Care Oncology co-founder Dr Robin Bannister is a chemist and pharmaceutical scientist with 35 years’ experience working with licensed medicines. Close personal experience of cancer first turned his attention to the possibility of ‘repurposing’ licensed medicines to help treat the disease. Almost a decade later, Care Oncology is thriving in both the USA and the UK. Here is Robin’s story – the motivation, and the scientific drive, behind a very personal mission.
The beginnings of an idea
I am always fascinated by how little we actually know about new medicines when they are brought to market. It’s only with the passage of time and after long periods of use in humans that we really begin to understand exactly what it is that our medicines can do. Everyone of course knows the tale of aspirin derived from components of willow bark chewed by the ancient Egyptians for pain relief and even now, 2000 years later, we are starting to investigate its use in cancer.
Good science takes time – but I believe it doesn’t have to take that long.
Put simply, my passion is to understand old drugs better. My great friend and co-founder Greg Stoloff shares my belief and my frustration that potentially very useful medicines are not available to patients, and that it still takes far too long to develop a new drug.
Going back to the example of aspirin; as early as the 1950s people noticed that the way aspirin worked could potentially help in cancer. Yet here we are over 60 years later – and as far as cancer is concerned, this drug is still on the shelf. Only now are full clinical studies underway, and it will still be another few years before results of these studies are fully understood.
Greg and I talked about this conundrum for a long time. But the spark that lit the fire finally came in 2011, when my wife’s breast cancer became metastatic. And like so many who have faced that numbing reality, and felt that raw frustration, I asked myself what could I do to help? Greg was the first to listen and we realized that with our combined skills, we could do something practical – and so the Care Oncology Clinic was born.
Our guiding principles
From the very beginning we had three guiding principles:
One: We knew we wanted to work with already licensed drugs, as anything which looked promising could then be brought into the clinic very quickly. My wife did not have a lot of time.
Two: Modern medicine has such a lot to offer, and we wanted our treatment to build on that – I wanted my wife to have the best of the old and the new. Only in this way could we build upon some of the hard-won knowledge and the gains that have been made in treatment over the years.
Three: We wanted to make a change that would not just help my wife but had the potential to help anyone with cancer. We knew that the only way to do this was to generate evidence showing that what we are doing works. We also knew that this evidence had to be of sufficient quality that it could be accepted by the entire medical community.
I wanted to realize my wife’s vision, and her wish to make a difference. She wanted to know that if cancer claimed her life, she had done something that could help make sure better treatments are available. She wanted to help people who must navigate a similar path. It’s a wish that I’m sure everyone is familiar with. We are all human.
The metabolic theory
So now we had our mission. I had the list of 6,000 or so compounds available in the Pharmacopeia of drugs and compounds as a starting point, and with this, we started to research aspects of cancer.
I was fascinated to learn about Otto Warburg’s original ground-breaking work in cell metabolism, for which he received the Nobel prize for medicine in 1931. Metabolism is the conversion of food to energy to run cellular processes and construct cellular building blocks. Warburg’s work really laid the foundations for the theory that the metabolism of cancer cells is fundamentally different to that of healthy non-cancerous cells. Since then, the science and understanding of cancer cell metabolism has of course hugely advanced, in a discipline now known as ‘metabolic oncology’.
Greg and I were convinced that manipulating the metabolic processes used by the vast majority of cancer cells represented a potentially effective way to target any cancer, regardless of type or stage. The theory goes that by using metabolically-targeted drugs to weaken the cancer cell’s ability to grow and thrive, the cell would then become much more susceptible to standard cancer therapies, such as chemotherapy, radiotherapy, and hormone or immunotherapy. With this insight, we decided to search for already licensed drugs that could target these metabolic processes.
We set about researching and ranking available evidence for existing licensed drugs which have a metabolic mechanism of action. This work was painstakingly centered around a number of scientific criteria we had predetermined as being very important.
Above all, we understood that whatever treatment we developed, it must not add significantly to the burden of a patient with cancer, who obviously can be very sick. Many patients must take cancer treatments which themselves can cause a range of difficult side-effects. It was therefore important that our treatment, which was to be taken alongside these standard treatments, was to be as gentle as possible from a side-effect perspective. Safety was very important to us, and we restricted our search only to drugs that had a strong record of use in the general population, (including in cancer patients). This way, we would have some evidence of their compatibility in patients who were also taking cancer treatments.
Next, we knew we wanted to find a combination of drugs that targeted related mechanisms involved in cancer cell metabolism. In this way the activity of each drug combined could potentially produce an additive or ‘synergistic’ effect and would definitely not interfere or impede each other. We termed this approach ‘mechanistic coherence’.
Finally, we also wanted to make sure that the drugs already had as much published evidence as possible supporting their activity and use in cancer. We took evidence from all available sources and weighed this evidence very carefully.
The COC Protocol
During the development stage we studied and discarded a huge number of drugs from the protocol. For example, drugs that did not have a good safety profile in cancer patients, or which had questionable or mixed evidence of effectiveness, or no real mechanistic reason for inclusion.
There are a huge number of drugs out there with evidence of activity against cancer, but which did not meet our strict criteria for inclusion in the protocol. We eventually arrived at an optimal regimen of four medications: metformin, atorvastatin, mebendazole, and doxycycline. We chose this combination not only because they met all our criteria very well, but also for one other very important reason. We believe this specific combination, with this particular number of drugs, gives us the best chance not only of providing patient benefit, but also for gathering sufficient evidence to start achieving our original vision, of really making a difference to all patients with cancer.
The next steps
One problem which is repeatedly encountered, and is well understood in the field of ‘drug repurposing’, is that although for many of these drugs there is a growing base of evidence supporting their use in cancer (which includes ‘test tube’ based studies, animal studies, patient tumor studies, small clinical trials, and epidemiological studies), there are no Phase III randomized placebo controlled trials. These trials are historically considered the ‘gold standard’ for evidence of effectiveness in patients. But they are also enormously expensive to run. As the drugs we work with are already licensed, and usually off-patent, there is little financial incentive for commercial pharmaceutical companies to pursue their further development.
So, we recognize that to help as many people as possible, we need to produce our own ‘gold-standard equivalent’ patient evidence. Therefore, we are very focused on our own research, to produce and publish high-quality real world data from patients attending our clinic. This is the reason why we spent an enormous amount of time and effort in designing a clinical study which the regulators would approve and endorse. In 2017, we secured approval from the MHRA (the regulator in the United Kingdom, the equivalent of the FDA) and their Research Ethics Committee (the equivalent of an IRB in the USA) to conduct an “Interventional Service Evaluation” which we have named METRICS. This was a big achievement for us as it allows us to publish our outcomes and to share our findings with the world.
We believe that our initiative is one of the only ways through which it is possible to generate the evidence we need. And we really are incredibly grateful to every patient who attends the Care Oncology Clinic, and who is helping to turn our vision of bringing benefit to all patients with cancer into reality.