Tactics to overcome mesothelioma treatment resistance

Zoe Leech Posted in Publications 26 July 2016

Mesothelioma is a cancer affecting the “wrapping” around our organs, specifically the tissue that covers the lungs. It is becoming steadily more common since the significant asbestos exposure of the 1960s.

The UK now has the highest rate of mesothelioma deaths in the world.

Scanning electron micrograph of asbestos fibres

 

Pioneering work in our labs has led to a new "starvation" treatment strategy for this disease, previously almost untreatable due to the difficulty of performing effective surgery and lack of available drugs. Clinical trials have begun to test this "starvation" method in patients.

However, tumours often develop resistance to drug treatments. Dr Sarah Martin has been investigating how mesothelioma could get around the attack with a view to preventing resistance and killing the cancer more efficiently.

Sarah explained why the study, published last week in Cell Reports, is so encouraging.


Our work on stopping mesothelioma

The drug now being tested, called ADI-PEG20, essentially prevents cancer cells from getting nutrients they need to survive. Arginine is an amino acid that most normal cells can make themselves using “ingredients” absorbed from the blood.

Some cancers cannot; around 50 per cent of mesotheliomas lack the enzyme ASS-1, which means they rely instead on absorbing “external” arginine from the blood. ADI-PEG20 blocks the supply of arginine from the bloodstream, causing the enzyme-deficient cancers to starve.

Dr Sarah Martin

What does this study mean for mesothelioma treatment?

We created the first model of ADI-PEG20 resistance in mesothelioma cells and identified a synthetic lethal dependence between ASS1-deficiency and polyamine metabolism. This could potentially be exploited for the treatment of ASS1-negative cancers.

Through co-ordinated transcriptomic and metabolomic profiling, we found a compensatory metabolic network in tumour cells, meaning that in the absence of the arginine biosynthetic enzyme ASS1, the polyamine metabolic pathway is upregulated.

Cancer cells often have very different metabolic pathways from normal cells, allowing them to survive in scavenger-like ways, getting materials needed for cell growth however they can.

Mesothelioma cancer cells unable to make their own arginine - and starved of an external supply - seem to compensate by increasing their production of enzymes that allow them to build nutrients similar to it, called polyamines.

 

Graphical abstract from the paper

This could confer treatment resistance, but if we could block this metabolic pathway at the same time as depriving the cells of arginine, the susceptible cells can still be killed.

 

What are the implications and next steps?

Our data suggest that this increase in polyamine metabolic gene expression drives cellular proliferation in ASS1-deficient cells and can be exploited clinically through the use of polyamine inhibitors.

Future studies will determine whether combinatorial treatment with ADI-PEG20 and polyamine inhibitors can overcome the generation of resistance to arginine deprivation by simultaneously targeting two compensatory metabolic pathways.

By inhibiting the polyamine-building enzymes that the ASS1-lacking tumour cells make more of, we could overcome this attempt at resistance to arginine starvation in mesothelioma. Given drugs are already available, this is an exciting possibility.

Can we expect a new treatment, and how soon?

Both ADI-PEG20 and polyamine inhibitors are in clinical use, therefore these drugs could be combined in a clinical trial in the near future.

These results are very promising, given the TRAP trial led by our Dr Peter Szlosarek has now progressed to a Phase II/III study.

The work was funded by the British Lung Foundation (APG12-10 and MESO15-12), the June Hancock Mesothelioma Research Fund, and Cancer Research UK (C16420/A18066). E.G. acknowledges research funding from the Barry Reed Cancer Research Fund.


Publication

Inhibition of the Polyamine Synthesis Pathway is Synthetically Lethal with Loss of Argininosuccinate Synthase 1
Locke M, Ghazaly E, Freitas MO, Mitsinga M, Lattanzio L, Nigro CL, Nagano A, Wang J, Chelala C, Szlosarek P, Martin SA. Cell Reports (2016)

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