Bite Sized Science: Fire with Fire

By Les Ogilvie

In particular circumstances, fighting fire with fire is an effective strategy for treating cancer. This paradoxical approach is possible because certain phenomena which drive cancer are invariably fatal to cells when allowed to run out of control.

An example of such a phenomenon is DNA damage. Many cancers are initiated and driven by unchecked damage to genetic information – often involving genes that control cell growth and proliferation. With these genes longer able to perform their function, the cell loses ability to regulate its division and cancer can be the result. This is where a family of genes known as “tumour suppressors” are supposed to step in to rescue our cell as it careers down the road to malignancy. Tumour suppressors are genes which orchestrate the cell’s response to this kind of damage; in certain cases by actually repairing the DNA themselves.

However, it’s crucial for the cancer cell that DNA damage is merely impaired and not allowed to run out of control. Complete loss of a cell’s DNA repair tools invariably results in the death of the cell – the more DNA that gets damaged the more likely it is that genes which control processes vital for life itself will be affected.

This fact is exploited by a family of cancer drugs known as PARP1-inhibitors. PARP1 is a protein which repairs DNA damage; it follows, therefore, that the inhibition of this entity results in partial loss of a cell’s ability to respond to damage to its genetic material. If alternative DNA repair mechanisms are already compromised then PARP1 inhibition can allow damage to DNA to tumble out of control. And the cell duly self-destructs.

Such alternative mechanisms are provided by the BRCA1 and BRCA2 tumour suppressors. And this makes PARP1 inhibition attractive as a treatment for the relatively small number cancers in which BRCA1 or BRCA2 are already faulty. With both repair strategies compromised, the cell is pushed beyond the point of viability. Unfortunately, this strategy hasn’t yet offered a terribly exciting prospect for manifestations of the disease in which the BRCA genes are operating correctly.

However, a group investigating the effects of PARP-1 inhibitors on the growth of cancer cells have recently published evidence that there is a way to make BRCA2 impotent while cells are treated with the inhibitory drugs. And the method is very simple – nothing more than the application of gentle heat.

The researchers, writing in the Journal PNAS, have discovered that around 41-42.5C the BRCA2 protein unwinds and loses its function. This isn’t a great surprise, in principle, because it has long been understood that proteins can suffer only very narrow changes in temperature (this is the principle reason that your body temperature is held tightly to 37C). However, the study has revealed that this effect allows cells with functioning BRCA2 to be sensitised to treatment through PARP1 inhibition.

The scientists noticed that cells heated to 41C had lost their ability to repair DNA through a pathway in which BRCA2 is important. Importantly, this observation correlated with the disappearance of BRCA2 from the cells, but not other entities which are important in the same pathway. It appears, the authors say, that the heat-damaged BRCA2 is detected by the cell and targeted for destruction. Moreover, the heated cells also gain sensitivity to treatment with PARP1 inhibitors – just like cells that are naturally deficient in BRCA2. The effect isn’t limited to cells in a petri dish, either. The study also examined if the effect would hold in cells which had been grafted into mice and allowed to develop into tumours. In this model, too, the heat treatment successfully sensitised the tumour cells to PARP1 inhibition.

Of course, this is still a long way from being a strategy that could be employed in the cancer clinic. However, it does highlight the diversity in strategy that can (and, indeed, must) be employed in the fight against this complex disease.

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