The mutations that drive cancers fall into two major groups: those that reduce or eliminate the activity of affected proteins and those that have the opposite effect and render the protein abnormally active. It’s intuitively easy to see how the latter work: if a protein (or more than one) in a pathway that tells cells to proliferate becomes more efficient the process is accelerated. Less obvious is how losing an activity might have a similar effect but this comes about because the process by which one cell becomes two (called the cell cycle) is controlled by both positive and negative factors (accelerators and brakes if you will). This concept of a balancing act – signals pulling in opposite directions – is a common theme in biology. In the complex and ever changing environment of a cell the pressure to reproduce is balanced by cues that ask crucial questions. Are there sufficient nutrients available to support growth? Is the DNA undamaged, i.e. in a fit state to be replicated? If the answer to any of these questions is ‘no’ the cell cycle machinery applies the brakes, so that operations are suspended until circumstances change. The loss of negative regulators releases a critical restraint so that cells have a green light to divide even when they should not – a recipe for cancer.
The cell cycle.
Cells are stimulated by growth factors to leave a quiescent state (G0) and enter the cell cycle – two growth phases (G1 & G2), S phase where DNA is duplicated and mitosis (M) in which the cells divide to give to identical daughter cells. Checkpoints can arrest progression if, for example, DNA is damaged.
We’re all familiar with this kind of message tug-of-war at the level of the whole animal. We’ve eaten a cream cake and the schoolboy within is saying ‘go on, have another’ whilst the voice of wisdom is whispering ‘if you go on for long enough you’ll end up spherical.’
Because loss of key negative regulators occurs in almost all cancers it is a high priority to find ways of replacing inactivated or lost genes. Thus far, however, successful ‘gene therapy’ approaches have not been forthcoming with perhaps the exception of the emerging field of immunotherapy. The aim here is to boost the activity of the immune system of an individual – in other words to give an innate anti-cancer defense a helping hand. The immune system can affect solid cancers through what’s become known as the tumour microenvironment – the variety of cells and messengers that flock to the site of the abnormal growth. We’ve referred to these as ‘groupies’ and they include white blood cells. They’re drawn to the scene of the crime by chemical signals released by the tumour – the initial aim being to liquidate the intruder (i.e. tumour cells). However, if this fails, a two-way communication sees would-be killers converted to avid supporters that are essential for cancer development and spread.
The tumour microenvironment. Tumour cells release chemical messengers that attract other types of cell, in particular those that mediate the immune response. If the cancer cells are not eliminated a two-way signaling system is established that helps tumour development.
There is much optimism that this will evolve into a really effective therapy but it is too early for unreserved confidence.
The obstacle of reversing mutations that eliminate the function of a gene has led to the current position in which practically all anti-cancer agents in use are inhibitors, that is, they block the activity of a protein (or proteins) resulting in the arrest of cell proliferation – which may ultimately lead to cell death. Almost all these drugs are not specific for tumour cells: they hit some component of the cell replication machinery and will block division in any cell they reach – which is why so many give rise to the side-effects notoriously associated with cancer chemotherapy. For example, the taxanes – widely used in this context – stick to protein cables to prevent them from pulling duplicated DNA strands apart so that cells, in effect, become frozen in final stages of division. Other classes of agent target different aspects of the cell cycle.
It is somewhat surprising that non-tumour specific agents work as well as they do but their obvious shortcomings have provided a major incentive for the development of ‘specific’ drugs – meaning ones that hit only tumour cells and leave normal tissue alone. Several of these have come into use over the past 15 years and more are in various stages of clinical trials. They’re specific because they knock out the activity of mutant proteins that are made only in tumour cells. Notable examples are Zelboraf® manufactured by Roche (hits the mutated form of a cell messenger – called BRAF – that drives a high proportion of malignant melanomas) and Gleevec® (Novartis AG: blocks a hybrid protein – BCR-ABL – that is usually formed in a type of leukemia).
These ‘targeted therapies’ are designed to not so much to poke the blancmange as to zap it by knocking out the activity of critical mutant proteins that are the product of cancer evolution. And they have produced spectacular remissions. However, in common with all other anti-cancer drugs, they suffer from the shortcoming that, almost inevitably, tumours develop resistance to their effects and the disease re-surfaces. The most remarkable and distressing aspect of drug resistance is that it commonly occurs on a timescale of months.
And being outwitted
Tumour cells use two tactics to neutralize anything thrown at them before it can neutralize them. One is to treat the agent as garbage and activate proteins in the cell membrane that pump it out. That’s pretty smart but what’s really staggering is the flexibility cells show in adapting their signal pathways to counter the effect of a drug blocking a specific target. Just about any feat of molecular gymnastics that you can imagine has been shown to occur, ranging from switching to other pathways in the signalling network to short-circuit the block, to evolving secondary mutations in the target mutant protein so that the drug can no longer stick to it. Launching specific drugs at cells may give them a mighty poke in a particularly tender spot, and indeed many cells may die as a result, but almost inevitably some survive. The blancmange shakes itself, comes up with a counter and gets down to business again. This quite extraordinary resilience of tumour cells derives from the infinite adaptability of the genome and we might do well to reflect that in trying to come up with anti-cancer drugs we are taking on an adversary that has overcome the challenges involved in generating the umpteen million species to have emerged during the earth’s lifetime.
Not the least disheartening aspect of this scenario is that when tumours recur after an initial drug treatment they are often more efficient at propagating themselves, i.e. more aggressive, than their precursors.