Preclinical testing Preclinical evaluation of potential targets for personalized treatment of sarcoma

In a previous study we investigated the case of a patient with high-grade metastatic DDLPS who had several rounds of surgery and been treated with a variety of chemotherapeutic agents. Previously confirmed amplifications of MDM2 and CDK4 were unsuccessfully treated with Nutlin-3a and Palbociclib, inhibitors of each of these targets, respectively. In the study we investigated the possible causes for therapy failure and identified other targets potentially suited for targeted therapy in liposarcoma. We characterized three metastases from that patient by exome and transcriptome sequencing as well as DNA copy number analysis. We identified genomic aberrations of several potentially therapeutically targetable genes. Of particular interest was amplification of KITLG and FRS2, in addition to the characteristic amplification of CDK4 and MDM2. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a patient-derived cell line (NRH-LS1). Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G₀ phase of the cell cycle.

In an ongoing investigation we have been able to demonstrate the potential of combining personal genomic characterization of the patient’s tumor with the therapeutic evaluation of potential targets in cells from a patient-derived xenograft. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2.

The aim of our personalized therapy studies is to combine the potential of high-throughput sequencing and targeted therapy for the development of novel and individualized treatment strategies for sarcoma patients who fail to respond to traditional therapies.