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Study uncovers promising new line of attack against aggressive prostate cancer

Study uncovers promising new line of attack against aggressive prostate cancer

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UC San Francisco researchers have discovered a promising new line of attack against lethal, treatment-resistant prostate cancer. Analysis of hundreds of human prostate tumors revealed that the most aggressive cancers depend on a built-in cellular stress response to put a brake on their own hot-wired physiology. Experiments in mice and with human cells showed that blocking this stress response with an experimental drug -; previously shown to enhance cognition and restore memory after brain damage in rodents -; causes treatment-resistant cancer cells to self-destruct while leaving normal cells unaffected.

The new study was published online May 2, 2018 in Science Translational Medicine.

“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,” said senior author Davide Ruggero, PhD, the Helen Diller Family Chair in Basic Cancer Research and a professor of urology and cellular and molecular pharmacology at UCSF. “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.”

“This is beautiful scientific work that could lead to urgently needed novel treatment strategies for men with very advanced prostate cancer,” added renowned UCSF Health prostate cancer surgeon Peter Carroll, MD, MPH, who is chair of the Department of Urology at UCSF and was a co-author on the new paper.

Prostate cancer is the second leading cause of cancer death for men in the United States: More than one man in ten will be diagnosed in his lifetime, and one in forty-one will die of the disease, according to data from the American Cancer Society. Tumors that recur or fail to respond to surgery or radiation therapy are typically treated with hormonal therapies that target the cancer’s dependence on testosterone. Unfortunately, most cancers eventually develop resistance to hormone therapy, and become even more aggressive, leading to what is known as “castration-resistant” disease, which is nearly always fatal.

As part of a “growth first” strategy, many cancers contain gene mutations that drive them to produce proteins at such a high rate that they risk triggering cells’ built-in self-destruct mechanisms, according to studies previously conducted by Ruggero and colleagues. But aggressive, treatment-resistant prostate cancers typically contain multiple such mutations, which led Ruggero and his team at the UCSF Helen Diller Family Comprehensive Cancer Center to wonder how such cancers sustain themselves under the pressure of so much protein production.

Deadliest Cancers Throttle Excess Protein Synthesis

To explore this question, Ruggero’s team genetically engineered mice to develop prostate tumors containing a pair of mutations seen in nearly 50 percent of patients with castration-resistant prostate cancer: one that causes overexpression of the cancer-driving MYC gene, and one that disables the tumor suppressor gene PTEN. They were surprised to discover that the highly aggressive cancers associated with these mutations actually had lower rates of protein synthesis compared to milder cancers with only a single mutation.

“I spent six months trying to understand if this was actually occurring, because it’s not at all what we expected,” said Crystal Conn, PhD, a postdoctoral researcher in the Ruggero lab and one of the paper’s two lead authors. But she saw the same effects again and again in experiments in mouse and human cancer cell lines as well as in 3-dimensional “organoid” models of the prostate that could be studied and manipulated in lab dishes.

Conn’s experiments eventually revealed that the combination of MYC and PTEN mutations trigger part of a cellular quality control system called the unfolded protein response (UPR), which reacts to cellular stress by reducing levels of protein synthesis throughout the cell. Specifically, these mutations alter the activity of a protein called eIF2a (eukaryotic translation initiation factor 2a key regulator of protein synthesis, by turning it into an alternate form, P-eIF2a, which tunes down cellular protein production.

Source:

https://www.ucsf.edu/news/2018/05/410336/research-finds-achilles-heel-aggressive-prostate-cancer

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