© Aart-Jan Venema

That the metabolism in cancer cells is highly abnormal is not a new discovery. In the 1920s, the German biologist and medic Otto Warburg noticed that cancer cells consume glucose at an enormous rate. He found that whereas most normal cells break down glucose and shunt its products into the mitochondria – the powerhouses of the cell – where they are burned in the furnace to produce energy, tumour cells partially suppress the activity of the mitochondria and use much of the glucose to create the building blocks of new cells. This metabolic process, known as aerobic glycolysis, takes nearly 20 times as much glucose as mitochondrial respiration to produce the energy that cells need – hence cancer cells’ voracious appetite for glucose.

Warburg believed this altered metabolism was the cause of cancer, and said so in a 1956 paper. But his provocative theory was soon overshadowed by the molecular biology revolution, as excited scientists began to look for the causes of everything in our DNA. The excessive appetite for glucose (the so-called Warburg effect), they said, was a consequence of malignant transformation of cells, not a driving force. But now evidence is mounting that metabolism does play an active part in tumour development after all. Recent work on p53 in particular, says Hainaut, points to the fact that metabolic factors are “absolutely fundamental to the biology of cancer”.

There had been clues around since the 1990s that p53 is involved in metabolism, but it wasn’t at all clear how this fitted the picture of the gene as a tumour suppressor. In 2005, however, scientists at the US National Institutes of Health compared the endurance of normal mice with ones whose p53 gene had been deleted. The mice were put into a bucket of water, and those lacking p53 went under much more quickly than the normal ones: clearly they were having difficulty generating enough energy to keep afloat. So, what was going on?

At her lab at Glasgow’s Beatson Institute, Karen Vousden and her fellow researchers have discovered that, in the normal course of events, p53 plays a subtle role behind the scenes. It’s not just watching and waiting to stop or kill potentially dangerous cells, but is actually helping cells to avoid or survive things that might damage them – that is, things that might trigger its anti-tumour response. In other words, p53 is playing a double game: it promotes survival under some conditions, but when it senses things are getting out of control, it calls in the death squad.

The way that p53 promotes survival, explains Vousden, is as a regulator of metabolism, by helping cells cope with fluctuations in the fuel supply. “This might be something that happens all the time, and you wouldn’t necessarily want to kill every cell that just transiently doesn’t have enough glucose. So in those situations, it’s pretty clear p53 helps cells survive. And it does so by allowing the cell to reorganise its metabolism.”

As a basic regulator of metabolism, p53 helps cells resist the glucose-guzzling, inefficient Warburg effect except in emergencies. It also helps clear away free radicals – the corrosive by-products of burning sugar for energy in the mitochondria – thus encouraging the survival of cells by limiting the damage these particles can do to DNA. But if the tumour suppressor isn’t working, harmful free radicals can proliferate, and corrupted cells are free to hijack the metabolic machinery and switch over to glycolysis, which enormously boosts their ability to replicate. This is cancer in the making.

This line of research into the metabolic abnormalities of cancer offers some tantalising prospects for patients. For example, what if we could raid the medicine cabinet for drugs that already exist for metabolic diseases and repurpose them as new treatments for cancer? “You wouldn’t even need to do clinical trials for safety,” points out Vousden, “because these drugs have already been used in millions of humans for years.”

It’s an idea many labs around the world, including her own and Hainaut’s in France, are already exploring with metformin, the most widely prescribed drug for diabetes, which targets faulty glucose metabolism. People with diabetes are usually at increased risk of cancer, but doctors started noticing that the cancer risk in long-term users of metformin seemed to be lower even than that of the non-diabetic population. Could the drug be having a protective effect? Experiments in the lab showed that it is indeed toxic to cancer cells.

“There are good and bad points,” cautions Hainaut. “Metformin will be easy to introduce into cancer treatment because it’s already on the market and there’s a lot of experience of giving it to patients: it’s safe, proven, easy to administer. It has all the characteristics to make a quick hit in cancer treatment if it has a positive effect. But in terms of addressing the glucose weakness of cancer cells, it’s not that strong.”

Metformin is already being tested beyond the lab, with clinical trials of cancer patients in many centres around the world, and Hainaut is encouraging Achatz to try it with some of her patients too. But doctors and scientists alike are acutely aware of the sensitivity of their research among Brazil’s Li–Fraumeni families, and the danger of exciting premature hopes in people desperate for breakthroughs.