Combining different drugs is nothing new in medicine – it is what allows us to treat patients with HIV or tuberculosis, and in cancer, chemotherapy drugs are very often given in combination.
But what is new, and the subject of a recent review paper, is the combining of targeted drugs which are specifically chosen to hit different cancer pathways.
Dr Timothy Yap, a clinician scientist at The Institute of Cancer Research and Consultant Medical Oncologist at The Royal Marsden, has published an assessment of the state of the evidence for how to combine different targeted cancer drugs. It’s an interesting read, and I thought I’d provide an overview of some of his main arguments.
Dr Yap starts off by stressing that we are well and truly in the age of precision medicine, with an armoury of novel cancer drugs that interfere with specific molecules involved in cancer cell growth and survival. These include agents that prevent cell growth signalling, interfere with tumour blood vessel development, promote the death of cancer cells, stimulate the immune system to destroy cancer cells, and deliver toxic drugs to cancer cells. A veritable arsenal of highly effective and well-honed weapons against cancer. Or are they?
More than 100 targeted cancer drugs have now been approved for patient use and they have represented a significant step forward in cancer treatment. But although there have been noteworthy successes, patient benefit with single-agent targeted therapies has been generally modest and despite promising results initially, drug resistance is inevitable.
There are several factors to bear in mind when considering strategies to combat drug resistance to new treatments. Firstly, because many targeted agents work by blocking molecules involved in cancer causing signalling pathways, tumour cells often find a way around this – either by changing the original pathway or by finding another way around the block. Secondly, cancer cells can acquire resistance through Darwinian evolution and natural selection. This is where a random mutation creates a single cancer cell that can survive the selective pressure of a drug, which then multiplies to become the dominant cancer cell type within the tumour. To add to the challenge, scientists are also discovering that many different cancer cell sub-types can be present within an individual patient’s tumour, harbouring a range of cancer-causing faults, putting the concept of a ‘magic bullet’ single cure-all cancer drug even further out of reach.
As Dr Yap explains, researchers are beginning to realise that the future of targeted therapies in cancer may lie in combining two or more targeted therapies together. Although tackling the genetic diversity of cancer may seem daunting, this new awareness actually opens a door to a new line of attack. Researchers can mimic the approach used many years ago in successfully combating HIV – simultaneously giving several different drugs, each one targeting a different genetic pathway.
I caught up with Dr Yap to talk about his review, published as an editorial in the British Journal of Cancer. He said: “Here at the ICR, we are already exploring different drug combinations, and in collaboration with The Royal Marsden and other UK hospitals, are currently trialling several novel combinations of drugs against different cancer types to overcome drug resistance.
“We are investigating combination treatments which use several drugs at the same time or in close sequence, and most importantly are using rational combinations of drugs to hit different cancer pathways at once, knocking out all the tumour sub-populations. With this approach, tumours are less likely to be able to escape the effects of the drugs.”
One exciting early phase trial in the pipeline is the ComPAKT study, which combines two targeted agents – the PARP inhibitor olaparib and an AKT inhibitor called AZD5363. The rationale for this combination was based on extensive laboratory studies that showed in cancers that occur sporadically, or that carry the BRCA1 mutation, attacking the PARP and PI3K pathway together created a synergistic effect.
Dr Yap is at the forefront of research to formulate novel strategies for using drug combinations, ensuring that they are optimally developed. He stresses the importance of robust preclinical models to test a drug combination’s effectiveness before it reaches the patient.
Dr Yap also told me: “We need better trial designs for combining targeted agents. In the ComPAKT study, we have utilised a novel intrapatient dose escalation – where the dose is escalated for an individual patient - approach for combination targeted therapies, so that we will be able to optimise drug exposures, minimise pharmacokinetic variability and reduce patient numbers needed for such studies. We are also undertaking translational studies involving the sequencing of patient tumours, measuring biomarkers of response, as well as monitoring drug parameters in both tumour and normal tissue. Taken together, this all means that the right patients can be chosen for the right drug combination in clinical trials.”
So what does the future look like for personalised medicine? Dr Yap said: “I envision more hypothesis-testing, biomarker-driven combination clinical trials of targeted agents and other novel classes of drugs, such as immunotherapies – a treatment that uses your body's own immune system to help fight cancer. This will undoubtedly be one of the greatest challenges for cancer medicine.” In the case of targeted therapies, researchers are beginning to realise that two drugs may indeed be better than one.
If you would like to find out more, Dr Yap has also published an editorial on the challenges in combining new molecularly targeted agents in cancer medicine
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