Abstract
Abstract Osteosarcoma (OS) is an aggressive pediatric bone malignancy that affects 400 children per year in the United States. It has one of the lowest 5 yr. survival rates of any pediatric cancer. OS is characterized by genomic instability and numerous copy number alterations (CNA). We hypothesized that CNA may be drivers of OS and that targeting cancer genes with CNAs may be a novel approach for treatment of OS. We have established a robust approach for generation of patient-derived xenografts (PDX) from patients with OS. To date, 12 PDX have been established from OS patients. Using whole-genome sequencing (WGS), we have identified possible target CNAs for individual patients and are currently testing them in their corresponding PDX. In one patient, an amplification in c-myc suggested possible susceptibility to the bromodomain inhibitor JQ1. In a second patient sample, amplification of Cyclin D1 in the setting of p16 loss and wild-type Rb suggested responsiveness to a CDK4/6 specific inhibitor. This patient sample also has an Aurora kinase B amplification, suggesting susceptibility to inhibition of this kinase as a therapeutic approach. We treated the corresponding PDX with the drug predicted to target the patient sample based on CNA. In one case, JQ1 treatment inhibited tumor growth in the PDX generated from the patient sample with c-myc amplification. In the second case, Aurora kinase B inhibition arrested tumor growth in the PDX harboring the Aurora kinase B amplification. We are currently testing whether CDK4/6 inhibition is sufficient to inhibit tumor growth as predicted by WGS. As a follow up we are currently submitting several more patient samples and paired PDX for WGS as well as RNAseq to determine other potential targeted therapeutics based on CNA. In summary, our work suggests that WGS can be used to identify potential novel therapies for patients with OS. Further work will be needed to determine whether response in PDX models correlates with clinical response in patients. Citation Format: Leanne C. Sayles, Marcus Breese, Alejandro Sweet-Cordero. Copy number alterations identify targeted therapies in preclinical models of osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 502. doi:10.1158/1538-7445.AM2015-502
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