We typically think of natural selection acting on animal or plant species, favouring those carrying advantageous traits and making those traits more common in the next generation. However, the same process also applies to populations of cells within our own bodies. Normal cells can become cancerous through mutations in their genes. And if these mutations allow its bearer to evade cell death and reproduce more prolifically than others, it will pass that mutation on to its daughter cells, and cells bearing that mutation will expand as a clonal population within tumours and beyond.
Dr Marco Gerlinger’s work has shown that cancer isn’t a linear process of a single cell undergoing clonal expansion – it is dramatically more complex than this. In fact, the ongoing process of mutation and selection in the developing cancer creates a great diversity of cells, with many distinct genomes and behaviours. Dr Gerlinger is a team leader in the new Centre for Evolution and Cancer at The Institute of Cancer Research, London, dedicated to using Charles Darwin’s idea of evolution by natural selection to understand cancer and explore new avenues for treatment. He says: “The parallels between cancer evolution and the evolution of species are astonishing. Darwinian evolution led to the incredible diversity of species on earth. When we started to investigate diversity in human cancers at great detail, we found that the very same process also generates profound diversity in tumours.” Genetic intra-tumour heterogeneity and branched evolution, which leads to multiple different cancer sub-clones evolving in parallel within individual cancers, has since been found in a large number of solid cancer types. Treating even a single type of cancer can be a bit like trying to take aim at a whole set of moving targets all at once.
So how can we start to pin down these moving targets, which pose such a major hurdle for the development of better treatment strategies? What mutations should we be concentrating on – those found on the trunk of the evolutionary tree, or those on the branches? Dr Gerlinger says: “The ideal drug targets are probably those found on the common trunk of the evolutionary tree in an individual cancer. These genetic changes are present in every cancer cell within the tumour, and may prove more effective therapeutic targets than the heterogeneous ‘tumour branch’ events. But under specific circumstances, it may be worthwhile to target branch events. For example, patients may benefit if we can specifically attack highly aggressive sub-clones which dominate the clinical outcome, or the sub-clones which harbour mutations leading to drug resistance.” Based on these insights, one of the main aims of Dr Gerlinger’s laboratory is now to define which genes are commonly mutated on the trunk and which ones are mutated on the branches in some of the most common gastrointestinal and urological cancers.
Intra-tumour heterogeneity probably explains why resistance to cancer drugs occurs rapidly in tumours. Heterogeneous cancer cell populations within the tumour could easily include a mutant variety that happens to be resistant to any individual cancer drug we might administer.
For example, previous research has shown that when patients with colorectal cancer are treated with cetuximab – a cancer drug which is only effective in patients whose tumour does not have any KRAS mutations – mutations in KRAS can evolve over time. Research shows that KRAS mutations were already present in many tumours before treatment started but only in small numbers of cells which were not detectable. So intra-tumour heterogeneity poses a major problem for predicting drug responses. “We have to assume that resistance mutations pre-exist in many tumours but finding and quantifying them with a diagnostic test is difficult,” says Dr Gerlinger. “We’re working on highly sensitive new methods to detect such sub-clones. This may allow more precise predictions about the likelihood that an individual patient benefits from a certain treatment and to detect evolving drug-resistant clones much earlier than currently possible. Switching therapy early – before the resistant cell population has expanded dramatically and has become heterogeneous – may be beneficial by delaying the evolution of drug resistance to the next line of therapy.” A major priority of the group will be to develop biomarkers which can assess heterogeneity from a simple blood sample.
By looking at the same processes that delivered our modern day birds from dinosaurs, and drove fish from the sea to land, researchers can begin to make sense of the features of cancer which make it so difficult to conquer.
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