BACR & ECMC: Therapeutic interventions for cancer prevention

Metformin in cancer prevention

Prof Michael Pollak – McGill University, Montreal, Canada

I gave a review of the current status of research on the anti-diabetic drug metformin in terms of repurposing it for applications in oncology. We drew a distinction between using the drug for prevention and using the drug for treatment of existing cancers. The take home message is that really we have lots of rationale for suspecting that metformin might have utility but we have very little data to actually demonstrate that. So it’s best regarded as research in progress and even though many people have strong opinions on this subject, some people believing that metformin should be almost put in the drinking water because it’s so obviously useful and other people having the opposite view saying that this is just an epi-phenomenon, that it has something in mice but is really clinically irrelevant. Neither of those extremes, in my view, accurately reflects the current state of research where we, in fact, have some unanswered questions and answers to these questions are expected within the next few years.

Can you give us a background on how metformin is used in cancer?

The question of why metformin ever came to be studied by oncologists probably relates mainly to pharmaco-epidemiology studies that were carried out about a decade ago where diabetologists were just interested in reviewing their records and seeing how their patients were dying. Some died of heart attacks and some died of strokes and some died of cancer and in reviewing their records they found in some cases, in some highly cited studies, that fewer diabetic patients were dying of cancer than expected if their diabetes was treated with metformin. So that’s what got the issue on the scientific agenda. It got even higher on the scientific agenda when laboratory studies with metformin appeared to show that metformin was slowing the growth of cancer cells in laboratories and it appeared at one point, maybe eight to ten years ago, that we had strong evidence both from the laboratory and from retrospective pharmaco-epidemiology that metformin really showed a lot of promise. But since that time, as is often the case with research, we’ve recognised it’s much more complicated and in the case of the retrospective pharmaco-epidemiology studies those were initially taken as very strong evidence but there have been now, with more time going by, other studies that failed to replicate those initial exciting results showing that diabetics treated with metformin had less cancer. There have been statistical arguments indicating that maybe some of the exciting studies were statistically flawed so that the population evidence from these retrospective studies is now regarded by most experts as highly controversial rather than proving a point. I don’t mean to imply that we are certain that the controversies are resolved and that the pharmaco-epi studies prove no association; rather we now have gone from an earlier stage where the association was thought to be very real and very interesting to the current state of affairs where the population evidence is now regarded as controversial and the recognition that we need prospective clinical trials to really sort it out in terms of efficacy. In terms of laboratory studies these laboratory studies in contrast are very reproducible, some of the effect sizes are large and easy to replicate and have been replicated around the world. But there there have been different discussions having to do with the exposure levels and dosing levels. Are those interesting doses that always seemed to work in mice, in certain mice models, are those doses really the doses that are relevant for humans? That’s also been a point of some discussion.

So really, if we put it all together, metformin is a very interesting agent, it certainly works for diabetes and I would have to summarise now that it remains very active in terms of a cancer research topic but we don’t have definite answers. It really fits into a more general interest, or research theme in oncology, which is oncology metabolism. Metformin research represents a small part of overall cancer metabolism research because we do recognise that metformin works fundamentally by inhibiting oxidative phosphorylation or the burning of carbohydrate fuels to create energy. That mechanism is very appealing because we know that cancers have a high need for… they’re vulnerable to strategies that deprive them of the energy that they need.

The whole agenda for metformin itself is can this anti-diabetic drug be repurposed for either cancer treatment or cancer prevention and I feel that that question is unanswered but there’s intensive research. There’s another area of research that deserves mention which is the synthesis of analogues of metformin that are specifically designed to be anti-neoplastic agents because they affect energy metabolism in a way that’s more potent than the effects of metformin. Several pharmaceutical companies are now exploring that area, synthesising new drug candidates based on the structure of metformin, that is new biguanides, and these may be taken towards clinical trials. Some of those might be a little bit more toxic than metformin itself but may be much more efficacious. That agenda is, I would emphasise, for cancer treatment not for cancer prevention. For cancer prevention you need an agent that has absolutely demonstrated safety because you’re giving a drug to healthy people so for cancer prevention the agenda is metformin itself, for cancer treatment we may be able to have more potent versions of metformin and hope that their toxicity is such that they’ll find that sweet spot where the toxicity will be acceptable but the efficacy may be better than metformin.

What topics have you been particularly interested in at this year’s BACR?

Prevention is a very difficult… it’s a harder job to do research in the prevention field than it is in the treatment field, chiefly because obviously if you have a cancer patient and you have a new agent it’s quite easy to determine whether it works – you just have to wait a few weeks or months of treatment and either you’re pleased or you’re displeased. If your goal is to prevent you actually have to study populations over many years or decades to determine whether a given intervention has worked. So at the meeting here we have not really heard about any breakthroughs and I think that that is the reason, that one needs to have a lot of patience to work in the field of cancer prevention.

Despite the challenges, the methodological challenges, of working in prevention where timelines have to be so long before you can draw conclusions, I feel that prevention research is absolutely essential because of the state of the art of treatment research. Cancer treatment, even with our best, newest treatments tends to be less effective than we would like and more expensive than we would want. So that notwithstanding the challenges, cancer prevention research has to be part of the overall cancer control strategy because if even at a pessimistic view a quarter of cancers could be prevented, and some people would argue it’s closer to 50%, but even if it’s only a quarter of cancers that could be prevented we have to do that so that our treatment facilities have less to work on or fewer patients to see. Because especially if you take a global perspective, the rates of increase of cancer on a global basis are frightening and we still really don’t have cheap and effective treatment mechanisms that would be useable in many of the countries that are facing upcoming upticks in cancer incidence. So, despite the challenges of cancer prevention, we feel we have to strongly push the envelope there and do as much as we can.