Rewiring cancers’ circuits – a new way to kill?

Scientists can kill cancer cells by targeting molecules inside the cells that help them survive.

But there are a lot of molecular targets to take aim at.

One of these, HIF-1, has been on scientists’ hit list for years.

But drugs developed so far haven’t worked as well as hoped.

New research from our scientists at the University of Southampton, published today in the journal ACS Synthetic Biology, could change that.

HIF-1 helps tumours grow new blood vessels, which the cells need to grow and survive. And the new study, led by Professor Ali Tavassoli, reveals a potential new way to cut off this blood supply by targeting HIF-1.

Assemble or disassemble?

Many of the molecules inside cells work by sticking to other molecules. And that’s true of HIF-1, which is actually formed from a molecular partnership between two molecules: HIF-1α and HIF-1β.

The two molecules stick together when oxygen levels around a cell are low. And an active HIF-1 molecule forms.

Once activated, HIF-1 changes how more than 300 genes are turned on and off inside the cell. One effect this can have is triggering new blood vessels to grow.

In healthy cells, this process is tightly controlled, and HIF-1 is rarely switched on.

But in tumours, it’s a different story. As they grow, tumours need more and more oxygen to survive. This means they need to create new blood vessels. So they hijack HIF-1 to produce the blood vessels they need.

Because of this, scientists have long tried to make drugs that stop the two HIF molecules coming together. By doing this they hope to cut off tumours’ blood supply and kill cancer cells.

But so far this approach hasn’t been very successful.

“There’s been a lot of investment into developing drugs that block molecules coming together, like HIF-1α and HIF-β binding. But this hasn’t translated into drugs that can benefit patients,” says Tavassoli.

So why is this? Tavassoli believes part of the reason is that “the tools used by scientists to understand the role proteins binding together plays in cancer are flawed”.

And that’s where his team’s latest study comes in. They’ve developed a new technique that forces cancer cells to make a molecule that stops HIF-1α / HIF-1β sticking together, causing the cells to die when starved of oxygen and food.

‘Short-circuiting’ cancer cells

To fully understand the role of HIF-1 in cancer, scientists need compounds that stop HIF-1α / HIF-1β joining together. But so far, they haven’t had access to any such compounds.

Instead, they have used techniques that completely remove HIF-1 from the cell.

It’s this approach that Tavassoli believes is flawed.

“At the moment scientists studying HIF-1 are doing so by getting rid of it completely. They’re using techniques that eliminate HIF-1α or HIF-1β from cells, and so are eliminating HIF-1 activity”, he says.

But this is very different from preventing HIF-1 formation by messing with how the molecules stick together.

“HIF-1α and HIF-1β have other roles in cells besides forming HIF-1. So if you remove them, you not only disturb HIF-1 formation but all of their other roles as well,” says Tavassoli.

His team set out to change this. They wanted to make a drug that would switch off HIF-1 by disrupting how HIF-1α and HIF-1β stick together.

They have previously reported being able to make a molecule that stops HIF-1 formation.

Now, they wanted to go a step further and modify cancer cells so they themselves could produce this molecule.

To do this the team created a ‘genetic circuit’ that contained the necessary instructions for a cell to make their molecule that the team hoped would come between HIF-1α and HIF-β.

The researchers then modified cancer cells in the lab so that this circuit was built-in to their DNA and the new molecule was produced.

To test its effect they plunged the cancer cells into low oxygen conditions, which would normally trigger HIF-1 formation.

HIF-1 didn’t turn on.

It had worked. Their ‘genetic circuit’ had stopped HIF-1 being switched on. Crucially, HIF-1α and HIF-1β weren’t eliminated from the cell, but they had been stopped from sticking together.

“Using this new technique we’ve managed to engineer cancer cells with an extra component in their DNA, which triggers the production of a HIF-1 inhibitor under low-oxygen conditions,” says Tavassoli.

It’s not as sci-fi as it sounds

This is an incredible new technique with a lot of potential.

But Tavassoli is quick to point out that changing the DNA of healthy people or cancer patients isn’t likely to happen any time soon.

“This ‘genetic circuit’ isn’t something we’d start putting into the DNA of people. Instead, we’d use it as a way to study HIF-1 in greater detail than ever before, and to get a better understanding of its role in cancer,” he says.

“We already know that HIF-1 helps tumours to grow. But we don’t know if it’s really worth targeting. And if it is, at what stage of the cancer process should we block it?”

Tavassoli also thinks the technique could help scientists figure out if it’s worth trying to target HIF-1 in cancers that have already spread.

“By giving us greater control over HIF-1, this technique will help us gain a better understanding of its role in cancer, and help answer a lot of questions.”

And it could lead to the development of new treatments.

We could use this ‘genetic circuit’ to help develop small drugs that inhibit HIF-1.

– Professor Ali Tavassoli

“We could use this ‘genetic circuit’ to help develop small drugs that inhibit HIF-1 in the same way it does – by stopping HIF-1α / HIF-1β binding.

“At the moment, we don’t have drugs that can do this. This technique could change that.”

Tavassoli and the team believe their built-in genetic circuit could also help researchers study and understand more about the roles of other important molecules involved in cancer, such as KRAS, p53 and MYC.

“This technology can be easily shared with other researchers who we hope will use it to study other molecules in different types of cancer.”

According to Tavassoli: “The technique we’ve developed eliminates the need for a man-made drug that needs to get inside cancer cells to work. Instead, we give the cells the tools they need to make inhibitory compounds themselves.

“This should make it easier for scientists to study a whole range of molecules in a more accurate way.”

New technique, massive potential

In order to develop new treatments for cancer, scientists need to know what they’re dealing with. They need to understand the underlying biology of the disease and figure out what to target if they want to kill the cancer cells.

This work by Tavassoli and his team is giving scientists a new way to do this.

Their technique could help scientists understand more about key molecules involved in how cancers grow and develop. And it could lay the foundations for developing new drugs.

This means the work may not directly benefit the cancer patients of today, but it certainly holds a lot of promise for helping patients of the future.

Áine