Improving the gold standard for brain tumours

Combining a drug called temozolomide (Temodal) with radiotherapy and surgery is now the international standard-of-care for thousands of people with the most common type of adult brain tumour, glioblastoma.

And we’re very proud of the fact that temozolomide is a drug our researchers discovered and developed – it remains a shining example of how the public’s generous support has made a real impact for cancer patients. You can read more about the history of our involvement here.

But although temozolomide offers hope to patients with glioblastoma, overall survival for brain cancer remains pitifully low. Not everyone responds to the drug, and even those that do will often eventually see their tumour cells become resistant.

Clearly, we need to do more. And we are. This week, Cancer Research UK scientists from the University of Bradford, led by Dr Richard Wheelhouse along with collaborators from the United States and Finland, have tested a modified version of temozolomide that might be able to get past cancer’s defences to the drug.

This is the first step on the road to a better version of the drug that could, one day, help more patients.

So how does it work?

Tagging DNA

Temozolomide adds small chemical tags, known as methyl groups, to the DNA inside cells.

Temozolomide adds chemical tags to DNA

When the tagged DNA is copied, the cell’s built-in repair systems – a ‘proofreading ‘system called DNA mismatch repair – stops the copying process, causing the tumour cells to die when they try to grow.

But our cells are adept at repairing DNA damage like this, and have several intricate molecular systems with which to do so. Cancer cells are no exception.

So whether temozolomide works depends on the presence or absence of another DNA repair mechanism, a protein called O6-methylguanine methyltransferase – MGMT for short.

MGMT removes the chemical tags added by temozolomide, allowing the cell to survive and the tumour to keep growing. So for a tumour to respond to temozolomide, it must have active mismatch repair systems, and be low in MGMT.

But some patients’ tumours contain high levels of MGMT, and this can negate the drug’s effect. Sadly, these patients often have worse outcomes.

But even for the patients with low MGMT levels, there’s nasty twist in the tail of temozolomide: tumours that respond to the drug generally only do so once. Temozolomide can cause faults in the DNA system so that it no longer works. So when the tumour grows back, it is resistant to the effects of temozolomide.

So what is the new drug?

In their study, published in the journal Molecular Cancer Therapeutics, the researchers looked at a new experimental drug called DP68, which is effectively two temozolomide molecules linked together.

Instead of adding small methyl group tags, DP68 creates chemical links that hold two strands of DNA together – a modification which MGMT cannot repair. In theory, this means the new drug could be more effective at killing the tumour.

They tested this in the laboratory by adding either temozolomide or DP68 to cancer cells carrying different levels of MGMT – to mimic the situation in patients with different types of glioblastoma.

“This could potentially plug the gap between the patients that best respond to temozolomide and those that are resistant” – Dr Paul Brennan, University of Edinburgh Cancer Research Centre

They found that DP68 was much more effective than temozolomide at killing cancer cells with low levels of MGMT. And, as expected, temozolomide’s ability to kill cancer cells dropped off in cells with higher levels of MGMT. But DP68 remained just as effective, no matter what the levels of MGMT were.

Also, they showed that DP68 does not need to the help of the mismatch repair system to work, and this led to one of the most exciting results in the study: lab-grown tumours could regrow after temozolomide treatment, even at high doses. But those treated with DP68 – even at modest doses – were unable to regrow.

What next?

Although there’s a way to go before it reaches patients, UK glioblastoma experts are keeping a close eye on the Bradford team’s results.

Dr Paul Brennan, a brain tumour expert at the University of Edinburgh Cancer Research Centre, told us: “This exciting research shows how we might bypass the MGMT repair process that limits the effectiveness of temozolomide for many patients.

“This could potentially plug the gap between the patients that best respond to temozolomide and those that are resistant.”

However, there are still significant hurdles to be overcome. For example, when the drug was tested in mice, the researchers found that DP68 disappears from the bloodstream much more quickly than temozolomide. So the next big challenge is to fine-tune its chemistry to ensure its stable in people, but retains the very properties that make it effective.

These are not trivial challenges. But we’ll all be keeping a close eye on their progress.

Alan Worsley is a senior science communications officer at Cancer Research UK

Reference

• Ramirez, Y., et al. (2014). Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth Molecular Cancer Therapeutics, 14 (1), 111-119 DOI: 10.1158/1535-7163.MCT-14-0113

Image

• Lego DNA image via Flickr under CC BY 2.0
• Note image via Flickr under CC BY 2.0