Starving a tumour – new research in cancer metabolism gives hope to patients with mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive cancer that affects the lining of the lungs and is associated with exposure to asbestos. It has a five-year survival rate of less than ten per cent. MPM is usually treated with potent chemotherapy drugs, but these are seldom able to halt the progression of the disease.  

Professor Szlosarek’s research team launched the ATOMIC-Meso study (sponsored by Polaris Pharmaceuticals, Inc.) to approach the problem from a different angle. For cancer cells to grow and reproduce, they need sustenance – an amino acid called L-arginine that helps the body build protein. In a randomised, double-blind trial, the researchers administered pegylated arginine deiminase (ADI-PEG20), a drug which blocks arginine. They used this treatment in combination with cisplatin and pemetrexed – the recognised chemotherapy regime for pleural mesothelioma.

How did the cancer respond to treatment?

The ATOMIC-Meso study showed very promising results overall in patients with non-epithelioid MPM – the patients who received ADI-PEG20 lived on average two months longer than those given the placebo.

Two forms of non-epithelioid MPM have proved more resistant to chemotherapy alone:

• sarcomatoid mesothelioma, a fast-growing cancer made up of ‘spindle-shaped’ cells that spreads widely, including to major organs such as the lungs and liver and the bones.
• biphasic mesothelioma, where the tumours contain at least 10 per cent of sarcomatoid cells as well as epithelioid cells.

The results of this study in this non-epithelioid subgroup were positive. One group of patients in the study have survived for more than three years, and their response to treatment will be further studied.

The cells that resist ADI-PEG20

While ADI-PEG20 is effective in treating MPM, some cancer cells develop resistance to the drug after six months or more of treatment. Further research conducted at the Barts Cancer Institute in collaboration with Dr Sarah Martin’s group, has shown that combining ADI-PEG20 with spermidine-analog GC7 gives positive results in treating these resistant cells. 

Exciting new steps for cancer metabolism studies

Asparaginase is an enzyme used to inhibit the amino acid asparagine. It is found in high amounts in asparagus. Asparaginase was first used to successfully treat childhood leukaemia in the mid-1960s. J.D. Broome discovered a source of asparaginase in guinea pig serum, and W.C. Dolowy and JM Hill subsequently used this to treat human patients for the first time. Since its introduction into paediatric treatment protocols, survival rates in children have risen to nearly 90 per cent.

Since then, however, the field of cancer metabolism has had less focus than other forms of treatment.

Now Professor Szlosarek’s exciting results herald new possibilities in this realm of cancer research. Following on the heels of ATOMIC-Meso, further studies are planned of ADI-PEG20 in patients with epithelioid MPM. It is hoped that this new therapy can be tested in many different forms of cancer. Understanding how tumours metabolise and how they can be “starved” could revolutionise cancer treatment.