Abstract B28: Genomic analysis of osteosarcoma for identification of targeted therapies

Abstract

Abstract Osteosarcoma (OS) is an aggressive pediatric bone malignancy that affects 400 children per year in the United States. 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, 15 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 two patients, an amplification in c-myc suggested possible susceptibility to the BRD4 inhibitor JQ1 or the CDK9 inhibitor AT7519. In a third patient sample, amplification of Cyclin D and Cyclin E in the setting of wild-type Rb suggested responsiveness to a CDK inhibitor. A fourth patient had a FOXM1 amplification which suggests a vulnerability to Palbociclib, a CDK4/6 specific inhibitor. This patient sample also had 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 all cases, treatment of the PDX with the drugs predicted show a significant reduction in tumor growth compared to vehicle alone or to the drugs predicted for the other patient CNAs. 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 Sayles, Marcus Breese, E. Alejandro Sweet-Cordero. Genomic analysis of osteosarcoma for identification of targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B28.