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More and more targeted therapy cancer drugs inhibit the effects of DNA errors in the cancer cell.

Unfortunately, cancer cells often are, or become, resistant to these drugs and they then continue to divide via an alternative signalling route in the cell. Molecular cancer researcher Dr Rene Bernards recently announced that he has exposed these routes in cancer cells by blocking all routes off, one by one, using genetic techniques such as CRISPR/Cas. He and his colleagues also stressed that combination therapies should increasingly be on pharmacists’ radars.

Dr Bernards first discovered one of these pathways in 2012. He wanted to know why a specific drug did nothing for a particular form of colon cancer that is difficult to treat, while working well for melanoma, involving
exactly the same DNA mutation. He deduced that it is possible to combine the first drug with a second that blocks this pathway — a revolutionary discovery that has led to a life-extending combination therapy that is now
being used worldwide. It has also led to a search for other alternative signaling pathways, as well as new combination therapies for other types of cancer.

Recently, Dr Bernards, his post-doc Dr Haojie Jin and their colleagues in Europe and China described a similar resistance mechanism in liver cancer in the journal Nature. They discovered why the drug lenvatinib, one of the few targeted drugs on the market for liver cancer, shows no effect at all in 75-to-80 per cent of patients.

The interferer turned out to be EGFR, a growth factor receptor that is activated in liver cancer cells as soon as the drug lenvatinib is administered, thereby spurring cell division. In mouse models, the researchers then saw that those tumours that were resistant to lenvatinib from the start did indeed activate the EGFR.

However, they also discovered that it is possible to override this resistance in cells as well as mice by combining lenvatinib with another drug, gefitinib, which inhibits EGFR. This is an existing drug that is already being used to treat lung cancer, for example Liver cancer is relatively rare in the West, although certain lifestyle factors have led to an increase in its occurrence. In Africa and Asia, however, liver cancer, mainly as a result of hepatitis B and C, is a major problem, and half of the world’s deaths related to liver cancer occur in China.

Dr Bernards and colleagues were able to set up a first-inhuman clinical study at the Eastern Hepatobiliary Surgery Hospital in Shanghai. This hospital alone has 600 beds for patients with liver cancer.

This phase 1 proof-of-concept study involved 12 patients who previously did not respond to treatment with lenvatinib and who had large amounts of EGFR in their tumour. A significant reduction of the tumour
was observed in four of the 12 patients and the cohort is now being expanded to 30. After that, larger clinical studies are needed before this combination therapy can be used in the clinic, said Dr Bernards. “This
study shows that it is possible to improve existing drugs by combining them. Another advantage is that gefitinib is off-patent, making it affordable.”

Because cancer is so complex and adapts so rapidly, combination therapies will become increasingly important, said the researchers. Pharmacists should therefore move towards an approach involving smart combinations
of drugs when developing medicines, Dr Bernards recently argued. Hopefully, that will mean that new therapies can reach patients more quickly, and that promising new drugs will be less likely to fail during development
because they do not work, or don’t do enough, on their own, he said.