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Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models
Harrison, D., Gill, J., Hingorani, P., Roth, M., Zhang, W., Teicher, B., Earley, E. J., Erickson, S. W., Gatto, G., Kurmasheva, R. T., Houghton, P. J., Smith, M. A., Kolb, E. A., & Gorlick, R. (2021). Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models. Cancer Research, 81(13), Article LB252. https://doi.org/10.1158/1538-7445.AM2021-LB252
Background. Copanlisib is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor with activity against all four PI3K class I isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ). Copanlisib was approved for use by the FDA in the treatment of refractory follicular lymphoma in 2017. Preclinical data have suggested that deregulation of the PI3K pathway is a key driver of multiple malignancies. The relevance of this pathway in osteosarcoma tumorigenesis remains a subject of debate, however, whole genome and RNA sequencing data have revealed several PI3K aberrations in osteosarcoma tumor samples. The in vivo effects of copanlisib were studied in the Pediatric Preclinical Testing Consortium osteosarcoma xenograft models. Methods. The in vivo anticancer effects of copanlisib were assessed in a panel of 6 osteosarcoma models (OS-2, OS-9, OS-31, OS-33, OS-36, and OS-60). Copanlisib was administered by oral gavage at a dose of 10 mg/kg/day, two days on and five days off, repeated weekly for 4 weeks. Time to event and tumor volume responses were defined and analyzed utilizing standard PPTC statistical methods. Results. Copanlisib was well tolerated in the models with minimal weight loss and no treatment related mortality as compared to controls. Copanlisib induced prolonged event-free survival (EFS) in 5/6 osteosarcoma models (p<0.05, Gehan-Wilcoxon). Tumor regression (mean minimum attained relative tumor volume (minRTV) < 1.0) was not observed for any of the tested models. 3/6 models exhibited lower min RTV compared to untreated controls (p < 0.05, Wilcoxon rank sum). All osteosarcoma models showed progressive disease as their objective response measure. Conclusions. While copanlisib induced prolonged EFS in 5/6 osteosarcoma models, no tumor regression was seen, with all models developing progressive disease suggesting minimal activity. While copanlisib did not result in tumor regression, further study is needed to fully explore the role of the PI3K pathway in the pathogenesis of osteosarcoma.
Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA