Deciphering the processes driving metastatic disease and death in lung cancer

Background There are numerous ways in which cancers are thought to lead to death and whilst many studies have highlighted processes contributing to metastatic disease, we lack a unified understanding of how metastatic disease impacts the host and ultimately results in death.

This proposal takes a broad approach incorporating the patient and the disease, as well as the multiple facets of tumour evolution, to begin to understand the aetiology of death in patients with lung cancer in a real-world NHS setting.

Aims The aim of this proposal is to demonstrate that the mechanism(s) contributing to death in lung cancer include the following: • Rapid tumour dissemination and increasing genomic instability • Metabolic disturbance mediated by catabolic factors and pro-inflammatory cytokines • Failure of the adaptive immune system otherwise capable of restraining tumour evolution Methods Using novel analytical approaches, incorporating detailed radiological mapping of tumour dissemination, DNA, RNA and tumour microenvironment analyses, primary and metastatic tissue within the TRACERx lung and PEACE autopsy studies will be analysed in order to meticulously trace the clinical disease course in the context of genomic, metabolic, immune and physiological studies to inform our understanding of how and why patients die of lung cancer, and to identify the features and behaviour of aggressive cancers destined to metastasise.

How the results of this research will be used The scientific and clinical need to understand the biology of metastatic disease and the underlying mechanisms leading to death in lung cancer is strikingly evident given the incidence and mortality rates worldwide.

Investigating the genomic, metabolic and immune processes involved may elucidate novel therapeutic opportunities and inform future patient care pathways.