The Anti-tumor Action and Skeletal Toxicity of Palovarotene, Retinoid Nuclear Receptor Gamma Agonists in Multiple Osteochondroma Mouse Model

Abstract

Osteochondromas are cartilage-capped tumors that arise near growing physis and are the most common benign bone tumor in children. They can lead to skeletal deformity, pain, loss of motion and neurovascular compression. Multiple osteochondromas (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 drug therapies for MO. Previous translational research suggested that retinoic acid nuclear receptor gamma agonist (RARγ) suppresses ectopic cartilage formation including osteochondromas in rodent models. A clinical trial of the systemic treatment of Palovarotene, a RARγ agonist for MO (NCT03442985) trial was terminated due to concerns of skeletal toxicity observed in pediatric patients in a different clinical trial. The purposes of this project are to determine whether refining systemic and local RARγ agonist treatment inhibits pre-existing osteochondroma growth, to minimize the adverse actions of the RARγ agonists on adjacent growth plate, and to elucidate the molecular action of RARγ agonists on osteochondromas. A mouse model involving the conditional deletion of EXT1 in cartilage was used as MO animal model. Palovarotene (1.76 mg/Kg, daily) treatment for 2 weeks, strongly suppressed osteochondroma development in the wrists and ribs. Osteochondromas became evident under the treatment with the same dose for an additional 2 weeks, however, was significantly reduced with the increasing the Palovarotene dose to 4.0 mg/Kg. However, this increase in the drug dose exhibited skeletal toxicity, including changes in trabecular bone, thinning of the cortical bone and articular cartilage deformity. Local delivery is an alternative theory to overcome systemic exposure concerns. Two-week local application of RARγ-loaded nanoparticles inhibited osteochondroma volume in the writs of our osteochondroma model without causing effects on limb lengths compared to vehicle control. Mechanistic studies demonstrated that RARγ agonist treatment of human osteochondroma explants inhibited matrix synthesis, stimulated matrix degradation and induced cell death while systemic treatment inhibited matrix synthesis and stimulated matrix degradation in our osteochondroma mouse model. These findings indicate that RARγ agonist exerts anti-tumor function, and that local drug therapy may be an alternative to avoid systemic toxicity.