"Starving" mesothelioma: a new treatment approach

Marianne Baker Posted in In the Press, Publications 09 December 2013

Starving cancer cells of a key amino acid slows down their ability to grow and multiply, according to new research co-ordinated by Dr Peter Szlosarek here at BCI. Dr Szlosarek announced the findings on October 28th at the World Conference on Lung Cancer in Sydney, Australia, and they are now published in the journal Cancer Research. The Daily Express has covered this news.

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The team have been working on one of Britain's deadliest rare cancers, mesothelioma, studing how cancer cells are prevented from growing when starved of the amino acid arginine. Cells are normally able to make arginine themselves, but Peter's work has shown that around half of tumours lacked this ability and need to be "fed" arginine in order to survive, leaving them vulnerable to starvation by deliberate arginine depletion.

The identification of this "Achilles' heel" has led to a Queen Mary University-run clinical trial sponsored by Barts Health NHS Trust and funded by Cancer Research UK to test a new drug that targets this weakness.

68 patients took part in the trial and results so far have been extremely promising. Treatment with the arginine lowering drug significantly slowed down disease progression in 44 patients receiving the drug and best supportive care, nearly doubling the progression-free survival (compared with the 24 patients receiving best supportive care alone).

The drug, ADI-PEG20 (developed by Polaris Group), deprives tumours of their external source of arginine in the blood (from digested food) by breaking it down. The tumour cells then die because they don't have this essential building block to make proteins needed for survival. The lab has also shown that this deprivation changes the way the tumour cells make and distribute their DNA building blocks, and because some chemotherapy drugs target DNA construction, a combination of ADI-PEG20 with chemotherapy could show an even better effect than arginine deprivation alone.

These findings could pave the way for a new approach to slowing the progression of mesothelioma and other cancers dependent on arginine for survival.  This is the first time a targeted drug treatment has been designed for this type of cancer with a positive effect in a randomised study of patients with mesothelioma.

Mesothelioma is a cancer affecting the "protective wrapping" around our organs, particularly the tissue surrounding the lungs.  It has become steadily more common since the 1960s due to asbestos exposure and the UK now has the highest rate of mesothelioma deaths in the world. Around 1 in 10 carpenters over the age of 65 can expect to develop the disease.

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Dr Szlosarek commented:

"Mesothelioma is one of the UK's deadliest cancers with rates increasing almost four-fold since the early 1980s. Despite this, it remains relatively under the radar and there is very little research on how to treat this form of cancer with new therapeutics.

"Our research found that putting the tumours on an arginine starvation diet was an effective way of weakening the cancer, which in turn prolonged progression-free survival amongst patients. Our latest research suggests that combining arginine starvation drugs with standard chemotherapy could show an even stronger effect in combatting mesothelioma. With the positive signal coming from the current trial, we are eager to launch this new combination trial in early 2014."

You can read more about Dr Szlosarek's work in our coverage of the 2013 AACR meeting; in his Journal of Clinical Oncology article from earlier this year about the effects of ADI-PEG20 on cancer cell metabolism; and in his 2006 Clinical Cancer Research article about arginosuccinate synthase (ASS1) in tumours.

In Summary

The drug is particularly promising because:

  • A key issue with chemotherapeutic drugs is their tendency to be quite toxic, due to the fact they affect healthy cells as well as tumour cells.
  • The new drug used in this trial, ADI-PEG20, only affects the tumour cells and seems to lack serious side effects.

Mesothelioma needs to be a priority in cancer research:

  • Last year approximately 2500 people in the UK were diagnosed with mesothelioma and patient survival is typically only up to one year from diagnosis.
  • The UK is disproportionately affected by mesothelioma, accounting for more deaths than any other country in the world. (To put it in perspective, last year there were only 3500 new cases of mesothelioma in the whole of the USA, whose population is five times the size of ours).
  • While still relatively rare, mesothelioma deserves our attention as the number of cases is rising steadily by around 100 cases each year. (By comparison there are less than 1,000 deaths due to cervical cancer per year).
  • Better treatments for the disease are needed; no significant advance has been made in the last 10 years since a standard for chemotherapy was set in 2003 and surgical options are limited.
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A mesothelioma patient's FDG-PET scans showing partial (40%) reduction in tumour metabolic activity (shadowed area) from 1: pre-treatment and 2: following 3 doses of ADI-PEG20. Scale bars = 10cm. See the JCO paper for details. 

 

What's next?

Building on this proof-of-concept work, further tests to find out how ADI-PEG20 can help mesothelioma and non-smallcell lung cancer patients are soon to begin. The "Tumours Requiring Arginine to Assess ADI-PEG20 with Pemetrexed and Platinum (TRAP) trial will start in the first quarter of 2014. In the TRAP trial, ADI-PEG20 will be combined with the current standard chemotherapy, pemetrexed and cisplatin: dubbed an ADIPemCis combination. The TRAP trial will run here at Barts, with the Guy's, Kings & St Thomas' (GKT) Hospitals, and Cambridge.

Finally, a review article discussing the Szlosarek team's recent work in the field, including the Cancer Research paper and the new TRAP trial, will be in the next edition of the the journal "Cancer Research and Treatment". (Phillips MM, Sheaff MT, Szlosarek PW "Targeting Arginine-Dependent Cancers with Arginine-Degrading Enzymes: Opportunities and Challenges" Cancer Res Treat 2013; 45(4):251-262)

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