PARP inhibitors have made an appearance many times on this blog. Designed to exploit a genetic “Achilles’ heel” in tumours, they’re currently showing promise in clinical trials for breast, ovarian and prostate cancer in patients with inherited faults in their BRCA1 or BRCA2genes.
But faulty BRCA genes only account for a relatively small percentage of cancers, and the hunt is on to expand the potential use of PARP inhibitors. Scientists now think that PARP inhibitors could be used to treat a wider range of cancers, depending on the particular genetic mistakes within a tumour.
This week, an intriguing new paper from a team of Dutch and UK scientists, funded mainly by research organisations in the Netherlands and published in the journal PNAS , suggests that there might be another way to use these drugs to treat cancer – by literally turning the heat up.
Here’s how it works. As their name suggests, PARP inhibitors are designed to block PARP – a molecule involved in helping cells repair damage to their DNA. In a similar (but slightly different) way, BRCA1 and BRCA2 are also involved in repairing DNA damage.
Although cancer cells lacking either BRCA1 or BRCA2 have problems repairing DNA damage, they can still use PARP to patch up mistakes, so they survive and continue growing. Adding in a PARP inhibitor acts as a ‘double whammy’ – without PARP or BRCA, the cancer cells have no means of repairing damage to their DNA, so they die.
In this new paper, the researchers were looking for other ways to knock out DNA repair in cancer cells, without the cells having to have a genetic fault in BRCA1 or BRCA2. Other scientists had previously noticed that warming up cancer cells by just a few degrees could increase the effectiveness of radiotherapy and chemotherapy – treatments that cause damage to DNA. So they figured that heating up tumours might make them more sensitive to the effects of PARP inhibitors too.
To find out, the scientists tested whether gently heating up mouse cells grown in the lab to 41 degrees centigrade (just 4 degrees over their normal growing temperature of 37 degrees) would increase their sensitivity to the DNA damaging effects of radiation. This turned out to be the case, and further tests showed that increasing the temperature was switching off the type of DNA repair normally carried out by BRCA2.
Looking a little more closely, the researchers discovered that turning the heat up was causing the BRCA2 protein to break down inside cells. This happened in a range of different types of cells, including human cancer cells grown in the lab and a fresh tumour sample taken from a patient with cervical cancer.
But did this heat-induced BRCA2 breakdown make the cells more sensitive to PARP inhibitors?
PARP inhibitors turn up the heat
When the team added a PARP inhibitor to cells grown at 41 degrees, they found a significant drop in cell growth compared with cells that hadn’t been treated. This result held up when the researchers tested different PARP inhibitors and different types of cells, proving that heating up the cells was making them vulnerable to PARP-blocking drugs.
Finally, to find out whether this intriguing finding in the lab could potentially be translated to treating cancer patients, the scientists studied mice carrying tumours grown from human melanoma cells that don’t normally respond to PARP inhibitors. They discovered that treating the mice with a PARP inhibitor caused the tumours to shrink, but only if the area around the cancer was heated to 42 degrees centigrade for an hour.
The researchers then confirmed these results in a different model – rats carrying human rhabdomyosarcoma tumours, which also don’t normally respond to PARP inhibitors. In this case, they tested a PARP inhibitor called olaparib, which is currently being investigated in clinical trials involving patients with breast, ovarian and prostate cancer caused by faulty BRCA genes. Again, the tests showed that olaparib could slow tumour growth, but only in combination with heating the surrounding tissue.
Finally, the team tried one more thing. They suspected that heat was disabling BRCA2 by causing the protein to literally unravel within cells. This unravelling is counteracted to some extent by a chaperone protein called HSP90, which helps to fold BRCA2 into the correct shape. Chaperones like HSP90 are already being investigated as promising targets for future cancer drugs by Cancer Research UK scientists and others around the world.
When the scientists tested the effects of heat, a PARP inhibitor and a drug that interferes with HSP90 in their animal model, the combined effect was striking. Tumour growth slowed dramatically, and survival increased significantly.
These results tell us that using heat to mess up BRCA2 – particularly in combination with a drug that stops it returning to its correct shape – could be a viable way of making tumours sensitive to the effects of PARP inhibitors.
And as well as the one-two punch of using heat to knock out BRCA2 and drugs to knock out PARP, there might be other combinations that will work. What about the effects of heat and radiotherapy or drugs that damage DNA?
Most excitingly, this research throws the door wide open to using PARP inhibitors in a much wider range of tumours, regardless of the genetic faults underlying the cancer. And it’s a nice demonstration of how a bit of lateral thinking could potentially bring big benefits for treating cancer patients in the future.
Another important thing about this paper is the temperatures that the researchers used. It’s certainly possible to heat up parts of the human body to around 42 degrees centigrade for a short time without causing ill effects – for example, there’s a clinical trial currently underway testing whether heating the bladder to this temperature can enhance the effectiveness of chemotherapy for bladder cancer.
It’s also important to remember that this work has only been done using cells grown in the lab and animal models. But, as the researchers point out in the conclusion of their paper:
“Our results could provide a rational basis for the development of therapies for a wide range of tumours.”
Although it’s going to be a while before we see this approach being used to treat cancer patients, combining localised heating with PARP inhibitors (and possibly also chaperone blocking drugs or other treatments) could be a very interesting avenue to explore further.
Krawczyk, P. et al (2011). Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1101053108