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Prostate cancer is the fourth most common cancer in both sexes combined and the second most common cancer in men. An estimated 1.1 million men worldwide were diagnosed with prostate cancer in 2012, accounting for 15% of the cancers diagnosed in men, with almost 70% of the cases (759,000) occurring in more developed regions.

Now, a team of UC San Francisco researchers has discovered something they refer to as the ‘Achilles Heel’ of treatment-resistant prostate cancer.

Compared with other cancers, prostate cancer prognosis is good today. In many cases, the disease is so mild that it does not require whole-body treatment, it can be removed by surgery or radiotherapy at an early stage.

But there are also more malignant and rapidly growing forms of prostate cancer that rapidly spread and are more difficult to treat. In these cases, hormonal therapy is often used to possibly keep the disease in check and slow down the spread.

In a new study, researchers have studied the most aggressive form of prostate cancer called castration-resistant prostate cancer. In principle, almost everyone that ultimately die due to prostate cancer has this form that no longer responds to treatment.

Protein Overload

Prostate cancer cells are dependent on the process of the cell that produces proteins, as it provides fuel for their growth. But there is a weakness if the cells get too much protein, they die.

Because of the rapid growth of the most aggressive prostate tumors, many proteins should be formed. But the researchers’ results show that the malignant cancer cells have developed a “brake” for the production of proteins so that they get just enough to grow and not too much so that they die.

This brake is also a kind of protein. The researchers, therefore, tried to find a way to block this ‘protein brake’, thus causing the cancerous cells to die from protein overload.

“We have learned that cancer cells become ‘addicted’ to protein synthesis to fuel their need for high-speed growth, but this dependence is also a liability: too much protein synthesis can become toxic,”

“We have discovered the molecular restraints that let cancer cells keep their addiction under control and showed that if we remove these restraints they quickly burn out under the pressure of their own greed for protein.”

– Senior author Davide Ruggero, Ph.D., the Helen Diller Family Chair in Basic Cancer Research and a professor of urology and cellular and molecular pharmacology at UCSF.

Protein Brake Deactivation

They found an experimental drug from another study called ‘ISRIB’, a laboratory study conducted on serious brain injuries for which researchers had developed a molecule that blocks this protein brake, but for another purpose.

The researchers first tested the drug on treatment-resistant prostate cancer tumors that they had grown into the laboratory. These tumors had been taken from humans. They then tested the drug on mice that received human prostate cancer tumors.

It was found that the drug caused malignant prostate cancer tumors to decrease in size while normal cells were left unaffected. Even less malignant tumors were left unaffected.

“Together these experiments show that blocking P-eIF2α signaling with ISRIB both slows down tumor progression and also kills off the cells that have already progressed or metastasized to become more aggressive,”

“This is very exciting because finding new treatments for castration-resistant prostate cancer is a pressing and unmet clinical need.”

– Crystal Conn, PhD, a postdoctoral researcher in the Ruggero lab and one of the paper’s two lead authors.


Hao G. Nguyen et al. Development of a stress response therapy targeting aggressive prostate cancer DOI: 10.1126/scitranslmed.aar2036