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Shutting down cells’ ‘back-up generator’ to beat kidney cancer

Posted Aug 17 2011 12:00am

As well as the ingenuity, dedication and skill of their staff, modern hospitals can’t function properly without a reliable electricity supply. This is so critical that hospitals have a back-up generator to keep their life-saving systems working in an emergency..

In a similar way, our cells also have their own emergency back-up systems. Thanks to years of painstaking research, we now know that our cells have evolved multiple sets of similar internal machinery to carry out key processes like repairing DNA, generating energy, and sensing signals from the outside world.

This redundancy may seem wasteful, but it’s actually extremely important – it’s the key to life’s adaptability, allowing cells to take repeated knocks and yet still keep ticking over in changing and challenging circumstances.

But these vital fail-safe mechanisms come with a heavy price. As well as keeping healthy cells going during hard times, they also provide cancers with a path to invincibility. Tumour cells exploit these ‘back-up’ systems, becoming grossly abnormal while still carrying on dividing, shrugging off even the harshest of cancer treatments.

Thankfully, researchers are discovering how to target cancer cells that have become dependent on their reserve systems. This concept – dubbed ‘ synthetic lethality ’ – is a hot topic in the search for better cancer treatments. The term may sound familiar to regular blog readers as we’ve written about it several   times before

This week, researchers at our Beatson Institute in Glasgow – working in collaboration with scientists in the US, Israel and Australia – have published a paper in the journal Nature  that could lead to new ways to treat kidney cancer, a disease that seldom gets much publicity despite affecting nearly 9,000 people a year in the UK.

Let’s take a look at the new study, and how it fits into an emerging success story in cancer research.

Dr Eyal Gottlieb ’s team at the Beatson focuses on understanding how cancer cells generate and use energy, and how this differs from normal cells.

Over the last few years, Dr Gottlieb’s team have been particularly intrigued by an extremely rare genetic condition called ‘ hereditary leiomyomatosis and renal cell carcinoma ’, or HLRCC. This affects around a couple of hundred families worldwide, and around one in ten family members with the condition go on to develop extremely aggressive kidney cancers.  

In 2002, scientists at our London Research Institute pinned down  the faulty gene responsible for HLRCC. The gene, called FH, normally tells cells how to make an enzyme called fumarate hydratase, a critical component of the Krebs cycle   (also known as the tricarboxylic acid or TCA cycle). This is the process by which almost all advanced life on earth generates energy from small molecules like glucose.

Researchers are starting to uncover exactly how faults in the FH gene lead to kidney cancer, but HLRCC also poses a deeper conundrum:  If cells carry a faulty version of the FH gene, they can’t make fumarate hydratase. In turn, this means they can’t use the Krebs’ cycle to generate energy. So how are they able to survive?

Clearly, the cancer cells must be using some sort of alternative energy source to survive – but what is it? And would targeting it with drugs  be a useful way to treat cancer? Dr Gottlieb’s team, armed with years of experience of studying how cancer cells generate energy, set out to find the answers.

Dr Gottlieb’s team carried out a series of ingenious and intricate experiments involving lab-grown kidney cells taken from mice carrying faults in their FH gene.

The results proved conclusively that Krebs’ cycle was completely switched off in kidney cells that lacked FH, but that some form of energy generation was still taking place inside the cells’ mitochondria  (the cells’ internal ’power stations’).

The team then switched their focus from the lab to the computer, using a cutting-edge computer programme they’d developed  with colleagues in Israel. This programme produces computer simulations of all the energy-generating (metabolic) pathways in a cell, allowing the researchers to examine the likely effects of switching off FH on other pathways in the cell.

The team then tested these findings in the lab, and discovered that drugs that could switch off haem production had a devastating effect on the faulty cells, stopping them in their tracks. And, crucially, it left normal kidney cells completely unharmed.

To confirm this discovery, the researchers tested the effects of switching off haem production in kidney cancer cells taken from a patient with HLRCC. Again, turning off this back-up system stopped the cells from growing.

According to Dr Gottlieb, it’s too early to talk about treating cancer patients with HLRCC based on the results of this paper alone – the team’s findings need confirming in larger studies, and they need to develop a safe way to block haem production in patients rather than just cells growing in a dish.

For a start, the researchers used a drug called hemin to switch off haem production in their experiments. Hemin is currently used to treat a liver condition called porphyria , but it’s not clear if the drug also works on the kidneys.

However, Dr Gottlieb is very positive, telling us that he expects to see trials in people with the disease “in the near future”, once more experiments have been carried out.

But while this is extremely important research for the handful of people who are unfortunate enough to inherit faults in their FH genes, the team’s findings could  have far wider significance, for two reasons.

Firstly, HLRCC is extremely rare, affecting only a few hundred families around the world.  But a research paper published in June this year suggests that the FH gene may be switched off in up to 7 out of ten cases of non-inherited (sporadic) kidney cancers.

Although it’s just speculation at the moment, this opens up the exciting possibility that targeting haem production could also prove to be a useful way to treat kidney cancer, which claims nearly 4,000 lives a year in the UK.

Secondly, alert readers may spot certain similarities between this story and the story of a new class of cancer drugs that we’re extremely excited about – PARP inhibitors .

As we’ve said before, these drugs were initially developed to target cells that carry faulty BRCA genes , which cause inherited breast, ovarian and prostate cancers.

Normally, BRCA genes allow cells to repair their DNA if it gets damaged.  But in cancers where these genes have gone wrong, the cells rely on a ‘back-up’ DNA repair mechanism involving a protein called PARP. Blocking this reserve system with drugs kills these cells, but leaves normal cells unharmed  - sounds familiar?

Recently, evidence has begun to emerge that PARP inhibitors can target a much wider range of cancers than just inherited breast and ovarian cancers. And taken together, these two stories suggest that this ‘synthetic lethality’ approach –identifying a faulty pathway in people with inherited disease, looking for its biological ‘back-up system’, and then knocking it out with targeted drugs – is one that holds immense promise for treating cancer in the future.

Dr Gottlieb agrees, saying that in his opinion, it’s “the best concept we’ve developed to date” for identifying new cancer drugs.

Although this is early work, it shows we’re on the right track. And it may offer a small crumb of consolation to people affected by genetic diseases like HLRCC that, by studying the molecular causes of their condition, researchers might be working out not only how to help them, but to help thousands of others whose lives are affected by cancer.

Henry

Frezza, C. et al  (2011). Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase Nature DOI: 10.1038/nature10363

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