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Cancer Discovery

February 29, 2012

(Ivanhoe Newswire) — Researchers have discovered how a protein “master regulator” goes awry, leading to metastasis, the fatal step of cancer.

The protein mTOR is a “master regulator” of human protein synthesis. It helps normal cells sense nutrients and control cell growth and metabolism. But in many forms of cancer, this process goes awry, and mTOR reprograms normal cells to aberrantly divide, invade and metastasize.

In the human body, mTOR is a molecular sensor that helps cells respond to favorable or unfavorable environments. Under ordinary conditions, it acts as a master regulator of genes that induce cells to growth and divide. In times of scarcity, when somebody is starving for instance, mTOR shuts down much of the machinery that makes proteins so that an organism can conserve energy.

“We are now discovering that during tumor formation mTOR leads to metastasis by altering the synthesis of a specific group of proteins that make the cancer cells move and invade normal organs,” Davide Ruggero, PhD, an associate professor of urology and member of the Helen Diller Family Comprehensive Cancer Center and the Multiple Myeloma Translational Initiative at UCSF, was quoted as saying.

In their research, Ruggero and his colleagues suggests why drugs like Rapamycin–a drug used to block mTOR– have failed.

“The problem,” said Ruggero, “is that they block mTOR, but not completely.”

When drugs like Rapamycin fail to completely stop mTOR from working, they allow it to continue pushing a cancer cell toward malignancy. Some newer compounds that block mTOR do so more completely, and the team led by Ruggero showed in preclinical experiments that this effectively hobbles the cancer cells.

In their research, Ruggero and his colleagues showed that a mouse model of human prostate cancer treated with a new experimental drug called INK128 did not metastasize. They also showed that the new drug has a strong therapeutic effect on human prostate cancer cells.

“While the experiments were primarily focused in prostate cancer, we believe this work is widely applicable in many tumor types because mTOR is a critical regulator of so many cancers,” author Andrew Hsieh, MD, a clinical oncologist in the UCSF Department of Medicine, Division of Hematology/Oncology and a senior member of the Ruggero laboratory, was quoted as saying.

“For example, clinicians Jeff Wolf and Tom Martin are now testing INK128 here at UCSF, in multiple myeloma patients,” Ruggero said.

The research also found that INK128 works better by also restraining abnormal protein synthesis when mTOR is hyperactive. “Deregulations in protein synthesis is now becoming a hallmark of cancer, and we are very excited by the opportunity to target the aberrant protein synthesis apparatus in many cancers,” Ruggero said.

SOURCE: The Journal Nature, February  2012




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