麻豆传媒

IN 1924, German biochemist Otto Warburg observed that cancer cells are extraordinarily greedy. Tumours tend to grow rapidly, so it made sense that they had outsized appetites. But Warburg also found that , or metabolised, the resources they gobbled so hungrily was different. He was convinced that this change in metabolism defined cancer 鈥� and figuring out what drove it would let us beat the disease.

His idea caught on. For much of the 20th century, Warburg鈥檚 altered metabolism idea guided approaches to understanding and treating cancer. That all changed in the 1970s, with the discovery that certain gene mutations can cause cancer 鈥� and with it a sea change in how we might tackle the disease. Target the genes responsible, the new thinking went, and we could stop cancer in its tracks. Warburg鈥檚 ideas largely fell by the wayside.

But it turns out that the genetics of cancer is vastly diverse, and quickly comes to resist the carefully targeted drugs we throw at it. What鈥檚 more, it has become clear that many cancer-causing genes do in fact work by altering how cells burn their fuel. And so Warburg鈥檚 notions are coming back on board.

There are relatively few ways that tumours metabolise, and they are often the same across many cancers. By targeting these common pathways, we may get treatments that work for many different tumour types, and greater numbers of people. Cancer鈥檚 endless appetite might not just define it; it may be its Achilles鈥� heel.

Laying waste

Although cancer cells have heartier appetites than ordinary cells, the actual process most use to make energy is more wasteful. Warburg liked to explain it by imagining two engines. One is fuelled by complete combustion of coal, the other by a less efficient version. Even if you know nothing about the engines, the strange smell coming from the second one makes it clear something is different. So it is with cancer.

To make energy, healthy cells break down glucose, then burn the resulting products in factories contained within the cell called mitochondria. In contrast, cancer cells burn these products elsewhere, using a less efficient process called aerobic glycolysis. Healthy cells do this when oxygen is scarce, such as in muscle during intense exercise, but tumours do this routinely, even when oxygen is plentiful.

This puzzled cancer researchers for many decades, but unravelling the mystery of the metabolic switch proved a major challenge with the available technology. 鈥淓ach experiment was extremely exhausting and complicated to do,鈥� says , a cancer biologist at Weill Cornell Medical College in New York.

Then in the late 1970s everything changed: we identified a gene variant that drives unbounded cellular growth. It was some of the earliest evidence that malfunctioning genes could cause cancer, and in the following years more of these 鈥渙ncogenes鈥� were discovered. Researchers also identified tumour suppressor genes that normally keep dangerous growth in check, but can also malfunction to cause cancer. Excitement grew that a cure was within reach: all you needed to do was develop drugs to combat the effect of these mutated genes.

鈥淭he cancer cell is having its cake and eating it鈥�

Nearly 40 years later, it hasn鈥檛 turned out that way. Although many such drugs have been developed, they often only buy a few more months of life because tumours quickly become resistant.

What has thrown metabolism back into the spotlight is the discovery that many common oncogenes actually drive metabolic changes within cancer cells 鈥� changes that are fundamental to a tumour鈥檚 ability to proliferate and spread. 鈥淐ancer cells rewire the way they do metabolism so that they are able to continue to build and protect themselves under conditions where normal cells would have stopped,鈥� says , chief scientist at Cancer Research UK. In other words, when Warburg said that deranged metabolism was a defining feature of cancer cells, he was correct. What he didn鈥檛 realise was the extent to which this metabolic rewiring occurs.

Healthy cells require two things to proliferate: nutrients and a growth signal from a specific protein or hormone. If they are deprived of either, the cells will enter a rest state. However, mutations in an oncogene like myc, which plays a part in about 70 per cent of tumours, enable cells to override the brakes. 鈥淭his change in metabolism really defines what the cancer is, and what the oncogenes do is make that metabolic change happen,鈥� says Cantley.

Having no brakes means that, when resources are scarce, tumours aren鈥檛 able to lie low and wait for better times, the way healthy cells can. 鈥淐ancer cells essentially become addicted to a continued nutrient supply,鈥� says , director of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. For cancer, it鈥檚 eat or die.

Starving cancer to death is straightforward in the lab: you just take away the food supply. That鈥檚 not so simple within a person鈥檚 body, because healthy cells need fuel too. But if you could eliminate the specific nutrient that a tumour is addicted to, could this kill the cancer?

Removing particular nutrients from the diet has been shown to work against metabolic conditions such as phenylketonuria, in which the body is unable to break down an amino acid called phenylalanine. But for tumours that crave glucose, it鈥檚 more complicated; cells have other ways to get the substances they break glucose into. Still, the role of diet has come under scrutiny in recent years, as researchers wonder whether our food choices may be driving metabolic changes that favour tumours (see 鈥�Starve your enemy鈥�).

For now, what is clear is that the constant need for nutrients drives tumours to adapt quickly. When cancer cells develop resistance to drugs that target specific oncogenes, they often do so by activating another gene that is able to take over the role. But the metabolic pathway they use frequently stays the same, says Cantley. So rather than targeting individual oncogenes, 鈥渙ne could argue that targeting the metabolic pathway may be a better strategy鈥�, says Cantley.

Imagine the cancer cell as a gas-guzzling car you want to bring to a standstill. 鈥淚f I take the keys away, you might be able to bypass the ignition system, but if I destroy the engine or prevent it from getting any gasoline, the car is not going to drive,鈥� says , a cancer metabolism researcher at the Massachusetts Institute of Technology.

There are several drugs being tested now that aim to do just this. Many cancer cells generate their energy through aerobic glycolysis, as Warburg observed. The final reaction in the sequence requires a particular enzyme, and when that enzyme was inhibited in mice with lung cancer, . Because the treatment blocks the whole pathway, and not a specific oncogene, in theory it should work against any tumours that use that pathway 鈥� as up to 80 per cent of cancers do. Clinical trials of drugs designed to inhibit production of the enzyme are expected within the next year or two.

Unfortunately, switching to aerobic glycolysis isn鈥檛 the only metabolic detour tumours can take. They can use several pathways, and new ones are still being discovered. That is a challenge, but also an opportunity. 鈥淕lucose metabolism is one pathway, but as we dig deeper, we find that more and more pathways are rewired or altered in cancers in a way that we could use,鈥� Vousden says.

The connected nature of these routes means we鈥檙e likely to need more than one roadblock, and possibly a combination working against both the metabolic pathways and the genetic mutations that send cancer cells down them.

To know where to put the roadblocks, we need an accurate map. In the past decade, the technology that enables researchers to plot this out has come on in leaps and bounds. Biochemists identify the products of cellular reactions using instruments called mass spectrometers. 鈥淭oday鈥檚 machines have unprecedented sensitivity,鈥� says , who studies cancer metabolism at Washington University in St Louis, Missouri.

New ways of imaging cellular metabolism may also provide methods for identifying very early changes as a tumour is forming (see 鈥�Watching cancer cells eat鈥�). And ever more sensitive technologies are enabling discoveries that fill in gaps we didn鈥檛 even realise existed. 鈥淚t鈥檚 like looking at Google Maps, then glancing out of the window and seeing a bunch of streets that shouldn鈥檛 be there,鈥� says Patti.

Indeed, his lab has been developing a technique that lets them tag nutrients and follow their passage through cells. As a proof of principle they tagged lactate, the final product of aerobic glycolysis, in cancer cells. They expected just to see this waste product gradually being removed. Not so.

Sneaking around

鈥淚f you look up lactate in a textbook you鈥檒l see that it鈥檚 a metabolic dead end,鈥� says Patti. 鈥� and all sorts of other molecules. It turns out to be a very important building block that cancer cells utilise.鈥�

This discovery, reported last September, helps explain the paradox that puzzled Warburg: why cancer cells burn glucose through aerobic glycolysis, when this process seems so wasteful. Some of the lactate is actually shuttled into the mitochondria, where it is used to produce energy and useful substances. 鈥淭he cancer cell is having its cake and eating it,鈥� Patti says.

The more we know about cancer, the . But probing the way tumours fuel themselves is already leading to possible new treatments. Genetic mutations found in both leukaemia and the aggressive brain cancer glioma cause metabolic enzymes to go haywire. Inhibitors of these enzymes, known as IDH 1 and 2, are being evaluated in leukaemia patients, and the IDH2 inhibitor is being fast-tracked by the US Food and Drug Administration on the basis of .

We may also be able to turn cancer鈥檚 gluttony against it. In studies in mice, Cantley was able to exploit the fact that the same genetic change that lets some types of cancer cells import more glucose also leaves them unable to cope with high doses of vitamin C harmless to other cells. 鈥淩ather than targeting the oncogene or the tumour suppressor gene directly, you are targeting the consequence of that gene mutation,鈥� Cantley says.

Then there鈥檚 metformin, already widely used to treat diabetes, another disease associated with abnormal glucose metabolism. Numerous studies have shown that metformin cuts the risk of cancer 鈥� particularly pancreatic, colon and liver cancer 鈥� in people taking the drug for diabetes. One way in which it might do this is by lowering levels of insulin, which can spur cell growth. There are now nearly 100 trials investigating whether it could be a powerful weapon against established tumours too.

Cancer may seem like an implacable foe, and a closer look at its inner workings will undoubtedly reveal a complexity that Warburg could never have imagined. But it will also identify some weak points. The challenge for the new generation of researchers is to understand which types of metabolism define which cancer cells and why. That鈥檚 no small feat, because cancer is a moving target that excels at evading our most sophisticated weapons. Achilles was felled with a single arrow to his heel, but cancer is a more formidable enemy. 鈥淭argeting metabolism is going to be incredibly useful as one of the arrows in the bow to attack cancer,鈥� says Vousden. But it鈥檚 unlikely to be the only one.

This article appeared in print under the headline 鈥淏locking cancer鈥�