Abstract LB518: Osteochondromas respond and its development is inhibited by retinoic acid nuclear receptor gamma agonist treatment
Authors: Garcia Sonia , Tian Hongying , Herzenberg John , Abzug Joshua , Ng Vincent , Cellini Ashley , Iwamoto Masahiro , Enomoto-Iwamoto Motomi 
Published: June 2022

Osteochondromas (OC) are cartilage-capped tumors that arise near growing physis and are considered the most common benign bone tumor in children. They can lead to skeletal deformity, pain, loss of motion and neurovascular compression. Occasionally, malignant degeneration can occur. OC is thought to arise by mysregulation of chondrogenesis or chondrocyte differentiation, leading to ectopic cartilage formation. OC can occur as a solitary or multiple OC (MO). MO can occur from a hereditary cancer syndrome in which EXT1 and EXT2 are the major causative genes. Currently, treatment is limited to surgical resection only. There are no available FDA-approved therapies for MO. Previous translational research suggested that retinoic acid nuclear receptor gamma agonist (RARγ) suppresses ectopic cartilage formation including OC in rodent models. These preclinical studies led to a clinical trial to study the efficacy and safety of Palovarotene, a RARγ agonist, for the systemic treatment of MO (NCT03442985). The clinical trial was terminated due to concerns of skeletal toxicity observed in pediatric patients. To overcome this adverse action, we should elucidate the molecular action of RARγ agonists on osteochondromas and refine the treatment regimen. The purposes of our study are to examine the mechanism in which RARγ elicits osteochondroma growth and to determine whether the responsiveness to RARγ agonists is different between OC and growth plate. Treatment of RARγ agonists on mouse chondrocytes stimulated cell death induced by hydrogen peroxide (H2O2). In addition, human OC explants treated with RARγ agonists contained more apoptotic cells than vehicle-treated OC explants. OCs were induced in AcanCreER; Ext1e2neofl/e2neofl MO mouse model via tamoxifen induction at P5. After two weeks, mice were treated with Palovarotene (1.76 mg/Kg) or corn oil, and 24hrs after treatment, forelimbs were harvested. In-situ hybridization analysis revealed that Palovarotene-treated OC had much more transcripts of Cyp26b1 (retinoid target gene) as compared with the corn oil-treated OC and that OCs had significantly higher response to Palovarotene compared to the adjacent growth plate. When Palovarotene (1.76 mg/Kg, daily) treatment continued for 2 weeks, OC development was greatly suppressed compared to vehicle control in the wrists and ribs as determined by histological staining and radiological assessments, whereas the Palovarotene-treated growth plate did not show histological abnormality. Together, these findings indicate that OC have higher sensitivity to RARγ agonist compared to the growth plate and RARγ agonists rapidly inhibits OC development without a significant negative effect on growth plate and may exert anti-tumor function on OC by inducing cell death via apoptosis.

Citation Format: Sonia Garcia, Hongying Tian, John Herzenberg, Joshua Abzug, Vincent Ng, Ashley Cellini, Masahiro Iwamoto, Motomi Enomoto-Iwamoto. Osteochondromas respond and its development is inhibited by retinoic acid nuclear receptor gamma agonist treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB518.