The preclinical team currently consists of approximately 15 members with a diverse range of specialties. Our in vivo team both generates and characterizes new models of small cell lung cancer (SCLC) and executes preclinical therapeutic experiments to test novel targeted biological agents. Our team of postdoctoral scientists and PhD candidates utilize both standard and novel models of SCLC to probe mechanisms of tumourigenesis, metastasis, and drug resistance.
What Do We Do?
Circulating Tumour Cell Derived Explant (CDX) Models
We use in vitro and in vivo models to examine a variety of aspects of SCLC biology. Until recently, the majority of preclinical studies focusing on SCLC have utilised established cell lines grown in culture. Unfortunately, a plethora of studies have demonstrated that these cell lines do not accurately model the behaviour of patient disease (REFs). Although several groups have established patient-derived xenografts that much more faithfully recapitulate SCLC, it is very difficult to generate PDX due to the low number of patients that are surgical candidates or can safely have biopsies taken. Recently, we have established the first patient-derived tumours originating from circulating tumour cells (CTC), termed CTC-derived explants or CDX (Hodgkinson et al). The CDX are easily established from 7.5ml of blood and can therefore be established both before and after treatment, as well as after relapse. These models display remarkable morphological, histological, and genomic resemblance to the patient tumour from which it was derived. Importantly, these models can recapitulate the patient response to standard-of-care chemotherapy, cisplatin/etoposide (FIG). We have generated a panel of chemosensitive and chemoresistant models that represent the spectrum of SCLC patients.
What are our current and future plans for CDX?
Our ultimate goal is to create a library of CDX in which every aspect of patient disease, including the full spectrum of genetic and epigenetic mutations, is represented. As capturing this heterogeneity is key to implementing a successful precision medicine strategy, we are continuously implanting patient samples every week to generate new CDX models.
As we build our CDX library we are also examining novel therapeutics, both alone and in combination, in conjunction with both academic and pharmaceutical partners. Furthermore we are mining recently published genomic sequencing data to uncover therapeutic vulnerabilities.
As part of our mechanistic studies dissecting the roles of specific genes and pathways in drug resistance, we have developed an ex vivo system to culture tumour cells. We have extensively validated this culture system, demonstrating minimal changes between our ex vivo cultured cells and in vivo CDX models. This system is currently being exploited to study mechanisms of drug resistance to standard-of-care and targeted agents, as well as screen novel therapeutics for future use in patients.
Vasculogenic Mimicry in SCLC
Vasculogenic Mimicry (VM) describes the ability of aggressive tumour cells with ‘stem-like’ plasticity to adopt endothelial characteristics and form fluid conducting channel-like structures independent of host vasculature (1). One proposed molecular regulator of VM is vascular endothelial (VE)-Cadherin (2), which is also expressed by a sub-population of CTCs from SCLC patients, indicative of a population of cells which may have altered ability to disseminate compared to the majority of CTCs (Fig). We have shown that VM occurs in SCLC and correlates with poor Overall Survival. Furthermore, VM is also present in CDX, and regions of high VM co-localise with VE-Cadherin expression.
What are our current and future plans to understand VM in SCLC?
Ultimately it is our goal is to provide clinical benefit to patients with SCLC by identifying proteins and pathways involved in VM which can be explored as potentially actionable drug targets in the various models of SCLC available in the lab. Research is underway to molecularly characterise SCLC cells undergoing VM at the genomic, transcriptomic and protein expression levels using a number of cutting edge research techniques including Next Generation Sequencing approaches to determine Copy Number changes, mutational analysis and gene expression data. Furthermore, development of single CTC identification and isolation methodologies in CEP will allow characterisation of the previously un-defined SCLC CTC sub-population which expresses VE-Cadherin in order to explore their role in dissemination and chemotherapy response, whilst chemosensitive and chemoresistant CDX models will also allow us to explore the association of VM with drug responses.
- Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol. 1999 Sep;155(3):739-52. PubMed PMID: 10487832.
- Kirschmann DA, Seftor EA, Hardy KM, Seftor RE, Hendrix MJ. Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res. 2012 May 15;18(10):2726-32. PubMed PMID: 22474319. eng.
- Kris Frese
- Kathryn Simpson
- Melanie Galvin
- Francesca Trapani
- Becky Bola
- Stewart Williamson
- Tsun Yee Tsang
- Alice Lallo
- Nadia Iqbal
- Hannah Gregson
- Nicole Simms
- Brian Chan
- Christopher Chester
- Sarah Evans
- Stuart Brown
- Scarlett Martindale