22nd European Association for Cancer Research, Barcelona, 8th July 2012

Underlying metabolic pathways in cancer

Dr Arkaitz Carracedo – Ikerbasque, Bilbao, Spain

Hello, Dr Arkaitz Carracedo. We’re here at EACR in Barcelona and you have been presenting some very interesting data on metabolism in cancer cells. Can you give us a summary?

That’s right, so our main interest is to understand how the different metabolic status in normal and cancer cells, how they take nutrients, how they use the nutrients to build cells or get energy, can be relevant to designing new therapeutic approaches. So the basics is what is the difference between normal and cancer cells in terms of metabolism and can we use this knowledge for therapy.

And you’ve been specifically looking at how cancer cells accumulate ATP.

Yes, that’s right. The basic idea is that in a cancer cell, so a normal cell would require nutrients to get ATP however, a cancer cell has a different purpose. The cancer cell wants to get nutrients, it gets enough ATP so it wants to redirect those nutrients to build new cells. So it takes the intermediates to build new lipids, proteins it will help propagate in the tumour. However, in certain conditions cancer cells need an extra push of ATP and in those conditions we think that a certain metabolic pathway that is burning lipids or fatty acids is essential in order for the cell to survive. These would be conditions of stress where it loses attachments so it doesn’t have any extracellular matrix that would help them survive.

So what does this mean for the growth of the tumour?

What we think it means is that we are looking at how to target that, how to target cancer, how to treat cancer. What we see is that certain genetic pathways that occur in cancer are responsible for promoting this pathway. This means that if we enhance this pathway we can make the cell survive; if we inhibit this pathway we can make cells die in those certain conditions. So this metabolic pathway that we are looking into is highly druggable, we have different compounds, some of them are already in the clinic, some of them are being suggested to roll in clinical trials. So the implications in the medium to long term are very important in terms of therapy, in the short term for basic knowledge it’s very important to understand how the genetic milieu and the environmental milieu could be very important to understand how metabolics could play different roles, so what to tackle in each step.

In your talk you were specifically saying that it’s relevant for breast cancer, can you amplify this a little?

Everything went in a very simple manner, we started with a hypothesis that cancer genes regulate metabolism as a way to promote cancer progression. This is an idea that has been coming from a few years and we took a very simple step. We took a cancer gene that was very highly characterised and we looked for its metabolic functions. We found a metabolic function that was burning fatty acids, so this gene was able to modulate the amount of fatty acids that a cell could burn. Then we wanted to know what is the implication in cancer so we started looking at what is the relevance of fatty acid oxidation in cancer and there was basically nothing at that time, this was late 2009. At that time I was in Boston and just across the road the group of Jon Brody discovered that fatty acid oxidation is very important in breast cancer when the cancer cell loses attachment, so when a cancer cell detaches from the normal epithelia. We went on to talk to them and to help them, to ask them for help, to see if we could apply this knowledge to breast cancer. We did it in vitro, we did it with cells and it worked. Then we did it in human samples, we collaborated with a pathologist and we found that although this gene was a tumour suppressor, so lost in a variety of human cancers, in breast cancer there was a subset where it was highly increased so it was very paradoxical but it matched the idea that it would promote this metabolic pathway. In fact, we looked deeper and we characterised this type of breast cancer and we found that it was cancer with bad prognosis and a genetic signature of an activation of this pathway. So we think that the discovery of this metabolic pathway regulated by this cancer gene allowed us to find a subtype that is dependent on this gene and this pathway for survival and it happens to be a very aggressive cancer that is very badly treatable. So we think that it was a bit of serendipity of having people around to interact and to apply the knowledge that was coming out at the time to find a possible new therapy or therapeutic approach in this type of cancer.

So are you now working on creating a possible drug?

Exactly, there are drugs available; I think that the potential is to test, to go one step further. We have done proof of principle that this gene is up-regulated so it’s possibly a therapeutic target so now we are evaluating deeply genetically and pharmacologically if this could be relevant to treat breast cancer. We are just in the initial steps because, as we all know, single agent therapy is unlikely to work in many cancers but we can start thinking about which is the possible combination that would synergise to be more effective in this type of cancer and if we could stratify cancers on the basis of this genetic situation or metabolic activity and be more efficient in eradicating that cancer.

They talk about now breast cancer obesity, because you’re talking about fatty acids, do you think there is any combination, anything linking them?

That’s a great question and I think that that’s what we have to start thinking about and actually that’s one of the lines of my current lab. We want to understand if obesity in breast cancer and in many other cancers is linked to cancer progression, not only because of the non-cell autonomous factors that could be hormonal alterations and so on, but also because of cell autonomous effects, so then then cell could uptake the nutrients that are in excess in obese patients, for example circulating fatty acids, and that would help the cancer to progress. So actually I think that is a key question to address and to see which are the markers which are different between cancer in a lean patient and in an obese patient. We are establishing collaborations with clinicians to look deeply into these in breast cancer and other types of cancers.

Thank you very much.

Thank you.