Pharma & drug development

Stopping cancer’s engine

Cancer is notoriously frustrating to treat because of the high rate of recurrence and metastasis. In many cases, this may be due to cancer stem cells, which conventional therapies struggle to eradicate. However, researchers at the Manchester Institute of Cancer Sciences have suggested these cells might be defeated by blocking their mitochondrial metabolism, in other words draining their ‘fuel tank’. Lead author Professor Michael Lisanti explains what the discovery might mean for future treatments.

Cancer stem cells have long been the subject of intensive research. Since they were first identified, the scientific community has debated their role in the formation of tumours and their wider implications. If the stem cell theory proves correct, it could dramatically shake up the template for cancer treatment.

According to this theory, the disease is primarily spurred by a small population of stem cells (also known as tumorigenic or tumour initiating cells), which have the potential to drive recurrence and metastasis. While ordinary cancer cells may cause issues, these are not capable of propagating the cancer. It is the stem cells, lying dormant in the body after treatment, that may lead to the patient’s eventual relapse.

While this theory does seem to hold true, at least for certain types of tumours, isolating the stem cells can prove difficult and understanding them is harder still. In order to wipe them out, it will be essential to determine their precise molecular properties. How do these cells proliferate and how might a treatment go about targeting that mechanism?

Targeting stem cells

“If you take stem cells from the tumour and inject those into a xenograft, then they’ll make a tumour, whereas if you inject the bulk cancer cells they won’t,” explains Professor Michael Lisanti, director of the Breakthrough Breast Cancer Unit at the University of Manchester. “The problem is that most conventional chemotherapeutics actually target the bulk cancer cells and not the cancer stem cells. So what we want to do is understand the difference between the two.”

Along with his colleagues at the Manchester Centre for Cellular Metabolism and the Cancer Research UK Manchester Institute, Lisanti recently discovered a new way of targeting these cancer stem cells. A recent paper, published in the journal Oncotarget in November 2014, revealed the role of mitochondria in promoting their growth and survival.

“We think that having more mitochondria is something that’s a characteristic of cancer stem cells, and it may give them a growth advantage because with more mitochondria they should be able to produce more energy,” he says. “Our major idea was that these mitochondria are can be targeted with specific inhibitors that interfere with mitochondrial metabolism.”

In essence, the mitochondria were shown to be the ‘engines’ of the cancer stem cell, with certain mitochondrial proteins enhancing their capacity to burn key nutrients. Through blocking the cellular uptake of these fuels, it may be possible to stop the engine and bring cancer growth to a grinding halt.

Breast cancer breakthrough

The researchers began by taking cancer cells from the breast, and enriching the sample for cancer stem cells. While less than 1% of the total cells were tumorigenic, when you place them on a dish coated with non-stick material, most of the bulk cancer cells will die and only the stem cells will propagate. They form globules known as mammospheres, which can be examined for a better insight into stem cell behaviour.

The researchers compared these mammospheres to a separate culture of monolayer cells. They found that the mammospheres showed significantly increased levels of 62 mitochondrial-related proteins. In fact, nine of these proteins were ‘infinitely upregulated’, meaning they were virtually undetectable in the monolayer cells but showed a dramatic increase in the mammospheres. Two nutrients in particular – ketone and L-lactate – were especially critical for this type of mitochondrial metabolism.

The upshot here is clear – if you know what fuels the mitochondria you are halfway towards depleting the fuel tank. Cancer Research UK currently has trials ongoing into whether MCT inhibitors might block the actions of these proteins and ultimately eradicate the cancer stem cells.

“Generally speaking the entire industry has shied away from inhibiting mitochondria, and I think that’s a big mistake because in the future some of the best cancer drugs will be in this class,” says Lisanti. “You really need to figure out what you want to target in the mitochondria, and there are side effects you should be aware of, but that shouldn’t stop you from trying.”

He cites metformin, the diabetes drug, which appears to have the secondary affect of inhibiting cancer stem cell mitochondria.

“What has been shown across many different cancer types is that diabetics who take metformin are protected to varying degrees from almost every cancer type,” he explains. “I think the idea that metformin is a mitochondrial inhibitor is very under-recognised, but if you put that existing data together with what we’ve shown, people may think about that as a new avenue of investigation.”

Moving towards viable drugs

In fact, this study has thrown up many possible lines of enquiry. The next step is to further test the validity of these findings, as well as checking whether MCT inhibitors may translate into viable drugs. It will also be important to determine whether these results apply only to breast cancer, or across other cancer types.

“We’re very interested in seeing how broadly applicable our findings are,” continues Lisanti. “I think we should also consider what other classes of compound may be used as safe effective mitochondrial inhibitors. There’s no reason why mitochondria in cancer stem cells couldn’t be selectively targeted without harming the normal cells. And we shouldn’t afraid to target the cancer stem cell-specific differences, because we may be missing a very important therapeutic opportunity.”

His latest paper, published in Oncotarget in January, has thrown up a particularly exciting set of results. He found that metformin was not the only drug that inhibits cancer stem cell mitochondria. In fact, five different classes of FDA-approved antibiotics produce a similar ‘side effect’, and are capable of eradicating cancer stem cells across eight tumour types. Lisanti suggests that these antibiotics may be repurposed for cancer treatment, effectively treating cancer like an infectious disease.

This study was inspired by a chance remark by his eight-year-old daughter Camilla (listed as a co-author on the paper) who suggested the cure for cancer might be “an antibiotic, like when I have a sore throat”.

“You should always listen to your children,” remarks Lisanti, “as they are usually right.”

A cancer treatment that attacks the tumorigenic cells only, leaving other cells unscathed and preventing recurrence – this may sound like a pipe dream for cancer research. But for scientists exploring the role of stem cell mitochondria, it could be a very real possibility. Through tackling the proteins that fuel cancer, we may one day be able to deplete that fuel tank altogether.

This article appears in the March 2015 edition of Pharma Technology Focus

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