Abstract 2880: Targeted drug therapies for osteosarcoma

Abstract

Abstract Osteosarcoma (OS) is a highly aggressive cancer that has had no new treatments options in over 30 years. OS is a heterogeneous disease which is characterized by widespread and recurrent somatic copy-number alterations (SCNAs) with relatively few recurrent point mutations. We have previously reported that SCNAs contain key oncogenic drivers that can be used to identify patient-specific candidates for targeted therapies (Sayles and Breese, et al. Cancer Discovery 2018). Using patient-derived tumor xenografts (PDX), we demonstrated that targeting of patient-specific oncogenes within SCNAs leads to significant decrease in tumor burden. However, no single agent therapy was able to regress tumors completely suggesting that combination therapies would be required for disease management. In order to assess the applicability of OS PDX models to the patient tumor and the stability of the oncogenes within SCNAs, we preformed whole genome sequencing (WGS). We observed that SCNAs are highly stable across samples from the same patient in addition to multiple PDX passages and PDX derived cells lines, highlighting the equivalence between the PDX models and their derived cell lines to the human disease. This allows us to use the PDX cell lines as a surrogate for the identification of combination drug therapies that may be of benefit in OS. Currently, we have generated six PDX cell lines that encompass the most common SCNAs observed in patients including MYC, CCNE1 and CDK4 gain and alterations in the PI3K/PTEN pathway. We have performed single agent drug screens in these cell lines and have identified heterogeneous responses as would be anticipated by the genomic diversity observed in OS. We are currently testing combination drug therapies and will validate using the PDX xenografts in vivo. We have found that MYC driven OS PDX cell lines and PDX xenografts show a striking re-sensitization to cisplatin after AURKB inhibitor (barasertib) pretreatment. We have two PDX and derived cell lines that were generated from highly aggressive metastatic disease. Both of these PDX have high MYC amplification and were resistant to cisplatin, which is part of the standard of care. We pretreated the PDX cell lines for 24hrs with barasertib then added cisplatin and saw a synergistic effect in vitro. Further studies in the PDX model demonstrated a decrease in tumor volume for the combination therapy compared to vehicle or either single agent alone. Additionally, we observed retention of the platinum adduct 24 hrs after cisplatin dosing only when tumors were pretreated with barasertib. Further work is needed to assess the mechanism of this synergy and whether it can be of use in other SCNA driven OS and to identify other possible combination therapies that could be of importance in this disease. Citation Format: Leanne C. Sayles, Amanda Koehne, Kieren Marini, Alex G. Lee, Stanley G. Leung, Avanthi T. Shah, Marcus R. Breese, E. Alejandro Sweet-Cordero. Targeted drug therapies for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2880.