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Can a Protein Garbage Truck Clear Out Mesothelioma Cells?

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Researchers are turning to cell garbage collectors, or the proteasome, in their latest attempt to fight cancer. Scientists have known for years that proteasomes clean out unneeded or damaged proteins, now, they are focusing on lassoing them to attack cancer cells.

Two biochemists, Craig Crews and Raymond Deshaies, began discussing this possibility in 1998 in a bar. Crews, the L.B. Cullman Professor of Molecular, Cellular, and Developmental Biology at Yale University,  has spent his career tinkering, as he calls it, with proteasomes. After years of research, he is on the cusp of a breakthrough treatment that can gobble up the proteins that help cause cancer.

This approach can target diseases that are considered undruggable or resistant to most treatments, like mesothelioma, a rare, terminal cancer. Currently, there is no known cure for the asbestos-caused disease that invariably recurs after building up a resistance to chemotherapy or other anti-cancer drugs that should kill the cancers. Mesothelioma is diagnosed in nearly 3,000 Americans each year.

In a 2010 presentation entitled, “Contemporary Treatment of Malignant Pleural Mesothelioma,” Nicholas J. Vogelzang, MD, Chair and Medical Director, Developmental Therapeutics Committee, US Oncology Research, Comprehensive Cancer Centers of Nevada, noted that proteasome inhibitors were one of “many new agents worthy of study” in the fight against mesothelioma. Dr. Vogelzang is a renowned medical oncologist, cancer researcher and mesothelioma expert.

Crews and Deshaies, Professor of Biology and Executive Officer for Biology Division of Biology & Biological Engineering California Institute of Technology, and founder of the Proteome Exploration Laboratory at the Beckman Institute at Caltech, have built their careers around the proteasome and have spawned several pharmaceutical companies, including Arvinas, focused on harnessing the power of the proteasome.

After rounds of research, Crews and his team found that when the proteasome was “jammed” up, toxic levels of old proteins built up in the cancer cells before the proteosome could clear them out. Without the help in throwing away the discarded proteins, the cancer cells were overwhelmed and died. Crews determined that this could be recreated by an anti-cancer drug.

“You can imagine a small molecule, a drug, that works under this new paradigm, will truly be one that can seek and destroy rogue, disease-causing proteins,” said Crews in a May 18 article in Stat News.

Crews was recently awarded the National Cancer Institute’s Outstanding Investigator Award. Crews, one of 60 U.S. scientists to receive the award, which brings $4.2 million over seven years to support his lab’s research, says the money will make a big difference in his research and could lead to “a second chance” for drugs that were abandoned because “they couldn’t block the function of rogue proteins.”

“This award will help us change the current small-molecule drug paradigm that fails to target 75% of rogue proteins,” Crews said. “Instead, we propose to hijack the cells’ quality-control machinery so that this new class of drugs can bind to and destroy these disease-causing proteins.”

If everything continues on track, Crews hopes that Arvinas, working with Merck and Genentech, will be testing this approach to cleaning up cancer within a year.

For the full story, “A tinkerer takes on cancer by hijacking the tiny garbage trucks inside every cell,” see the May 18 article in Stat News.

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