Driving cancer drug discoveries

At the Drug Discovery Unit (DDU), the fundamental biology discoveries made within the Cancer Research UK Manchester Institute, the Manchester Cancer Research Centre and The University of Manchester form the basis of potential new treatments for cancer. With a career in cancer therapeutics spanning over 30 years, DDU Director Professor Caroline Springer tells us how the unit is innovating.

As soon as I started working in medical research, I knew I didn't want to do anything else. It's absolutely fascinating and I still get excited about all our research projects in the DDU.

One example is the Gene-Directed Enzyme-Prodrug Therapy (GDEPT) project. Although it looks quite complicated at first glance, when you peer more deeply, you see that what it's actually trying to achieve is something relatively simple – to target only the cancer cells and avoid the healthy cells.

Much of what we do involves working with our Cancer Research UK (CRUK) colleagues in Manchester to find selective new targets within cancer cells that don't appear in normal cells. Then we work out how to make inhibitors that work selectively on those targets to stop the cancer cells dividing. We've got many such targets in our portfolio of projects at the moment.

Previously, conventional chemotherapy cancer treatments used targets within the cancer cell that were also present in normal cells, so that while these conventional drugs were good at killing cancer cells, they were often good at killing the normal cells too, thus causing unwanted side-effects, such as nausea and vomiting.

So, we're aiming to find new ways of directly tumour-targeting these types of cytotoxic drugs - the drugs that kill cancer cells, and thus spare normal cells.

Professor Caroline Springer

Caroline Springer is Director of Drug Discovery at the CRUK Manchester Institute.

 

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As soon as I started working in medical research, I knew I didn't want to do anything else. It's absolutely fascinating and I still get excited about all our research projects in the DDU.

One example is the Gene-Directed Enzyme-Prodrug Therapy (GDEPT) project. Although it looks quite complicated at first glance, when you peer more deeply, you see that what it's actually trying to achieve is something relatively simple – to target only the cancer cells and avoid the healthy cells.

Much of what we do involves working with our Cancer Research UK (CRUK) colleagues in Manchester to find selective new targets within cancer cells that don't appear in normal cells. Then we work out how to make inhibitors that work selectively on those targets to stop the cancer cells dividing. We've got many such targets in our portfolio of projects at the moment.

Previously, conventional chemotherapy cancer treatments used targets within the cancer cell that were also present in normal cells, so that while these conventional drugs were good at killing cancer cells, they were often good at killing the normal cells too, thus causing unwanted side-effects, such as nausea and vomiting.

So, we're aiming to find new ways of directly tumour-targeting these types of cytotoxic drugs - the drugs that kill cancer cells, and thus spare normal cells.

Old versus new

In conventional chemotherapy, the original way of working was to take drugs that were toxic to the cancer cells and deliver them in the highest possible dose that the patients could withstand, in order to spare their normal cells.

Traditional chemotherapy works because it kills cells. However, the side-effect is that the drug also works in inappropriate places. You can't divorce those two things because it's the way that those drugs have been designed to work.

Many types were designed to inhibit the replication of cancer cells by targeting their DNA – cancer cells need to replicate their DNA to proliferate – but, unfortunately, the drugs also work on the normal cells that divide, like those in the bone marrow, gut and hair follicles.

Selective drug delivery

Our GDEPT project uses the design of these sorts of cytotoxic drugs, but delivers them selectively to tumours so they can't kill normal cells in the gut or bone marrow. To do this, we synthesise a detoxified form, called a ‘prodrug', whereby we have attached a molecule that chemically deactivates the drug.

The prodrug is no use on its own, however, so we need something that activates the prodrug to form the cytotoxic drug – but only in the tumour.

The first step involves using a non-toxic vector that can hone in on tumours selectively. The vector forces the tumour to produce a completely new enzyme that is different from all the natural enzymes in the patient.

We've been working on a new viral vector, which is a virus with some of its critical genes removed so it's no longer active as a virus, but which retains some of the properties that enable it to infect cells.

We've removed those virus-essential genes, which mean that the virus no longer has toxic effects, but can still act as a delivery vehicle to take foreign enzyme genes to cancer cells. This enzyme is not a mammalian enzyme and is different from our native enzymes, so it's able to catalyse a different reaction. It's not harmful, but acts in a different way from any other enzymes that we have.

Then, we inject the modified viral vector, which contains the gene for the bacterial enzyme, and which is excellent at seeking tumours. We have designed the vectors to avoid normal cells. When the vector arrives at the tumour, it produces a lot of the foreign enzymes. We designed our prodrug so that it is cleaved only by the bacterial enzyme to release the cancer-killing drug.

Once we have administered the viral vector, we then wait a number of days for it to localise in the tumour. Then we administer the prodrug. As soon as the prodrug arrives at the tumour, it's cleaved by the bacterial enzyme there to form the active drug, and now this active drug is only in the tumour.

Challenges

Cancer is not just one disease; it's hundreds across many different tumour types, and each of them will require different kinds of treatments and drugs. We need to look at each cancer individually to see what's driving it and identify the best therapies for treating it.

There may be multiple subtypes of each cancer and multiple resistance mechanisms, such that the focus needs to be on each individual patient's disease, rather than globally on a disease type, as has happened previously.

The term 'personalised medicine' is key in ensuring that every patient receives the correct drug for their particular tumour type, but obviously the challenges here are great and the research is expensive to undertake. We're fortunate that CRUK funds our core drug discovery research, so we're able to continue driving these discoveries.

Ambitions

At the DDU, we are working collaboratively with the local science community, using the fantastic skills and expertise of the scientists and clinicians in Manchester, to deliver new inhibitors and drugs. 

Ultimately, we all just want to get the inhibitors we discover into clinical trials as quickly as possible, so that cancer patients can benefit from them much earlier. We want these inhibitors to be effective and benefit those patients who need them. I love what I do and so do my colleagues here.