Cancer breakthrough reveals old drugs with new tricks may limit spread

Metastasis, the ability of cancer cells to spread to other parts of the body, is notoriously difficult to treat and is the leading cause of death, which means that early diagnosis and treatment are essential.

Cancer is triggered when certain changes occur in the genes located in the nucleus of a cell - the cell's command center that contains its DNA.

When examined under a microscope, cancer cells look abnormal. For more than 150 years, scientists have used changes in the size of the cell nucleus to diagnose cancer and its severity.

In many types of cancer, these size changes are linked to increased metastasis, the ability of cancer cells to spread, which reduces the chance of survival. Yet few treatments specifically target metastasis.

To address this problem, researchers at the Universities of Edinburgh, Montreal and Eastern Finland tested drugs in the laboratory that reversed changes in the size of the nucleus in the cells of three cancers: prostate, colon and lung.

The screening identified many existing anti-cancer drugs, but also drugs not previously used to treat cancer, including those used for depression, heart disease and parasitic worm removal.

While each identified drug must undergo further testing to see if it is effective in reducing metastasis in cancer patients, the screening identified more than a dozen drugs that may be effective for each of the three cancers.

Because the drugs can target specific types of cancer cells and are generally nontoxic, they could be added to existing treatments to reduce metastasis without worsening the current toxic side effects of chemotherapy.

The researchers found that in each type of cancer, a different set of drugs could change the size of the nucleus in the opposite direction to the changes associated with increased metastasis.

Understanding why was confusing because the size changes went in both directions: increases in metastasis followed size increases in prostate and breast cancers and decreases in lung cancer.

Research into the causes of metastasis is ongoing, but it occurs when cancer cells break away from the original tumor and move through the bloodstream to other parts of the body.

A smaller nucleus might make it easier for the cell to squeeze through blood vessel walls into other tissues, while a larger nucleus might be more malleable to allow such compression.

In almost all of the drugs tested, the change in nucleus size - in the opposite direction to what normally occurs with metastasis - reduced the cell's ability to move and invade tissue.

These size changes are likely to affect the speed and ability of the cell to move, because the nucleus is tightly bound to a network of filaments, called the cytoskeleton, that controls its movement.

Similar screens for other types of cancer are likely to identify additional drugs that have the potential to target specific types of cancer and reduce metastasis while limiting toxic side effects.

The study, published in ACS Chemical Biology, was funded by Wellcome, the Medical Research Council UK, the National Institutes of Health USA, the European Research Council, the Canadian Institutes of Health Research, the Sigrid Juselius Foundation and the Cancer Society of Finland.

Professor Eric Schirmer, personal chair of nuclear envelope biology at the University of Edinburgh's School of Biological Sciences, said, "The tissue and cancer type specificity is the most interesting to me, because it means the drugs are less likely to produce systemic toxicity or other side effects.

"That means they could be added to existing treatments to reduce metastasis without adding to the toxicity of those treatments for the patients themselves. In addition, because we only tested FDA- and EMEA-approved drugs, they could be brought to the clinic much more quickly."