PI3-kinase Inhibitor Opens New Pathways for Treating Two Bone Diseases

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Ectopic bone formation
Ectopic bone formation (left) and no bone formation after treatment with BYL719 (right). [Dr. Francesc Ventura]

Scientists from the Bellvitge Biomedical Research Institute and the University of Barcelona report that a PI3Kα (BYL719) inhibitor can block bone formation in mice. This could lead to improved treatments for two pathologies: heterotopic ossification (HO) and fibrodysplasia ossificans progressiva (FOP; a rare bone disease), according to the research team.

The study (“Inhibition of phosphatidylinositol 3‐kinase α (PI3Kα) prevents heterotopic ossification”), which appears in EMBO Molecular Medicine, was led by Francesc Ventura, PhD, head of the cell signaling and bone biology group at the University of Barcelona.

“Heterotopic ossification is the pathological formation of ectopic endochondral bone within soft tissues. HO occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva. FOP patients carry a conserved mutation in ACVR1 that becomes neomorphic for activin A responses. Here, we demonstrate the efficacy of BYL719, a PI3Kα inhibitor, in preventing HO in mice. We found that PI3Kα inhibitors reduce SMAD, AKT, and mTOR/S6K activities. Inhibition of PI3Kα also impairs skeletogenic responsiveness to BMPs and the acquired response to activin A of the Acvr1R206H allele,” the investigators wrote.

“Further, the efficacy of PI3Kα inhibitors was evaluated in transgenic mice expressing Acvr1Q207D. Mice treated daily or intermittently with BYL719 did not show ectopic bone or cartilage formation. Furthermore, the intermittent treatment with BYL719 was not associated with any substantial side effects. Therefore, this work provides evidence supporting PI3Kα inhibition as a therapeutic strategy for HO.”

HO consists in the appearance of ossifications in inappropriate places (ectopic formation), such as tendons, muscles, and connective tissue. For this pathology there are risk factors such as prolonged immobility, spinal injuries, burns, hip operations, and muscle traumas. “Despite knowing this we still do not have a full understanding of the causes and the most appropriate treatment for the disease,” said Ventura.

On the other hand, FOP is a rare disease similar to HO but has its origin in a genetic mutation. FOP patients have mutations in the gene encoding a bone growth factors receptor, ACVR1. The disease is gradually induced by episodes of inflammation that eventually result in the progressive formation of bone in muscles, tendons, and ligaments. These ossifications reduce drastically the mobility and life expectancy of those affected. There is currently no treatment for this disease.

“What we have observed in this study is that, in stem cells cultures and in preclinical models of the disease, the BYL719 inhibitor prevents the ectopic bone formation induced by mutations in ACVR1,” explained Ventura.

The BYL719 inhibitor has been approved by the FDA for its use in patients with metastatic breast cancer. Therefore, there is a large amount of information about the use of BYL719 in humans. “In this study, we have shown that it can also play an important role in the ossification and treatment of these bone diseases,” added Ventura.

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