Almost exactly three years ago (goodness me, it seems like a couple of months!) I wrote a piece about one of the novel approaches to cancer therapy being tried around the world. This exploits an effect called synthetic lethality that refers to the death of a cell as a result of a combination of mutations in two or more genes whilst mutation in either of these genes alone leaves the cell perfectly functional. The example involved two distinct pathways that repair damaged DNA – recall that our genetic material is being continuously assaulted in a variety of ways and that we’ve evolved very effective repair strategies. One of these involves a pair of familiar ‘cancer genes’, BRCA1 and BRCA2, mutated forms of which can be inherited to give rise to several types of cancer. The other requires an enzyme called PARP (for poly (ADP-ribose) polymerase). So the idea is that if BRCA mutations block that route the cell becomes dependent on PARP. Stop PARP functioning and the cell accumulates genetic damage that it is eventually unable to live with. Result: death of a cancer cell.
Synthetic lethality. If there are two distinct signaling pathways in a cell, each of which can be blocked without harming the cell but when both are inhibited simultaneously the cell dies, the effect is called synthetic lethality. The enzyme PARP (poly (ADP-ribose) polymerase 1) normally repairs single-strand DNA breaks. When this pathway is blocked by PARP inhibitors single-strand DNA breaks accumulate together with double-strand DNA breaks. If cells have normal BRCA, the double-strand breaks are repaired by a second pathway involving BRCA and the cell survives. However, in cancer cells with mutant BRCA this pathway is impaired. The use of PARP inhibitors means that neither pathway can work and the inhibitors, in effect, selectively target and kill cancer cells with BRCA mutations.
‘Three cancers for the price of one’ summarized small-scale clinical trials of several related PARP inhibitors, including one called olaparib, treating breast, ovarian and prostate cancers (BRCA mutations cause about 5% of breast cancers and 10% of ovarian cancers and they can also give rise to prostate cancer). The drugs showed effects on all three tumour types but in a subsequent trial there was no significant survival benefit for breast cancer patients.
Whilst that was a set-back I was sufficiently prescient to comment that ‘the PARP story is far from over’ and indeed further trials have shown significant effects on ovarian cancer, olaparib prolonging progression free survival from 4.3 months to 11.2 months. On this basis Lynparza (aka Olaparib) was approved in December 2014 in both Europe and the USA for the treatment of advanced ovarian cancer with mutated BRCA.
This is only one more small step along the road to equipping us with a comprehensive anti-cancer drug cabinet but it is, of course, good news for the patient group who should benefit. For my colleague Steve Jackson and his team who developed this approach it must be a wonderful moment and they can look forward to following the success of the drug, now being marketed by Astra-Zeneca.