‘More research should be directed towards understanding and controlling the evolutionary process in tumours before it reaches the late stage seen in clinical cancer.’
P Nowell, 1976
Cancer therapeutics has had its successes but the reality remains that very few advanced or metastatic malignancies are amenable to effective control or eradication. Genetic variation in CSCs, particularly if fermented by genetic instability, provides the substrate for selective escape. In addition, other mechanisms of positive selection by therapy exist that are non-genetic; these can involve signalling plasticity (or oncogene bypass)86
or epigenetic changes88
, though many of these may depend on heritable and thus selectable epigenetic variation. There has been great expectation that the audit of cancer genomes, by identifying recurrent and drug able mutations, will herald in a new phase of highly specific or targeted small molecule inhibitors and personalised medicine89
. Oncogene addiction appeared to be the Achilles heel for cancer in this respect90
. The success of imatinib and derivative ABL kinase inhibitors in chronic myeloid leukaemia (CML)90
was encouraging. But CML is an atypical cancer. It is essentially a pre-malignant (albeit ultimately lethal) condition driven, most probably, by a single founder mutation (BCR-ABL1
fusion), which provides a universal target. Even in this most favourable of circumstances, escape occurs either via quiescence (and coupled resistance) of CSC91
or via mutation of the ABL kinase target. Once CML evolves to overt malignancy or blast crisis, with more genetic complexity, ABL1 kinase-directed therapy is often ineffective.
Other specific small molecule inhibitors directed at mutant products produce initially encouraging results in patients with advanced disease but the benefits have turned out to be transitory as cancer clones re-emerge with resistant features. When targets selected are non-founder mutations, even if they dominate the neoplasm, therapy can be anticipated to select for sub-clones lacking the mutant target70
. Alternatively, sub-clones may have additional mutations that enable signalling bypass of the drug target, as with MET amplification in EGFR
mutant lung cancer treated with EGFR kinase inhibitors92
What is a way out of this impasse? Champions of targeted therapy and personalised medicine argue that the problem can be solved by artful combinations of drugs targeting components of networked signalling and tailored to the individual patient’s cancer genome. Synthetic lethal strategies hold promise in this regard93
Self-renewing cancer cells are the ultimate target so the development of high throughput screening for selective inhibitors is encouraging71
. Targeting components of the self-renewing programme itself (independent of specific mutant genotype) deserve exploration, especially if a distinction can be made with normal adult stem cells (see Supplemental information
). The problem of intrinsically resistant (and quiescent?) stem cells, in the case of CML, has been addressed by combining selective kinase (ABL1
) inhibitors with inhibitors for histone deacetylase94
. But ultimately it may prove difficult to thwart the plasticity or adaptability of cancer cells (or CSC) that is an inherent evolutionary feature of advanced disease. A Darwinian bypass may be required. A clear implication of cancer’s evolutionary diversity is that prevention (e.g. cessation of smoking, avoidance of sunburn, prophylactic vaccines, etc) makes a great deal of sense as does early detection and intervention, i.e. prior to extensive genetic diversification and dissemination.
An alternative therapeutic strategy directs attention away from the cancer cells and towards their micro-environmental habitats. There are many opportunities here for so-called ‘ecological’ therapy, directed at changing the essential habitat and dependencies of cancer cells96
. Anti-angiogenesis is a prime example of this tactic and may provide a potent restraint on CSCs97
. Other examples include interference with bone remodelling with bisphosphonates in prostate cancer, aromatase inhibitors in breast cancer, exploiting hypoxia, inhibitors of inflammation or tumour infiltrating macrophages and blockage of CSC interactions with essential stromal or niche components96,98
A further alternative is to seek to control cancer, rather than eradicate it, turning cancer into a chronic disease. Since the speed of evolution is proportional to the fitness differential between cells, cytotoxic drugs are predicted to rapidly select for resistance5
. They likely cause competitive release99
, by removing all the competitors of the resistant cells. In contrast, cytostatic drugs should delay progression and mortality longer than cytotoxic drugs, because sensitive competitor cells remain to occupy space and consume resources that would otherwise benefit the resistant clones. In addition, by suppressing cell division, cytostatic drugs also suppress the opportunities for new mutations. Intriguingly, Gate by and colleagues have recently shown that by treating an aggressive ovarian cancer (OVCAR-3) xenograft tumour to maintain a stable size, rather than eradicate it, they were able to keep the host mice alive indefinitely. Moreover, the dose of carboplatin necessary to keep the tumour in check declined over time100
. We should be asking what phenotypes can we select for that would make neoplasm less deadly and more clinically manageable?
The evolutionary theory of cancer has survived 35 years of empirical observation and testing and so may be considered a bona fide scientific theory today. While the basic components of somatic evolution are well understood, the dynamics of somatic evolution remain largely opaque. Fortunately, there are tools from evolutionary biology that may be applied to neoplasms in order to address many of the fundamental questions in cancer biology, such as the order of events in progression, distinguishing driver mutations from passengers, as well as understanding and preventing therapeutic resistance. The dynamics of clonal diversification and selection are critical to understanding neoplastic progression and response to therapy. There are exciting clinical opportunities in directly addressing the evolutionary adaptability of neoplasms and designing interventions to slow, direct or otherwise control that evolution so as to delay or prevent cancer mortality.