We are generally interested in the problem of how the metabolic state of the individual is affecting the growth and the progression of the cancer which is something that sometimes is overlooked because when people talk about metabolism in cancer very often they’re talking about metabolism in cancer, in the cancer cell. We are more interested in to how the metabolism outside of the cancer is shaping the growth of the cancer itself.
Does this start with epidemiology?
Yes, absolutely. So the epidemiological evidence is incredibly strong nowadays. It’s very well established that obesity was considered to be the second most common avoidable risk factor for cancer death after smoke. So there really is a tremendous need for understanding of what the molecular mechanisms for this are because this is where we have been a little bit ignorant up to now. We know that the epidemiological evidence is pretty strong but we don’t really understand how this is influencing cancer.
What have been your findings related to acute promyelocytic leukaemia?
APL is a weird disease because now it’s the most treatable form of AML but in the past, just up to twenty years ago, it was one of the worst forms of AML. If you want, APL has been an interesting case study for the whole world of oncology because it’s where the first targeted treatments with retinoic acid have been identified. So we are particularly interested in that because even if it’s curable and it’s rare but it has a very well understood biology, at least for some aspects, and there are good mouse models that reproduce very well the disease in humans. So it works out as a really good mechanism, a really good system, to understand biological mechanisms. Also from an epidemiological point of view we and others have published that there is a very strong correlation between obesity and APL, both in terms of outcome, because obese patients tend to have a higher risk of relapse after induction therapy, and also in terms of incidence, because we and others in the past have found that there is a very, very strong relationship between obesity and the risk of developing APL. This is held in different cohorts around the world, in Americans who tend to be fatter, of course, but even in European cohorts.
What about the mechanisms that might be causing this?
Yes, we still have preliminary evidence but it’s getting stronger and we’re seeing that obesity may be acting in two non-mutually exclusive ways. First of all, the obese individual tends to have a shift in metabolism in which the stem cell metabolisms start relying more on substrate, on energetic substrates, that give rise to genotoxic by-products when they are processed. So the stem cells that are the cells that ultimately give rise to cancer, and this is very well known in leukaemia, tend to accumulate DNA damage with a higher rate than stem cells in a normal individual.
The genotoxicity can cause mutations?
Absolutely. This is well understood; what is not well understood is what can be so genotoxic as to cause these mutations. There has always been a suspect around obesity, this is very well understood from smoke, for instance; it has been suspected for obesity for a while but we lacked the tools for understanding that and we have preliminary evidence that that may be the case.
Can the risk factors be modified or has someone with obesity for example already done the damage?
This is an extremely interesting question, also in mechanistic terms, because, as I said, we have evidence that this may be due to a genotoxic mechanism and in a way this would mean that an obese patient that got his cancer through an obesity related mechanism would be doomed because the DNA is fixed and if it’s damaged it’s already there. But, as I said at the beginning, we have another non-mutually exclusive hypothesis that may be just as important because we are seeing evidence that obese environments tend to alter the pattern of mutations that are accumulated in these cases and they tend to promote particularly adverse mutations. Now what we also see, and this is also very well established both in the mouse and other experimental models and in epidemiology, is that dietary intervention programmes, caloric restriction or intermittent fasting or other types of dietary restriction programmes can have a huge impact on the outcome of the disease. So there definitely is some part of the mechanism that can be corrected by altering the metabolic habits of the individual.
What might doctors do with this information in these early stages?
Eating a healthy diet is certainly going to be good for pretty much everything and there are also trials on-going on that. Unfortunately, they are very hard to enforce, all these changes in dietary habits, and so some of the trials that we are going to start at our institute as well are going to see how dietary intervention programmes can be targeted on the needs of the individual so as to make them more acceptable for the individual. Caloric restriction has a relatively poor record for compliance on patient side so patients tend to restrict their caloric intake for a little while but then they rebound after very little. There are a few trends, a few new waves, of dietary intervention trials like intermittent fasting or protein restriction; the evidence is starting to build up on that and the compliance of, for instance, intermittent fasting seems to be better than caloric restriction. But we’re going to see, we’re going to have to do a few trials and we’re going to see what’s going to happen.
