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Science Talk – What are combination therapies for cancer treatment?

When people think of how cancer is treated, what typically springs to mind might be surgery, chemotherapy, or radiotherapy. However, there’s rarely a single way to treat cancer. Many cancer patients are treated with combination therapies. These are treatments that combine two or more drugs or different types of therapy, such as surgery and chemotherapy.

Data from The National Cancer Registration and Analysis Service (NCRAS) shows that, between 2013-2019, surgery combined with chemotherapy and radiotherapy was the third most common form of treatment in people aged under 60 in England after surgery and other care (such as hormonal therapy or management of symptoms).

Now we are entering a new era of combination therapies, where two or more new drug therapies are combined that are designed to work together to give a much better response than either alone. According to our own survey from 2019, nearly a third of surviving patients are receiving targeted cancer therapies, but to keep them effective they often need to be delivered together with other treatments.

Why we need combination therapies

There are three key reasons we develop combination therapies: to make them more effective, reduce side effects and to tackle cancer drug resistance.

Professor Udai Banerji is Professor of Molecular Cancer Pharmacology at the ICR and has led early trials to develop new drugs and combination therapies. He explains why we need to find new combination therapies to tackle cancer’s ability to evolve resistance to treatment.

“Cancers are very clever and learn to live through certain types of treatment, with each individual treatment having a limit on how much it can achieve on its own. Cancer is also a very complex disease, so it’s very rare that there’s going to be one thing driving it, which can be slayed by a ‘silver bullet’,” explains Professor Banerji.

By discovering clever new combinations that aim to treat cancer in different ways, targeting several different weaknesses within the tumor, we hope to prevent cancer from developing resistance from the outset.

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How do we find the right combinations?

In the past, scientists developed new combination therapies empirically by experimenting and observing successful drugs. So, if one drug worked well in a certain cancer type and another drug was also effective then they might explore whether they could be better together. This led to some effective combinations to treat cancer very broadly, for example, by tackling DNA replication.

But over the last 20 years, there has been a shift to more logical and targeted combinations. With the rise of technologies such as artificial intelligence (AI), we can better test and develop smarter and more targeted combination therapies.

“What we are hoping to achieve with drug combinations is ‘more than a sum of its parts’,” comments Professor Chris Jones, Professor of Childhood Brain Tumor Biology at the ICR. He and his team focus on finding new treatments, including combination therapies, for children with brain cancers.

“We’re looking to see whether the effects of different combinations of drugs are ‘synergistic’. This is when the drugs are working in concert in some way to produce an enhanced effect when combined, giving a much better response than either alone.”

Identifying the best possible drugs to combine may be a long and complex process, but Professor Jones’ team recently partnered with an AI company to identify a new potential drug combination for children with the incurable brain cancer, diffuse intrinsic pontine glioma (DIPG), who have mutations in a gene called ACVR1. Professor Jones comments how the results of this study still need to be confirmed in the lab, but “saved potentially years of development time”.

The ‘Goldilocks’ combination: challenges of combination therapies

However, the development of potential new cancer combination therapies is not without its difficulties. Most drugs have a range of side effects and using more than one drug at the same time may lead to even more severe or unpredictable side-effects that may be too toxic for patients.

Working out which combination is neither too toxic, nor too feeble, but just right is the first challenge faced by researchers. Then there’s the task of finding the best order in which the combination must be used.

“Even if side-effects are manageable, working out how to use multiple drugs together is a challenge – depending on the mechanism of action,” says Professor Jones. “It may be better to give both drugs at the same time, one after the other, or switch between the two intermittently.”

But it’s not just the physiological complications that may arise from combining two different drugs, but the practical challenges involved in testing them together. Professor Jones provides the example that, “the ideal combination for a given cancer may involve two drugs from two different pharmaceutical companies – this causes challenges in convincing the companies to work together to run clinical trials with both of their drugs.”

What is the future of combination therapies?

Professor Banerji believes combination therapies are the future of cancer treatment and will play an increasingly important role in years to come. Patients are living longer and better on treatments, but he says combination treatments are important for patients with more advanced cancers, particularly for those with currently limited treatment options.

Professor Banerji adds, “Once many cancers have spread, they are considered incurable, but that doesn’t mean that patients can’t live well with cancer on these treatments. Combination therapies help people by providing more personalized treatments, given that side-effects are tolerable and do not affect quality of life.”

Professor Banerji is currently developing an AI test that can predict which combinations of drugs are likely to work for cancer patients in less than two days. The test analyzes large-scale protein data from tumor samples and may be able to predict patients’ response to drugs more accurately than is currently possible.

There are also the unexpected combinations. Some of the most exciting developments in cancer treatment over the last decade have been immunotherapies. A study involving ICR researchers showed that an immunotherapy combination of nivolumab and ipilimumab could be an alternative to the current ‘extreme’ standard treatment in some head and neck cancers.

This immunotherapy combination, designed to spark the immune system into action against cancer, led to a positive trend in survival in patients with relapsed or metastatic head and neck cancer whose tumors had high levels of an immune marker called PD-L1.

Professor Banerji concludes, “Combination therapies are the future, and the good news is that treatments are getting better and are longer lasting for patients. I think in the future, there will be more and more specific tests that will tell us what combination treatments are needed to treat an individual’s cancer, and that’s what we’re working on at the ICR.”

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