THE weakness in Achilles’ heel didn’t pose much of a problem until it came into contact with Paris’s arrow – at which point it killed him. Now a range of tumours are meeting a similar fate thanks to drugs that turn otherwise insignificant gaps in their defences into fatal flaws.
A pioneering therapy that exploits such weaknesses is allowing women with late-stage, drug-resistant breast and ovarian tumours to survive for longer. More recent discoveries of similar genetic weaknesses in a range of other cancers are opening up the promise of new treatments for hard-to-treat tumours.
These “Achilles’ heel” therapies have another advantage over existing ones. Because they exploit weaknesses that are unique to cancer cells, they are less likely to cause the devastating side effects characteristic of many chemotherapy agents, which attack healthy cells as well. “It has the potential to be a landscape-shifting change in the way we approach cancer,” says oncologist of Merck Research Laboratories in Boston.
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Until recently, most anti-cancer drugs have followed a more obvious line of attack. They work by interfering with the activities tumours are specially good at – and which are responsible for the damage they do – such as proliferating in an uncontrolled way or overriding signals that should tell abnormal cells to die.
“Most drugs target the activities tumour cells are specially good at – and which do us damage”
But what if we could target tumours’ weaknesses, as well as their strengths? “Cancer cells have all kinds of changes that could be paired with another change – or a drug – to be lethal,” says of Harvard Medical School in Boston.
The idea, known as “synthetic lethality”, is not new. It was shown to work in fruit flies as long ago as the 1940s, when it was noticed that the insects could survive the mutation of a single gene unscathed, but were killed if two such genes were knocked out at the same time. But it is only recently that at the Institute of Cancer Research in London and his colleagues have found a way to apply the same method to selectively kill cancer cells.
Ashworth’s team focuses on genes called BRCA1 and BRCA2, which, when mutated, interfere with an enzyme that cells use to repair DNA and increase the chances that breast and ovarian cells will accumulate cancer-causing mutations. Several years ago, the team gave molecules called PARP inhibitors, which inhibit a different DNA repair enzyme, to women with breastor ovarian cancer caused by the mutated versions of the BRCA genes. They reasoned that because the cancer cells have no other means of repairing their DNA they would die, while normal cells would not be badly affected.
The idea seems to work. This week Ashworth reported at a , UK, organised by the National Cancer Research Institute (NCRI) that in 11 out of 27 women with recurrent breast cancer given the PARP inhibitor olaparib, the tumour shrank significantly; in one of the women it disappeared completely. In 33 women with recurrent ovarian cancer, nine partially responded to the drug while in two the tumours disappeared.
“Essentially, women are living for much longer than expected with very heavy tumour burdens,” says Ashworth. The women also experience very few side effects compared with existing chemotherapies.
The same principles are also being applied to a variety of other common cancers. A separate study by Esther Hammond at the University of Oxford and her colleagues suggests that PARP inhibitors might work on cancer cells that are deprived of oxygen – which is common in aggressive tumours – as hypoxia suppresses the same DNA repair process as mutant BRCA genes.
Meanwhile, a study published last month suggests that PARP inhibitors could treat cancers carrying common mutations in a gene called PTEN, which also impairs a cell’s ability to repair DNA ().
Ashworth also recently showed that an existing cancer drug called methotrexate could kill colorectal and endometrial cancer cells with a defect in MSH2, a DNA repair gene (). He believes this is due to synthetic lethality.
But DNA repair mechanisms are not the only chink in tumour cells’ armour. Genes that drive the tumour growth may also provide an opening for a similar approach. One is Ras, a genetic switch that enables cells to divide. In many cancers, a mutation in the gene, called KRAS keeps it permanently switched on, so the cells keep dividing. An obvious line of attack on such cancers would be to create drugs that bind to KRAS and block its actions, but this has always failed. “Even though we know it’s a driver for a broad spectrum of human cancers, we’ve never been able to drug it,” says Gilliland.
Now separate teams led by Elledge and Gilliland have tried the synthetic lethality approach. Taking cancer cells with KRAS, one of the commonest mutations in human cancer cells, they knocked out other genes one by one. This allowed them to pinpoint a bunch of genes involved in a different aspect of cell division called mitosis, without which cells with a KRAS mutation could not survive (Cell, ). Cells with normal Ras were relatively unscathed. Gilliland identified a gene in a different process which also seems to work.
“Unlike normal cells, those with a mutation could not survive without certain genes involved in mitosis”
“The implications of these findings are both important and immediate,” says of the Memorial Sloan-Kettering Cancer Center in New York. The next step is to develop drugs that block the expression of these genes and test them in patients with KRAS mutant tumours.
Elledge estimates that screening for other synthetic lethal combinations could identify hundreds of new drug targets. Some of them will be a gene that healthy cells need. “The question is what level do they need it at,” says Elledge. “If the cancer cells need it more than normal cells, you might be able to get away with messing with it.”
The tendency of cancer cells to mutate as the disease progresses means that they may develop resistance to PARP inhibitors and other synthetic lethal drugs. But it may also be possible to use synthetic lethality to combat drug resistance, by searching for a drug that overcomes the resistance and using it in conjunction with the original chemotherapy.
Merck is already using this approach to overcome resistance to at least one common chemotherapeutic agent. “We’re very hopeful that this is going to make a difference in outcomes for patients,” says Gilliland.
Stand-alone trees or a bed of weeds?
A controversial idea that challenges established notions of how cancer grows and spreads in the body got a fresh airing at the NCRI cancer conference in Birmingham, UK, this week. If verified, it could explain how cancers quickly grow so big, and also suggest ways in which cancer drugs could be used more effectively.
The conventional picture is that a tumour grows from a single clump of cells that divide uncontrollably. Like a tree, the tumour only acquires the ability to send out “seeds”, or metastases, once it becomes mature. Following this thinking, therapy of early stages of cancer tends to target cell division, not metastasis.
But in 2006, Larry Norton and Joan Massagué at the Memorial Sloan-Kettering Cancer Center in New York suggested an alternative scenario: rather than growing solely by cell division, young tumours grow by metastasis too (). These seeds are released into the bloodstream, circulate around the body, and then return to the original tumour site – or occasionally lodge elsewhere. The result looks like one big tumour but is really lots of little ones growing next to each other, like a bed of weeds.
The model would explain how aggressive cancers grow quickly, which ordinary cell division does not, says Norton. It also suggests that it might pay to target metastatic processes in cancer’s early stages.
The idea remains preliminary, but one especially contentious part – that cancer cells circulate around the body and then return to where they formed – now seems more plausible.
In Birmingham, Norton described how he and Massagué implanted mice with two fluorescently labelled early-stage tumours on opposite sides of their bodies. The tumours constantly released and exchanged cells, demonstrating that even young tumours can send out seeds. Meanwhile, other researchers have reported that women with early, “stage-zero” breast cancer already have large numbers of tumour cells circulating in their bodies (Cancer Cell, ).
As tumours manipulate their local environment to make it easier for them to grow there, Norton reasons that if a cancer is releasing seed cells, these are most likely to take root back at the primary site, rather than elsewhere in the body. This might also explain why metastases often don’t manifest themselves until a primary tumour is removed, he says.
