Abstract CN07-01: Using CTCs to improve outcomes in SCLC: Single cell profiling, ex vivo cultures, and mouse models

Abstract

Abstract There is increasing agreement that minimally invasive biomarkers to monitor patients receiving targeted therapies have significant potential to facilitate personalized medicine. The rarity and heterogeneity of CTCs make them a technically demanding source of biomarkers but one that holds great promise as the technical challenges are met. Marker independent technology platforms are in development which will better assess CTC subpopulations, but none so far have been fully validated for clinical trial use and treatment decision-making. CTC enumeration with CellSearch (EpCam and cytokeratin positive CTCs) has prognostic significance in many epithelial tumors, and in diseases with prevalent CTCs such as small cell lung cancer (SCLC) the dynamic range of CTC number allows pharmacodynamic evaluation. Biomarkers based on multiplex protein analysis and FISH are also evaluable in CTCs if sufficient can be detected. Examples of CTC based biomarkers in clinical trials will be presented. Developments in single CTC isolation and genomic profiling are increasingly reported by allowing insight to the biology of invasive tumor cells, including cellular co-expression of cancer specific mutations. I will present our progress in DNA profiling of single SCLC CTCs, and how this approach may inform on inter- and intratumor heterogeneity, and via serial sampling, on mechanisms of drug resistance. Most recently, we developed lung cancer patient CTC derived mouse models (termed CDX). SCLC CDX models faithfully recapitulate patient drug responses and will be useful to test novel therapeutics. CDX are generated at patient presentation and for those patients who first respond and then relapse with drug resistant disease, the relapse blood sample can be used to generate a paired CDX. Alongside single CTC profiling, the CDX approach will allow a comprehensive analysis of acquired drug resistance to chemotherapy, the discovery of new drug targets and testing of targeted therapies and drug combinations. I will also describe recent research exploring vasculogenic mimicry (VM) in SCLC, whereby tumor cells adopt endothelial characteristics and form vessels to increase nutrient and oxygen delivery to tumor independent of host vasculature. SCLC VM may explain the prevalence of CTCs and the early dissemination of this dismal disease and VM pathways may provide novel therapeutic targets. Finally, I will present a case report on a NSCLC patient whose blood sample contained no CellSearch CTCs yet generated a CDX model. CTC filtration of this patients blood revealed a high proportion of mesenchymal CTCs consistent with Epithelial to Mesenchymal Transition (EMT). Citation Format: Caroline Dive. Using CTCs to improve outcomes in SCLC: Single cell profiling, ex vivo cultures, and mouse models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN07-01.