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To sarcoma surgeon and Huntsman Cancer Institute (HCI) investigator Kevin B. Jones, MD, synovial sarcoma is a matter of life and death—in more ways than one. By studying cell death and cell survival pathways in this rare but deadly disease, Jones and his colleagues found a possible treatment that may improve the survival chances of his young patients.The study was published in the journal Oncogene.
Synovial sarcoma is one type of soft-tissue sarcoma, cancers that occur in muscles, fat, connective tissue, blood vessels, and the nervous system. Synovial sarcoma primarily affects teenagers and young adults. The surgeries Jones and others like him perform to remove the cancers can be effective for a single location of the cancer, but they can’t prevent the cancer spreading to other parts of the body. Survival odds for synovial sarcoma patients are about 50/50.
“Some of the patients for whom my heart breaks most deeply have had synovial sarcoma,” says Jones. “These people are in their twenties and thirties. They’re just getting started with a career or a family when this devastating cancer comes along. Then they get a flip of a coin. That's just not right.”
To find clues for treatments that would increase patient survival, Jones began researching how synovial sarcoma cells live and die. Researchers have known for years that synovial sarcoma cells have high levels of a protein called BCL2, which helps cells stay alive. Other cancers such as lymphoma and lung cancer also have high levels of BCL2, so drugs have been developed to block the protein. But cancer cells have an “escape route” from anti-BCL2 drugs—a protein called MCL1. If a tumor is treated with an anti-BCL2 drug, MCL1 will take over and send signals that keep the cancer cells alive.
While studying the cell death and survival pathway, Jones and his colleagues, including HCI investigators R. Lor Randall, MD; Sunil Sharma, MD; and Mario Capecchi, PhD, found something unexpected—synovial sarcoma has very low levels of MCL1. Jones calls this phenomenon “a serendipity of nature. This very deadly cancer almost creates its own Achilles heel by naturally turning off the powerful MCL1 anti-death signals.”
That means anti-BCL2 drugs are very effective in synovial sarcoma. “When we compared cells from synovial sarcoma to other cells that are also high in this BCL2 anti-death signal, this drug killed the synovial sarcoma cells so much better. It’s not because the BCL2 was higher in synovial sarcoma than in the other cancers; it’s because the escape route was gone.”
Jones and his colleagues aim to one day develop a synovial sarcoma clinical trial using this anti-BCL2 drug. In the meantime, says Jones, “We may find other cancers that share similar biology. We have started looking at what cancers lack—in other words, escape routes that are missing—rather than looking at what they have in abundance. In that way, this discovery may impact other cancers as well.”