Caroline Dive - Clinical and Experimental Pharmacology

Heterogeneity in Small Cell Lung Cancer

Small Cell lung Cancer (SCLC) is the most aggressive type of lung cancer with a dismal prognosis and with no impact thus far of novel targeted therapies. A cardinal feature is early dissemination of circulating tumour cells (CTCs) with resultant widespread distant metastases.

Our data thus far show a remarkable genomic heterogeneity amongst and between individual patients CTCs but the functional relevance of this heterogeneity is unclear. We recently demonstrated that a copy number alteration signature in individuals CTCs predicts whether a patient is initially chemosensitive or chemorefractory (Carter et al, Nature Medicine 2016), setting a precedent for understanding SCLC biology via CTC molecular analysis.

In 2014 we pioneered the development of CTC derived patient explant models (CDX), whereby donor patient blood samples enriched for CTCs give rise when injected s.c., to SCLC tumours in immune compromised mice (Hodgkinson et al, Nature Medicine 2014). We currently hold 45 CDX models including those generated from the same patient pre-treatment and upon chemoresistant disease progression (Frese et al, CCR submitted). In these studies, there was a 50% chance that a patient whose matched blood sample contained >100 EpCam positive CTCs per 7.5ml would generate a CDX model. We have also shown that as few as 5 CDX cells can recapitulate CDX growth (Jahchan et al, 2016). However, we do not know what precisely defines whether a particular SCLC subclone(s) is more tumourigenic and whether there is any common molecular trait(s) for CTC tumourigenicity. This project will identify biomarkers of tumourigenicity in SCLC CTCs by comparing isolated CTC phenotypes and genotypes with those of patient matched and disaggregated CDX cells both at baseline and at disease progression in CDX models driven by neuroendocrine progenitor markers ASCL1 and NEUROD1. The project will build on our established workflows for single molecular CTC analysis and CDX generation and exploit ongoing developments in CDX cell labelling with in vivo tracking. The project seeks to define key capabilities in CTCs that facilitate primary and secondary tumour growth in the mouse host with a view to therapy target discovery. New targets would be prosecuted in collaboration with the CRUK MI DDU.