Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma

Abstract

Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell cycle analysis, migration, and invasion were studied using alamarBlue® assays, FACS, and Transwell® assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment.

UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts

“…After injection, the mice were randomized to receive vehicle-treated, RA-treated (53 mg/kg/day), or UAB30-treated chow (100 mg/kg/day) (n = 10 mice per group). These dosages were based upon previous in vivo experiments [19, 20, 28]. The flank tumors were measured twice weekly using calipers.…”

“…These doses were based upon previous data in the literature [19, 20, 28]. The animals were monitored twice daily for neurologic symptoms and followed for overall survival.…”

“…We have previously demonstrated the efficacy of UAB30 in other pediatric solid tumors, including the neuroectodermal tumor, neuroblastoma [19, 20]. This knowledge, combined with effects of other retinoids on medulloblastoma noted by others, has led us to hypothesize that treatment of group 3 medulloblastoma patient-derived xenografts (PDXs) with UAB30 would lead to decreased tumorigenesis in vitro and in vivo .…”

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

“…A novel retinoid, 9- cis -UAB30 (UAB30), a synthetic analog of 9- cis -retinoic acid, binds selectively to the retinoid X receptor (RXR) leading to activation of genes involved in induction of differentiation and apoptosis [7, 8]. UAB30 has minimal toxicity compared to other retinoids [7, 9 – 11], and has recently been found to be effective in decreasing xenograft tumor growth in neuroblastoma [12]. Investigators have demonstrated the effectiveness of retinoids against adult liver [13] and kidney tumors [14].…”

“…Investigators have demonstrated the effectiveness of retinoids against adult liver [13] and kidney tumors [14]. These data in neuroblastoma [12], and the prior results with retinoids in adult renal and hepatic malignancies [13, 14], led us to believe that UAB30 may have an effect upon tumorigenicity in rare pediatric renal and hepatic malignancies.…”