Abstract LB-115: Preclinical assessment of retinoid X-receptor agonist, UAB110, for potential treatment of cutaneous T-cell lymphoma

Abstract

Abstract Cutaneous T-cell lymphomas (CTCLs) are a group of non-Hodgkin diseases characterized by localization of neoplastic T-cells in the skin. The most common forms of CTCLs are mycosis fungoides (MF) and Sézary syndrome (SS). Bexarotene (Targretin®) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist (rexinoid) for the treatment of CTCLs. Despite its low toxicity compared to retinoids and other chemotherapeutic agents, it induces hypothyroidism and markedly elevates serum triglycerides (TGs). Thus, improved rexinoids for the treatment of this indolent disease is necessary. A potential candidate is the novel rexinoid, UAB110, which does not elevate TGs in animal studies and effectively prevents mammary cancer development. Compared to bexarotene, it has higher binding affinity for RXRα receptor and transcriptional activation activity. The purpose of this study is to assess preclinical efficacy, mechanism of action of UAB110, and compare its action with bexarotene and the rexinoid 9-cisUAB30 (UAB30) using human-derived CTCL cell lines, MyLa and HuT78, which are representative of MF and SS, respectively. Cell proliferation analysis and cell-cycle related markers were determined by hemocytometer and Western blot analysis, respectively. UAB110 is as effective as UAB30 and bexarotene in suppressing cell proliferation. Furthermore, it significantly (p < 0.05 relative to DMSO control) suppresses the protein expression of SKP2 (S-phase kinase-associated protein 2, a F-box protein that targets p27kip1 for degradation by 26S proteasome) and PSMA7 (proteasome subunit alpha type 7, a component of the 20S proteolytic complex in 26S proteasome). The decrease in SKP2 resulted in a concomitant up-regulation of p27kip1 protein, the major cell cycle inhibitor. The downregulating of PSMA7 impaired the 20S proteasome activity in both cell lines. These findings indicate that the novel rexinoid is effective in inhibiting cell proliferation of CTCL cells, in part, by suppressing SKP2 expression and the 20S proteasome activity resulting in increasing p27kip1 protein. In sum, UAB110 and also UAB30 with minimal effect in elevating serum TGs are both possible alternatives to bexarotene for the treatment of CTCLs. Citation Format: Chu-Fang Chou, Jason Esla, Venkatram Atigadda, Donald Muccio, Clinton Grubbs, Elmets Craig, Pi-Ling Chang. Preclinical assessment of retinoid X-receptor agonist, UAB110, for potential treatment of cutaneous T-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-115.