Abstract 973: Uncovering gene signatures of Ewings sarcoma drug sensitivity during the evolution of resistance

Abstract

Abstract The evolution of chemotherapeutic resistance can cause treatment failure in patients with metastatic Ewings sarcoma (EWS), a rare pediatric bone cancer. As resistance to the first-line therapy evolves, there is potential for the tumor to develop sensitivities to other chemotherapeutic agents besides the active treatment. This concept is known as collateral sensitivity, and it presents an opportunity for medical providers to plan more effective treatment regimens. However, it can be difficult to predict due to the stochastic nature of evolution. By analyzing gene expression patterns among independent populations of an EWS cell line that have repeatedly evolved collateral responses, we aim to extract a collection of gene signatures, or sets of genes, that will predict states of collateral sensitivity against various existing chemotherapies. To accomplish this, we will treat independently evolving replicates of an EWS cell line (A673) with the standard-of-care therapy to evolve resistance. Throughout this treatment regimen, we will regularly screen for collateral sensitivity against 100 FDA-approved cancer drugs and perform bulk RNA-sequencing. When collateral sensitivity against a drug is observed, we will utilize the RNA-sequencing data to extract gene signatures using differential expression analysis. The signatures will then be validated using patient-derived xenografts collected in our lab as well as from collaborators. When completed, the sizable archive of sensitivity signatures we expect to assemble could greatly streamline the process of treatment planning for EWS patients, especially those with advanced disease. When a patient's response to primary therapy begins to decline, RNA- sequencing can be performed on a tumor biopsy, gene expression patterns can be compared with the validated signature library, and the most appropriate drug for the individual patient can be determined and used for subsequent treatment. Using this method, a patient's sensitivity profile can be reassessed at any point. This proposed method of treatment planning mitigates the need for excessive treatment regimens that are not guaranteed to be effective for every patient, thereby expanding the reach of precision medicine and potentially improving outcomes for EWS patients. Citation Format: Kristi Lin-Rahardja, Jessica Scarborough, Masahiro Hitomi, Jacob G. Scott. Uncovering gene signatures of Ewings sarcoma drug sensitivity during the evolution of resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 973.