AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida

New line of basic cancer biology

Dr Tak Mak – University of Toronto, Canada

Dr Tak Mak, you’ve been looking at the Warburg effect and it’s apparently relevant; it was discovered some many years ago but it is relevant to some of the mechanisms that we have in the cancer cell about mobility, synthesis, proliferation and so on. Could you explain what you’ve been doing?

I think the cold realisation that we now know there are 18,000 out of the 22,000 genes that can be mutated in cancer. And every cancer is perhaps different from another cancer in the history of developing, at least for a solid tumour. So the original paradigm of shooting the horses to stop the cart makes it very difficult to think that there will be enough bullets to shoot the 18,000 different horses.

Can you explain what is the Warburg effect, for those of us who aren’t fully familiar with it, and how you might harness this to stop cancer in the future?

So in view of the almost diversity of the different mutations, many of them are lost functions, we start thinking about what are the consequences of all these mutations and can we harness those properties to try to target cancer. One of which was actually originally observed in 1928 by Otto Warburg in Germany and for which he went on to receive the Nobel Prize in 1931, but we have soon forgotten about what he observed. What he observed was that cancer cells, even in the presence of oxygen, prefer to use glycolysis. In other words, it takes the glucose down to pyruvate and what usually that does is harness two ATPs. But now you take the pyruvate and convert it to acetyl CoA and it goes into the Kreb’s cycle, that gives you 32 ATPs. But the cancer cells, for some reason, decided not to be greedy, even though they are hungry for energy, to only concentrate on the glycolysis and the question is why.

Well, let me put that question to you: why does that happen and, of course, how might it help cancer doctors in the future?

I think it is imperative for us to start thinking about what I would call the lost paradigm of targeting oncogenes for the last thirty years because there are too many oncogenes, they are too redundant and every patient has a different set of oncogenes. We’ve pretty much done what we can do, you can see the last two years FDA in the US has not approved a single novel agent. So that means we must be running out of ideas about targeting oncogenes.

So basically, the fact that there is an oncogene involved and you simply target it to switch it off or on and then you may treat cancer, that’s a naïve concept is it?

That is mostly a naïve concept now. I think it’s pretty much done what it can do, there may be a few small victories but the overall picture of, for example, targeting EGFR was probably the most sensational discovery and even at its best we’re talking about three months per patient extended life.

So now how do you think that the Warburg effect could, in fact, be harnessed to give us perhaps more than that or even more progress in treating cancer in the future?

To begin with, all these oncogenes and tumour suppressor genes that are mutated, it doesn’t really matter. At the end it changes the metabolism because the cancer cell needs more energy, it needs more building blocks and it needs to put out the fire, the reactive oxygen that is a consequence of the cancer state. These three are basically the same in every cancer cell then, for example NADPH - there are only three ways our cells can make NADPH, whether we are yeast, we are man or we are crocodile. So instead of the hundreds and thousands of oncogenes, we’re down to very, very specific limited pathways.

So in other words we can cut to the chase and go for the thing that’s going wrong; what is that and how do we do that practically?

Make sure they don’t have enough energy, make sure they do not have the Achilles heels of certain building blocks and, in some cases, let the reactive oxygen burn the cell down, kill it.

So are there molecular pathways that can be targeted, a small number of pathways that help clarify the whole situation then?

One absolutely amazing mutation that has been found recently is a mutation called isocitrate dehydrogenase. Now this converts isocitrate to alpha ketoglutarate. This enzyme is mutated in 80% of all gliomas and secondary glioblastomas; 30% in all acute myeloblastic leukaemias. This is not an oncogene, this is converting isocitrate to alpha ketoglutarate. That mutation is, and can cause cancer, isn’t that amazing?

Can you summarise then, just in a few words, what can come out of this and what cancer doctors might be able to take home?

We have to reverse the Warburg effect so that the cancer cells cannot siphon off the metabolites of glucose for building blocks and for reducing agents. I think that is not a bad start.

And do you think there are some clues to doing this, very, very briefly now, among the research you’ve been doing?

Yes, there are. There are big clues because cancer cells use a different form of pyruvate kinase.

So you can target that?

Yes, you can target that and by targeting that it switches cancer cells back to pyruvate kinase 1, which is what normal cells use, but cancer cells use pyruvate kinase 2. So you can target that.

So how hopeful are you then, very, very briefly, that some new steps forward will be made which are a little bit bigger than the ones we’ve been doing so far with molecularly directed therapies using other mechanisms?

I don’t want to be recklessly optimistic because we all know that cancers have taken twenty or thirty years to be where they are and they are as clever as any bacteria that you can think of. But, at the same time, the sooner we realise that targeting oncogenes has a very limited future because of the number of mutations that we can find, we start looking at other ways.

So the metabolism is a better target?

It certainly is worth revisiting.

Dr Tak Mak, it’s great having you with us here in Orlando for the American Association for Cancer Research Annual Meeting. Thanks for joining ecancer.tv.

You’re welcome.

AACR 102nd Annual Meeting, 2—6 April 2011, Orlando, Florida