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Cancer killer combination could make cells more sensitive to chemo

by Emma Smith | Analysis

15 July 2015

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yew tree
Taxane drugs were first discovered in yew trees

There’s much talk about the move towards ‘personalised’ cancer treatment, with the hope of bringing cures for more people and making treatments kinder.

Over recent years drug development has mainly focused on targeted therapies – ‘smart’ drugs designed to home in on specific molecules in tumour cells known to drive the growth or spread of cancer.

But because these treatments rely on those molecules’ presence, they won’t work if a patient’s cancer doesn’t have them. So there remain many patients for whom there are currently no suitable targeted drugs. And even for the types of cancer where they do exist, tumours can evolve and become resistant to their effects over time.

So while targeted therapies continue to play an important and growing role in treating cancer patients, we can’t lose sight of one of the cornerstones of cancer treatment – chemotherapy.

Since it was first developed in the 1940s, chemotherapy has helped save and extend the lives of thousands of cancer patients, and it’s an extremely powerful weapon against cancer. But it has a bad reputation due to some serious side effects, and it’s not always effective – particularly in late-stage cancers.

So can we make it better and – just as importantly – kinder? New research from Cancer Research UK scientists, published earlier this week in the journal Cancer Cell, suggests the answer is a tentative ‘yes’.

The taxane family

In search of answers, Professor Stephen Taylor – one of our Senior Fellows at the University of Manchester – has been investigating a family of commonly-used chemotherapy drugs called taxanes. This includes paclitaxel and docetaxel, used to treat a range of cancers including breast, ovarian, prostate and lung tumours.

Taxanes work by attacking dividing cells, stopping the formation of molecular ‘ropes’ that normally pull the chromosomes (DNA) apart as cells split into two. By blocking this crucial process, they stop the cells in their tracks and force them to self-destruct.

Many patients’ cancers respond to taxane treatment, although the side effects can be unpleasant. But sometimes patients don’t respond – and unfortunately this isn’t something that doctors can predict, meaning that some people will end up having treatment that doesn’t help them yet still causes side effects.

On top of this, in some patients whose tumours do respond, the cancer becomes resistant to the drugs over time.

So Professor Taylor and his team set out to discover why some cancers don’t respond to taxanes and whether they could boost the effectiveness of this important treatment – meaning patients could safely receive lower doses with fewer side effects – by weakening cancer cells first.

Cheating cell death

Cancer cells treated with taxanes usually stop dividing and die, but occasionally they manage to escape death and carry on growing, developing into drug-resistant tumours.

Figuring that the key to this death-defying ability must lie in the cancer’s genes, Professor Taylor and his team studied bowel cancer cells growing in the lab that had been treated with taxanes.

Using biological ‘off switches’, known as siRNAs, they turned off hundreds of different genes one by one to pin down which of them were enabling the cells to cheat death in response to treatment.

One intriguing suspect stood out: a gene called Myc, which normally acts to fuel the growth of cancer cells. But in this case it seemed to be critical for telling cells to die when given taxane chemotherapy.

This dual role of Myc – acting as a cancer accelerator in some instances and a cancer-killer in others – has been a puzzle for years.

Professor Taylor found that, in response to drug treatment, Myc was marshalling a network of other molecules inside the cancer cells, instructing them to trigger the cell’s natural self-destruct mechanism.

But without Myc, the cancer cells didn’t die.

But this is the case for cancer cells growing in dishes in the lab. To find out whether Myc was involved in helping real tumours to cheat death, the researchers looked at levels of the gene’s activity in cancer samples taken from breast cancer patients.

The results revealed that levels of Myc matched how well the patient had responded to taxane chemotherapy: all those whose cancers who didn’t respond had low amounts of Myc, while those with high Myc levels fared better.

By further unravelling the roles of the molecules controlled by Myc, the team saw that one molecule in particular – a protein called Bcl-xL – seems to be important for helping cells survive.

As a final experiment, Professor Taylor and his team treated some taxane-resistant cells lacking Myc with both an experimental drug that blocked Bcl-xL, and a taxane.

The combination hugely boosted how powerful the taxane drugs were at killing the cancer cells.

From a bright idea to a new treatment?

These experiments suggest that Bcl-xL-blocking drugs could help to make kill tumours with taxane chemotherapy, or even overcome drug resistance. The good news is that such drugs are being developed by pharmaceutical companies, and are currently being tested in patients, including one early-stage trial in the US looking at their effectiveness in combination with chemotherapy for advanced laryngeal cancer.

Professor Taylor hopes that his work will lay the foundations for clinical trials here in the UK, taking advantage of the strong ties between the University of Manchester and the Christie Hospital, including their early-stage trials unit.

One area he wants to focus on is ovarian cancer – a disease commonly treated with paclitaxel, but which often becomes resistant to it.

He also wants to study cancer cells over time, to see what happens to Myc and Bcl-xL when women with ovarian cancer stop responding to chemotherapy, in order to work out how to overcome drug resistance.

All of this adds up to important progress that will help to shape cancer treatment in the future. Chemotherapy is still an important weapon in our fight against cancer – and one that’s likely to still be around for some time to come – but vital research like this is making it kinder and more effective.

– Emma

Reference

Topham, C., Tighe, A., Ly, P., Bennett, A., Sloss, O., Nelson, L., Ridgway, R., Huels, D., Littler, S., Schandl, C., Sun, Y., Bechi, B., Procter, D., Sansom, O., Cleveland, D., & Taylor, S. (2015). MYC Is a Major Determinant of Mitotic Cell Fate Cancer Cell, 28 (1), 129-140 DOI: 10.1016/j.ccell.2015.06.001