Repurposing the PI3Kα inhibitor Alpelisib for the treatment of Multiple Hereditary Exostoses

About This Grant

Multiple hereditary exostoses (MHE) is an autosomal dominant disorder that affects one in every 50,000 children worldwide and is characterized by the formation of cartilage-capped osteochondromas, known as exostoses, adjacent to the growth plates of long bones and other skeletal elements. Due to their location and size, exostoses can cause skeletal deformities, growth retardation, chronic pain, and undergo malignant transformation in ~5% of the patients. Currently, there are no approved treatments for this disorder besides surgery and pain management; therefore, there is an urgent need to develop new therapeutic approaches to prevent and/or slow the progression of the disease. Greater than 90% of cases are caused by heterozygous loss-of-function genetic mutations in exostosin-1 (EXT1) or exostosin-2 (EXT2), genes that encode enzymes responsible for the biosynthesis of heparan sulfate (HS), which can lead to truncation of the HS chains and a consequent decrease in HS levels in various tissues. Current evidence suggests that a decrease in HS content disrupts multiple signaling pathways through which growth factors regulate the organization and function of chondrocytes in the growth plate. Regardless of the mechanism, the primary defect is in the assembly of heparan sulfate, suggesting that restoring the level of heparan sulfate would diminish the frequency of exostoses. Here, we propose that over-stimulating the expression of the normal EXT allele to compensate for the activity of the mutant allele could be a promising therapeutic approach to restore functionally normal levels of HS and homeostasis at the growth plate. Recently, we developed drug repurposing screens to search for small molecule agents that could upregulate EXT expression and HS levels in cells. From these screens, we identified the clinically approved PI3Kα inhibitor, BYL-719 (alpelisib), as a potent activator of EXT1/EXT2 expression and HS biosynthesis in human and murine chondrocytes. Subsequent studies confirmed the PI3K/AKT pathway as a promising target to enhance HS assembly and inhibit chondrogenesis. BYL-719 is a potent, selective, and orally active PI3Kα inhibitor and is clinically approved for treatment of metastatic breast cancer and PIK3CA-related overgrowth spectrum (PROS) disorders in patients as young as two years old. Additionally, it was recently shown to inhibit ectopic bone and cartilage formation in a mouse model of heterotopic ossification (HO). In this project, we aim to leverage an approved drug with known properties and clinical approval status to expedite a potential therapeutic application for MHE. The objective of this R21 proposal is to investigate the therapeutic efficacy of BYL-719 to reduce exostoses in an established mouse model of MHE. To accomplish this, we will (i) evaluate BYL-719’s ability to reduce and/or slow exostoses formation in Ext1+/-Ext2+/- mice, and (ii) assess its in vivo mechanism of action via analysis of isolated exostoses and primary chondrocytes. The successful completion of these aims will provide essential preclinical data supporting the feasibility of BYL-719 as a viable treatment for MHE, thus improving the quality of life for patients with this devastating disease.