A molecule described as the ‘lynchpin’ of cancer spread has been identified, paving the way to potentially life-saving treatments.

Targeting the protein DNA-PKcs could prevent the deadly spread of prostate cancer and possibly other cancers as well, scientists believe.

Metastasis, the migration of tumours away from their original site to vital organs such as the liver and brain, is usually what causes cancer to kill.

US lead scientist Karen Knudsen, director of the Sidney Kimmel Cancer Centre at Thomas Jefferson University, said: “Finding a way to halt or prevent cancer metastasis has proven elusive. We discovered that a molecule called DNA-PKcs could give us a means of knocking out major pathways that control metastasis before it begins.”

Before cancer spreads, tumours develop DNA mutations that make their cells more mobile and able to enter the bloodstream. The cells also become ‘sticky’, which helps them anchor into new locations such as the bone, lungs, liver or brain.

The processes by which this happen are complex, involving many different biological pathways – but the research suggests that just one molecule, DNA-PKcs, lies at the root of many of them.

We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic

The molecule is a type of enzyme known as a ‘repair kinase’ that fixes broken or mutated DNA strands in cancer cells. Because of DNA-PKcs, defective cells that should normally self-destruct are kept alive.

Previous research has shown that the molecule helps drive treatment-resistance in prostate cancer by repairing damage to tumours caused by radiation and other therapies.

Knudsen’s team found that DNA-PKcs also seems to act as a master regulator of signalling networks that turn on the whole metastatic process.

It has effects that allow many cancer cell types to become mobile, and is involved in other pathways responsible for cell migration and invasion.

In mice with human prostate cancer, blocking DNA-PKcs prevented the spread of tumours. Cancer growth in metastatic sites was reduced in animals with aggressive human tumours.

Further analysis of tissue samples from 232 prostate cancer patients revealed that spikes in kinase levels strongly predicted metastasis and poor outcomes.

DNA-PKcs was much more active in men with prostate cancer who had ceased to respond to hormone therapy.

“These results strongly suggest that DNA-PKcs is a master regulator of the pathways and signals that lead to the development of metastases in prostate cancer, and that high levels of DNA-PKcs could predict which early stage tumours may go on to metastasise,” said Knudsen.

The findings are reported in the journal Cancer Cell.

A drug that inhibits DNA-PKcs made by the pharmaceutical company Celgene is now being tested on patients with advanced solid tumours and leukaemia in an early-stage phase 1 clinical trial.

The drug, code-named CC-115, suppresses both DNA-PKcs and another cancer-driving molecule.

“We are enthusiastic about the next step of clinical assessment for testing DNA-PKcs inhibitors in the clinic,” Knudsen added.

“A new trial will commence shortly using the Celgene CC-115 DNA-PKcs inhibitor. This new trial will be for patients advancing on standard of care therapies.

“Although the pathway to drug approval can take many years, this new trial will provide some insight into the effect of DNAP-PKcs inhibitors as anti-tumour agents.

“In parallel, using this kinase as a marker of severe disease may also help identify patients whose tumours will develop into aggressive metastatic disease, so that we can treat them with more aggressive therapy earlier.

“Given the role of DNA-PKcs in DNA repair as well as control of tumour metastasis, there will be challenges in clinical implementation – but this discovery unveils new opportunities for preventing or treating advanced disease.”

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