A crucial molecule which enables cancer to spread has been identified by scientists for the first time, paving the way for new treatments. The disease is one which relies on cell growth, and in most cases tumours only become lethal once they metastasise, or spread from their first location to other parts of the body.
Today, researchers at Thomas Jefferson University in Philadelphia revealed they have found a single molecule that appears to be the ‘lynchpin’ driving metastasis in prostate cancer. They hope their findings will enable them to target the development of a drug that could prevent cancerous prostate tumours spreading. And their aspirations do not end there.
The team hope it will eventually pave the way for treatments to target other forms of the disease. Karen Knudsen, professor of urology at the 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.’ Metastasis is thought of as the last stage of cancer. The tumour undergoes a number of changes to its DNA – mutations – that make the cells more mobile allowing them 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 new research suggests that just one molecule lies at the root of many of them. That molecule is a DNA repair kinase, called DNA-PKcs.
The kinase – a type of enzyme – rejoins broken or mutated DNA strands in a cancer cell, acting as a glue to the many broken pieces of DNA, thus keeping alive a cell that should normally self-destruct. Finding a way to halt or prevent cancer metastasis has proven elusive.
We discovered that a molecule called DNAPKcs could give us a means of knocking out major pathways that control metastasis before it begins Karen Knudsen, professor of urology, Thomas Jefferson University Past studies had shown that DNA-PKcs was linked to treatment resistance in prostate cancer, in part because it would repair the usually lethal damage to tumours caused by radiation therapy and other treatments.
Importantly, Prfoessor Knudsen’s work showed that DNA-PKcs has other, farreaching roles in cancer. The team found the molecule also appears to act as a master regulator of a network that turns on the entire programme of metastatic processes.
Specifically, the DNA-PKcs modulates another enzyme, which allows many cancer cells to become mobile, as well as other key processes such as cell migration and invasion. Furthermore, Dr Knudsen and her team were able to show that in mice carrying human models of prostate cancer, they could block the development of metastases by using agents that suppress DNAPKcs production or function. And in mice with aggressive human tumours, an inhibitor of DNA-PKcs, reduced overall tumour burden in metastatic sites. In a final part of their investigations, researchers analysed 232 samples from patients with prostate cancer.
They measured the amount of DNA-PKcs those cells contained, and compared those levels to the patients’ medical records. They discovered a spike in the kinase levels was a strong predictor of developing metastases and poor outcomes in prostate cancer.
And they showed that DNA-PKcs was much more active in human samples of castrate- resistant prostate cancer, an aggressive and treatmentresistant form of the disease. Dr Knudsen said: ‘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 DNAPKcs could predict which early stage tumours may go on to metastasize.
‘The finding that DNA-PKcs is a likely driver of lethal disease states was unexpected, and the discovery was made possible by key collaborations across academia and industry.’
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