Tumour-seeking salmonella may combat deadly brain cancer

By: PTI | Washington | Published:January 12, 2017 2:52 pm

Scientists, including those of Indian origin, have genetically modified salmonella – a strain of bacteria that causes food poisoning – to make them seek and detroy tumours, an advance that may help fight the deadliest form of brain cancer. Clinicians sorely need new treatment approaches for glioblastoma, the most aggressive form of brain cancer. The blood-brain barrier – a protective sheath separating brain tissue from its blood vessels – makes it difficult to attack the disease with drugs. It is also difficult to completely remove through surgery, as even tiny remnants inevitably spawn new tumours.

Even with the best care currently available, median survival time is a dire 15 months, and only 10 per cent of patients survive five years once diagnosed. Researchers at Duke University in the US decided to pursue an aggressive treatment option to match its opponent, turning to the bacterium Salmonella typhimurium. With a few genetic tweaks, scientists turned the bacterium into a cancer-seeking missile that produces self-destruct orders deep within tumours.

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Tests in rat models with extreme cases of the disease showed a remarkable 20 per cent survival rate over 100 days -roughly equivalent to 10 human years – with the tumours going into complete remission. Previous studies have shown, quite accidentally, that the presence of bacteria can cause the immune system to recognise and begin attacking tumours.

However, follow-up clinical trials with genetically 0detoxified strains of S typhimurium have since proven ineffective by themselves. To use these common intestinal bacteria as tumour-seeking missiles, researchers including Nalini Mehta and Ravi Bellamkonda, selected a detoxified strain of S typhimurium that was also deficient in a crucial enzyme called purine, forcing the bacteria to seek supplies elsewhere.

Tumours just so happen to be an excellent source of purine, causing the bacteria to flock to them in droves. Then, scientists made a series of genetic tweaks so that the bacteria would produce two compounds called Azurin and p53 that instruct cells to commit suicide – but only in the presence of low levels of oxygen.

Since cancerous cells multiply energetically, the environment around tumours has unusually low oxygen. “A major challenge in treating gliomas is that the tumour is dispersed with no clear edge, making them difficult to completely surgically remove,” said Bellamkonda. “So designing bacteria to actively move and seek out these distributed tumours, and express their anti-tumour proteins only in hypoxic, purine rich tumour regions is exciting,” he said.

“At the doses we used in the experiments, they were naturally cleared once they’d killed the tumours, effectively destroying their own food source,” he added. The results appeared in the journal Molecular Therapy -Oncolytics.