Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

Abstract

Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side effect profile. In this current study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo. We successfully demonstrated decreased cellular proliferation, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should further be investigated as a developing therapeutic in these rare and difficult to treat, pediatric solid organ tumors.

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

“…We have previously demonstrated that UAB30 causes decreased cell migration and invasion in other pediatric solid tumors [19, 20], prompting us to investigate whether similar phenotypic changes occur in MB PDX cells following RA or UAB30 treatment. Using Transwell™ plates, we noted that both RA and UAB30 significantly decreased cell migration and invasion in all three MB PDXs.…”

“…Following injection of D425 cells (2.5 × 10 6 ) into the right flank of athymic nude mice, animals 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 doses were based on previous animal studies and have been shown to be well-tolerated in this species [19, 20]. Flank tumors were measured twice per week and animals were euthanized when tumors reached IACUC parameters.…”

“…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 .…”