Scientists are combining drugs and radiotherapy, hunting for better results

Radiotherapy has been around for decades, and is often extremely effective. But researchers are still discovering new ways to use it.

This includes testing new drugs alongside radiotherapy.

“The aim is to increase the chance of a cure by making the radiotherapy more effective at killing cancer cells,” says Professor Anthony Chalmers, a Cancer Research UK-funded radiotherapy expert at the University of Glasgow.

But avoiding making side effects worse is a challenge. So research is focused on finding drugs that enhance the effects of radiotherapy on cancer cells, while leaving normal cells unaffected.

Professor Kevin Harrington, joint head of the Division of Radiotherapy and Imaging at The Institute of Cancer Research (ICR), London, says the precision of radiotherapy will have a big part to play in this.

“The more precise we get in radiation delivery the better the opportunities we have to combine some of the new smart drugs with radiation,” he says.

High-tech radiotherapy methods that deliver as little radiation to normal tissues as possible, while maintaining or escalating the dose to the tumour, are ideally suited for these combinations.

And studies are underway to test if certain drugs can make radiotherapy more effective, or if radiotherapy can make other drugs yield better results.

‘Doping’ radiotherapy

Radiotherapy causes damage to DNA inside both cancerous and healthy cells. If cells can’t repair this damage, they die. This is good news if cancer cells are dying, but not if it’s healthy cells that are affected.

Crucially, some cancer cells are reliant on certain processes to repair the damage caused by radiotherapy. And it’s this knowledge of how cancer cells respond to radiotherapy that researchers are exploiting in combination studies with targeted drugs.

“The idea is that the radiation triggers DNA damage, the tumour relies on a specific pathway to fix that DNA damage and you come in with a drug that blocks that pathway,” says Harrington. “Normal cells have other backup pathways they can use to get around the drug whereas the tumour is absolutely addicted to this pathway, and you’ve blocked it with a drug.”

Different drugs that target key DNA damage response (DDR) molecules are already being tested with radiotherapy in clinical trials covering a broad range of tumour types.

One molecule involved in repairing DNA damage is PARP, and Chalmers is studying how blocking it might make radiotherapy more effective.

“We’ve shown that PARP inhibitors increase the effect of radiotherapy on rapidly multiplying tumour cells, but have no impact on non-proliferating cells,” he says.

This is the case in a type of brain tumour called glioblastoma. “It’s made up of rapidly proliferating tumour cells, but the cells of the surrounding normal brain are essentially non-proliferating,” Chalmers adds.

And they’re testing this out in two early glioblastoma trials.

It’s important to work out which patients will benefit from using these drugs alongside radiotherapy. Identifying and measuring molecules that distinguish between normal and cancer cells – called biomarkers – is one way of doing this.

As part of these trials, the team will collect tumour and blood samples from patients, with the aim of identifying biomarkers to predict who might benefit in the future.

PARP inhibitors are clinically furthest along this journey, but others are being developed that could be more effective in sensitising tumours to radiotherapy. The early work around all of these treatments will make sure they don’t increase side effects.

And it’s not just how cancer cells repair their DNA that scientists are targeting. The way tumours produce energy, respond to their harsh environment, and spread around the body are all different to normal cells, and so have the potential to be exploited with drugs and radiotherapy combined.

But there’s also another side to the combination coin.

Vaccinating the patient

“There’s growing interest in a completely different approach, which is to use radiotherapy to boost the effects of drug treatment,” says Chalmers.

Perhaps the best example of this is using radiotherapy in combination with immunotherapy.

A radiation hit to a cancer can sometimes shrink not only the tumour itself, but also affect distant sites of the disease (metastases) that haven’t been irradiated. This is known as the abscopal effect.

When radiotherapy kills tumour cells, they release molecules that alert the immune system. Immune cells can then potentially target the original tumour, as well as other cancer cells that have spread around the body.

Harrington describes this as using radiotherapy to ‘vaccinate’ the patient against their own disease.

But the abscopal effect is rare.

So researchers are looking at how immunotherapies such as checkpoint inhibitors can provide a boost. These drugs release the brakes on the immune system so that it can better fight the tumour.

“Not surprisingly there’s huge interest in this abscopal effect of radiotherapy,” says Chalmers. “Researchers are working to identify the best dose and timing of radiotherapy to use, and the best drugs to combine it with.”

“The early data is tantalising but it’s mainly single reports or case studies,” says Professor Tim Illidge, a Cancer Research UK-funded radiotherapy expert at the University of Manchester. “What we don’t know is whether we can increase the proportion of patients who benefit and how best to do that.”

Plenty of questions need to be answered: which immunotherapies and doses should be used? Will this be different for different tumours? Is it better to give a patient one big dose of radiotherapy or lots of smaller ‘fractions’?

Better together

This kind of work illustrates the potential of using cutting-edge treatments alongside older tried and tested techniques.

And it’s an example of how researchers are trying to be smarter about the tools they have to hand, combining treatments to improve effectiveness and reduce side effects.

But some of the usual questions remain: which treatments will best suit which patients? And will any positive effects be long lasting?

The journey to find the best way to combine drugs and radiotherapy has only just begun.

Michael