Diabetes drug, metformin, repurposed for use against several cancers including breast

Share :
Published: 10 Jul 2014
Views: 3352
Dr Francesco Bertolini - European Institute of Oncology, Milan, Italy

Dr Bertolini talks to ecancertv at the 4th Metronomic Chemotherapy Meeting in Milan about metronomic therapy and drug repurposing with particular reference to the use of metformin against breast cancer, formerly used in diabetes.

I think that there is a very unfair imbalance between what pharma is gaining from the sale of new targeted drugs and the budget of a national healthcare system that cannot simply afford these new drugs. For instance, in Italy we have a budget that is shrinking, of course, in sovereign economies and the cut of 1.8 billion in the forecast for 2014 will not allow Italian patients to receive the second generation of new targeted drugs like TDM1 or pemetrexed or ibrutinib. This is something that cannot be accepted by the clinicians and scientific community at large.

How are we going to deal with the rising number of cancer patients?

We have to move together towards a more intelligent balance between the cost of new drugs and what the national healthcare system can provide to the patients. We need biomarkers to select the patients; we need the most clever way to administer these drugs to the patient but we have to clearly ask the pharma to revise this policy of pricing these new drugs.

What about cheaper metronomic drugs?

There are a number of old drugs, old means that they are out of patent, that are very active and the most efficient way to administer them is frequently at low continuous dose for longer periods of time because they have really almost no toxicity. So the oncological community is revising this concept, revamping the use of some old drugs like cyclophosphamide, capecitabine, in this new fashion and in the meeting that we are having here at the IFOM-IEO Campus we are focussing on new trials and a new way to combine this approach with new targeted drugs.

How can we fund trials if the drug companies are not on board?

There are new innovative ways to get funded for trials. For instance you can also ask the general population whether a new way of administering drugs with a lower toxicity can be funded by the general population through charities like IARC or through other innovative ways of funding. Otherwise we will be never able to understand whether there is, as we feel as a gut feeling, an advantage in using metronomic low dose continuous administration of chemotherapy compared to the old way of maximum tolerable dose including a lot of side effects.

What about drug repurposing?

The idea started when we observed that the spread of the Western lifestyle in the world is associated with a global epidemic of obesity. Obesity in turn increases the incidence, the severity and the mortality of several types of cancer; not all the types of cancer, particularly the types of cancer which grow embedded in fat like breast, colorectal and prostate. So some years ago we found that some progenitors embedded in the adipose tissue have some promoting role in breast cancer, for instance. We worked out more recently that some very safe and extremely cheap drugs used in type 2 diabetes, metformin, are extremely active, not only against breast cancer solid cells but also against these progenitors embedded in the white adipose tissue. So we are measuring in the laboratory several models how to combine these bigonists like metformin or phenformin along with metronomic chemotherapy or new targeted drugs. We do believe that this repositioning of old drugs like metformin or phenformin, which are extremely safe, extremely cheap, along with new drugs can really contribute to a general revision of how a patient should be treated, minimising the side effects and maximising the efficacy of the therapies.

Have you looked at how metformin works in the lab?

There are several possible ways of action of metformin. One is against the pathway of AMPK which targets also the mTOR which is already the target of several new so-called intelligent drugs like rapamycin and so on. Another intriguing opportunity is to target the altered metabolism of cancer cells which uses much more glucose compared to healthy tissues. What is very interesting is that metformin mimics very well the so-called caloric restriction which is an approach that in mice has been shown to reduce the incidence and severity of several types of cancer. So proposing caloric restriction to patients is something feasible but not very pleasant for our patients; mimicking it with metformin can be very interesting.

What about the tests you’ve been doing with parasites?

In our lab we have observed that metformin has different activities against the two measured progenitors present in the adipose tissue. It targets more efficiently the endothelial progenitors compared to the mesenchymal progenitors. As a result, the vessels in the tumour of mice receiving metformin are much more dysplastic because they are much more covered by parasites in the lack of endothelial cells. So there is a distribution of blood flow and nutrients and drugs in the tumours that are more favourable to cure the tumours, at least in mice.

Do you think metformin shows early promise?

Metformin is very promising, also it has been shown that it’s able to prolong lifespan and healthspan in mice. What is probably even more effective is phenformin which is a derivative. The problem with phenformin is that it had been used for many years for the treatment of types of diabetes then there were some reports of severe acidosis so it’s no longer in the arsenal of approved drugs. But we do believe that combining phenformin with some other drugs like DCA can reduce the acidosis so phenformin can be used in cancer patients extensively.