Areas of Interaction with Other Teams
TRAcking non-small cell lung Cancer Evolution through therapy (Rx) TRACER-X
The aim of the study is to define the relationship between intra-tumour heterogeneity and clinical outcome following surgery and adjuvant therapy for Non-Small Cell Lung Cancer (NSCLC) and to establish the impact of platinum-containing therapies on tumour heterogeneity in relapsed disease. This is a large multi-centre study which aims to recruit up to 842 patients over 5-8 years. The Clinical and Experimental Pharmacology group are involved in the translational aspect of the study which aims to assess tumour heterogeneity in the Circulating Tumour Cells (CTCs) isolated from participating patient blood samples. CTCs will be firstly enumerated throughout treatment by the CellSearch platform then enriched using the DEPArray or alternatively enriched using the Parsortix device then banked. CTCs will be subjected to genomic analysis in order to investigate tumour heterogeneity within the CTC population and relate this to the evolution of the tumour.
EU Framework 6 integrated project (www.chemores.org) is a study designed to improve the outcome of cancer chemotherapy by developing novel tools to predict tumour response to treatment as well as individual toxicity to chemotherapy. The project seeks to identify and validate mechanisms of intrinsic and acquired chemotherapy resistance, using clinical samples and preclinical models, as well as predictors of efficacy and of individual toxicity. The project was initially approved at The Christie Hospital and within CEP in 2007. This study has continued to provide a foundation for various areas of research interest within CEP.
The aim of the ChemoRes study is to recruit patients with Small Cell Lung Cancer (SCLC) and Metastatic Non-Small Cell Lung Cancer (NSCLC) being assessed for treatment with chemotherapy or targeted therapies asking them to donate blood and tissue for research. These samples are used to discover and validate novel molecular mechanisms underlying treatment resistance, therapeutic escape, efficiency and toxicity.
To date, the focus for ChemoRes has been CTC analysis. CTCs have been identified, validated, and published as a prognostic marker in both Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC) as a direct result from this study.
This has led onto the discovery of Circulating Tumour Micro-emboli (CTM) in SCLC . CTCs/CTM in the blood provided an unprecedented opportunity to study the molecular mechanisms of metastatic spread, and progression of cancer before and after treatment.
ChemoRes has also allowed the PreClinical Team to successfully generate 16 CDX mouse models from patient samples. This is an ongoing area of research with the group hoping to generate further models to help support our understanding of the physiology of these lung tumours.
The study design of ChemoRes has further given us the opportunity to explore the possibility of stratified medicine in patients with lung cancer. Working closely with our in house Nucleic Acid Biomarker (NAB) team we are developing analysis allowing us to identify the unique genetic signatures between those patients who are chemotherapy resistant and those who are sensitive to our standard therapeutic agents.
Current ChemoRes samples are being directed towards the following areas of method development within CEP and our collaborators:
- Validating an assay for γH2AX in CTCs
- Collaboration with AZ (The AZD9291 Translational Biomarker Study)
- Validating the use of the Clearbridge ClearCell FX1 for use with clinical samples
- Providing samples for external collaborators to test equipment and processes for CTC analysis
The AZD9291 Translational Biomarker Study
AZD9291 (Tagrisso) is a highly selective, irreversible inhibitor of both activating sensitising mutant EGFR and the resistance mutation, T790M, while sparing the activity of wild type EGFR. In the AURA series of trials, which include the Christie, AZD9291 is being administered to NSCLC patients who have progressed on other targeted therapies. Although early clinical data is promising with many patients doing well on AZD9291, it is important to understand the basis for drug resistance where this occurs.
In this AstraZeneca sponsored and funded study, CEP will collect and store CTCs from bloods from NSCLC patients at The Christie, including those enrolled on AURA trials, for genetic analysis including Whole Exome Sequencing. In addition, bloods from the same patients will be used to try to generate NSCLC CDX models. Therefore, all CEP Teams are participating in a joint effort to build understanding of AZD9291 molecular heterogeneity of response and resistance, and to provide the capability to develop future therapeutic strategies.
The Moulton Study
This is an observational experimental medicine study assessing the tumourigenicity of CTCs isolated from the pulmonary vein that drains from the NSCLC tumour-bearing lung. The aim is to assess whether enriched CTCs taken during resection can form CTC-derived explants (CDX), whether this predicts for disease recurrence, and whether the resulting CDX can be used to inform future clinical decisions upon relapse. Matched tumour biopsies will be used to generate parallel patient derived explant models PDX models, allowing disease profiles in generated CDX and PDX models to be compared with that of the patient. The study also banks cfDNA, miRNA, isolated CTCs, and tumour tissue for molecular analysis and validation of any preclinically-derived biomarkers.
Breast Cancer Research
Within CEP, this comprises the studies CHAMPion, T-POETIC and TuFClot as well as the upcoming TIP trial. These are led by the NIHR Clinician Scientist Dr. Cliona Kirwan and are examining the symbiotic relationship between cancer and the clotting system through the study of systemic biomarkers. The TIP Trial will be the first clinical trial of novel oral anticoagulants (NOACs) as an anti-cancer agent.