Three cancers for the price of one?

Damaging the DNA Double-helix

A colleague of mine works on double-stranded DNA repair, as it’s called in the trade. This is something that goes on in all of us as our cells patch up DNA that’s being continuously assaulted by things that cause mutations. One source of damage is radiation that can snip the double helix, leaving separate bits of chromosomes floating around in the nucleus. Anything involving ‘snipping’ suggests a pretty potent type of mutation and it does indeed present a real problem because the cell has to find ways of tagging the floating ends, bringing them together and stitching them up. Amazingly, Nature has come up with not one but several ways of doing this and, by and large, they work pretty well. In ferreting around to define the proteins involved, my friend and his team also tried out drugs that might block repair. Having found a very effective one they set up a company to develop it – duly taken over by AstraZeneca, with the result that I now know one person in science who is very rich. The hope is that the drug might work against ovarian, prostate and breast cancers – which would be very good news for AstraZeneca!

But, you may already be asking, what’s the use of a repair blocker? Surely that’s the last thing you want in staving off cancer? Well, yes – and no. All things being equal, you do want to keep repair systems working but, if one of them becomes defective as part of cancer development, knocking out another may push the cell over the brink so that it can’t deal with the DNA chaos and commits suicide.

Bear in mind that our picture of cancer is one of widespread damage to DNA. But the genetic anarchy of cancer has parallels with the political variety in that both have limits. If the Molotov cocktail fraternity so disrupt society that the binmen stop collecting rubbish, everyone dies of cholera – not exactly a great social reform. Cancer too walks a tightrope between the disruption needed to overcome normal cell control and an extreme level of chaos that would simply kill the cell.

Two of the most familiar ‘cancer genes’ are BRCA1 and BRCA2, mutated forms of which can be inherited to give rise to several types of cancer. It turns out that both BRCAs play roles in DNA repair. The drug that has improved my friend’s bank balance is olaparib and it targets another DNA repair pathway – involving an enzyme called PARP (for poly (ADP-ribose) polymerase). So that’s why it’s useful: if the BRCA route is already blocked by mutation, inhibiting a second repair pathway (PARP) may scupper the cancer cell.

BRCA mutations cause about 5% of breast cancers and 10% of ovarian cancers and they can also give rise to prostate cancer. Small-scale clinical trials of olaparib and several related PARP inhibitors have shown anti-tumour effects against all three of these cancers. However, the most recent trial showed no significant effect on survival of breast cancer patients. Whilst this is a set-back for the PARP inhibitor field, another trial has shown significant effects on ovarian cancer.

As so often in the history of cancer treatment, great expectations have taken a bit of a knock but the PARP story is far from over and it still holds the promise than one class of drugs may be effective against several different types of cancer. If it were to turn out that way it would be great news for some cancer patients – and not bad for one or two bank balances.