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Blocking cancer stress signal shows promise in bone marrow cancer

Potential new drugs that block a safeguard used by cancer cells to stay alive in stressful conditions have shown promise against myeloma, a new study reports.

Blocking a signal that triggers cancer’s response to stress using the new prototype drugs killed myeloma cells in the lab and slowed tumour growth in mice.

Cancer cells often have to grow under stressful conditions as they compete for oxygen, nutrients and space during their rapid growth and division – and also have to withstand stress caused by overactive cancer genes.

Scientists at The Institute of Cancer Research, London, believe that targeting the cell’s stress response could be one way of treating myeloma, and potentially other cancers, more effectively.

Their new study was largely funded by Cancer Research UK, and is published today in the journal Clinical Cancer Research.

HSF1 is a molecular switch that regulates the levels of hundreds of proteins involved in a cell’s response to stress, and is super-activated in many cancer types.

The molecule also plays a role in regulating the amount of proteins in cells, making it an especially promising target for myeloma, in which cancer cells in the bone marrow produce an abnormally large number of antibodies.

A team at The Institute of Cancer Research (ICR) – a research institute and a charity – analysed genetic information from more than 250 people with myeloma.

They found that those people whose cancers had high activity of the HSF1 gene had poorer survival than those whose cancers had low activity – suggesting that the stress signal may play an important role in myeloma.

Next, the researchers showed that when HSF1 was genetically depleted in myeloma cells in the lab, those cells died – showing that HSF1 is indeed important for their survival.

The researchers then treated myeloma cells with two prototype drugs designed to block the HSF1 pathway – CCT251236, which was discovered at the ICR, and another called KRIBB11. They found that both inhibitors killed a substantial proportion of human myeloma cells in the lab.

When given in combination with an existing myeloma drug, bortezomib, both HSF1 inhibitors enhanced the drug’s effect.

In mice treated with CCT251236 or KRIBB11, myeloma tumour growth was significantly slowed compared with animals that did not receive any treatment.

Both HSF1 inhibitors also caused some cell death in healthy bone marrow stem cells and white blood cells, but to a much lesser extent than in myeloma cells.

The researchers now plan to carry out clinical studies to look into the possible benefits of an HSF1 inhibitor in people, and to further investigate the benefits of combination therapy with bortezomib.

Study co-leader Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said “We found that prototype drugs that block a major signal that triggers cells’ response to stress could be effective against the bone marrow cancer myeloma. The inhibitors we tested killed myeloma cells in the lab and blocked the growth of human myeloma tumours in mice. We hope that HSF1 pathway inhibitors could offer a potential new and much needed way to treat myeloma. The next stage will be to start testing the new treatment approach in patients in early-phase clinical trials."

“If we’re going to deliver step-change improvements for cancer patients, we need to find brand new ways of attacking cancers. Blocking cancer’s ability to cope with stress is one such innovative idea, and our study shows that it offers real promise. I’m excited to see this new approach to treatment assessed in cancer patients as soon as possible.”

Professor Karen Vousden, Cancer Research UK’s Chief Scientist, said “This study’s identification of a new way to kill myeloma cells is a step towards improving the outlook for people with this cancer. While there has been some progress, survival from this disease still lags behind many other cancers. But before this can be turned into reality, we will now need to see if this approach could work in people.”

Source: ICR



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