Mitigating smoothened inhibitor-induced growth plate closure with parathyroid hormone.

Abstract

9562 Background: The Hedgehog pathway plays an important role in regulating growth plate patency by activating PTH/PTHrP signaling, and loss of PTH/PTHrP signaling is an expected pharmacological effect of smoothened (Smo) inhibition. LDE225, a Smo inhibitor currently in phase I/II trials for the treatment of basal cell carcinoma (BCC) and medulloblastoma (MB), causes closure of the epiphyseal (growth) plate in rodents and dogs. As a therapeutic strategy to mitigate these effects, we investigated whether administration of human parathyroid hormone (PTH amino acids 1-34 or PTH1-34) could prevent premature growth plate closure caused by LDE225. Methods: Oral LDE225 was given once daily to rapidly growing male rats (starting at 4 or 6 weeks of age) in combination with hPTH1-34 administered subcutaneously as a continuous infusion (to mimic signaling by locally-produced PTHrP) or as once-daily injections. Femur and tibial growth plates were scanned by microCT and growth plate volumes were calculated. Growth plates were also assessed histologically. Results: Continuous delivery of hPTH1-34 provided the greatest effect for maintaining patent growth plates compared to once-daily subcutaneous injections. However, the dose of continuous hPTH1-34 giving the greatest protection was not well-tolerated beyond 1 week due to PTH-induced hyperparathyroidism, confirmed by clinical chemistry and histological assessment. Reduction in the dose of continuous hPTH1-34 improved tolerability, but provided less protection to the growth plate. Once-daily hPTH1-34 injection for two weeks was well-tolerated, with anabolic effects clearly observed by histology and microCT. The extent of closure in animals co-treated with LDE225 and once-daily hPTH1-34 injections was less compared to that caused by LDE225 treatment alone. Conclusions: As shown in this preclinical model, hPTH1-34 administration mitigates LDE225-induced growth plate closure. Although hPTH1-34 shows promise experimentally, current use is restricted in pediatric patients and further study will be needed before considering hPTH1-34 treatment concurrent with LDE225 therapy in children or adolescents.