strain A/J mice. The epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) erlotinib also repressed cyclin D1 expression, but through different mechanisms. The rexinoid bexarotene was combined with erlotinib. Effects on transgenic lung cancer cell growth and cyclin D1 expression were studied when KRAS or KRAS/p53 mutations were present or not. Over the past decade, this work was confirmed by extending analyses into the cancer clinic through a series of five clinical trials that moved this work through successive phase 0, phase I, and phase II trials. In window of opportunity trials, pharmacodynamic responses (cyclin repression and induced necrosis and inflammatory responses) were seen when intratumoral drug levels were comparable to those detected in vitro. Cyclin D1 levels were measured in pre-treatment versus post-treatment tumor biopsies. A phase II trial in heavily pre-treated stage IV non-small cell lung cancer (NSCLC) cases was performed. EGFR expression and KRAS mutations were examined in these cases. Findings revealed substantial cyclin repression and reduction of lung cancer growth by combined treatment with a rexinoid and EGFR-TKI. Cyclins were repressed while necrosis and inflammatory responses were induced in the window of opportunity trial independent of KRAS or activating EGFR mutations. This refractory NSCLC trial had 3 major clinical responses (2 had KRAS or EGFR mutations) with prolonged survival, as will be discussed. Median survival was 22 weeks (16 weeks for controls). Hypertriglyceridemia or rash significantly increased median overall survival to 24 weeks. This regimen revealed anti-tumor activity independent of the presence of EGFR or KRAS mutations in NSCLCs. Notably, these findings were independently replicated in the lung cancer BATTLE trial. An analogous approach was used to uncover a distinct rexinoid-induced protein destabilization pathway that involves the deubiquitinase USP18/UBP43, as will be discussed. Taken together, these findings reveal that rexinoid-induced cyclin destabilization is a previously unrecognized antineoplastic pathway. Thus, additional rexinoid trials for cancer therapy and prevention are warranted. Citation Format: Ethan Dmitrovsky. Rexinoid nuclear receptors and cancer prevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED05-03.