Deciphering Cellular and Genetic Features that Give Rise to Osteonecrosis of the Jaw (ONJ R01) - ABSTRACT Osteonecrosis of the jaw (ONJ) is a damaging condition characterized by exposed and necrotic bone in the maxillofacial region, and arises most commonly in patients taking anti-resorptive medications, including bisphosphonates (BPs) and anti-RANK ligand antibodies (denosomab). This pathology, which can lead to, among other symptoms, chronic pain, jaw bone infections, and disfigurement, is most common amongst cancer patients taking high doses of these drugs, who harbor a ~5% risk of developing ONJ. Treatment strategies for ONJ vary, but none are without their downsides, making prevention of this condition, and prediction of its risk all the more important. Our goal with this proposal is to identify the mechanisms that give rise to ONJ while taking BPs, and develop a polygenic risk score based on genetic factors that we identify as associated with susceptibility to this condition. To do this, we will build upon our previous work that identified novel regulators of bisphosphonate function to investigate how use of these drugs can lead to ONJ. Using genome-wide CRISPR screens, we found over 200 genes that affect the cellular response to BPs, and identified ATRAID as encoding a lysosomal protein required for the trafficking of BPs. Loss of Atraid inhibits the effects of BPs on mouse models of osteoporosis, and in our preliminary data, variants in this gene were enriched in patients who developed ONJ. Our overall proposal applies an integrated approach to (i) elucidate mechanisms that give rise to ONJ, including which cell types, and which molecules, including ATRAID, are driving this dysregulated response, and (ii) identify genetic markers of ONJ susceptibility by conducting pharmacogenomic analyses of germline DNA collected in SWOG S0702, an NCI-funded clinical study that has available DNA and ONJ information from more than 2000 patients with metastatic bone disease treated with zoledronate, a commonly prescribed bisphosphonate, ~5% of whom developed ONJ. We will then validate these genetic loci with high-throughput cellular CRISPR screens using our previously established BP screening tools. Upon completion of this proposal, we expect to have a mechanistic understanding of ONJ and a detailed knowledge of the genetic factors that confer susceptibility to ONJ. These will have a positive impact by providing critical insights that will enable patient-centered treatment strategies for these drugs that both help alleviate concerns about ONJ among patients who need these drugs, and reduce the risk of its occurrence.
