Molecular Vulnerabilities Discovered in Cancer

Synovial sarcomas and rhabdoid tumors are two of the most difficult types of cancer to treat. Synovial sarcomas are found in the soft tissues and are most often diagnosed in young adults. Rhabdoid tumors typically develop in the brain, kidney and other organs of children under two. Both of these cancers are deadly and have survival rates around 30 percent, but a recent discovery of a molecular vulnerability by scientists at the Dana-Farber Cancer Institute could offer new treatment options.

Researchers discovered a “molecular machine” called ncBAF that regulates gene activity. This molecular machine, called a chromatin-remodeling complex, is essential to the development and maintenance of cancer. These complexes are made of proteins that determine how DNA is packaged in a cell and regulate which genes are expressed. Researchers found that disabling components of the molecule hindered the cancer’s ability to reproduce. Dr. Cigall Kadoch was senior author of the report published in Nature Cell Biology.

Kadoch’s team focused on a group of complexes called the SWI/SNF family. They found that the molecules travel to different locations in the DNA within a cell and impact the genes that are turned on, as well as the creation of proteins. It is estimated that 20 percent of human cancers are associated with mutations in the chromatin-remodeling complex, disrupting gene expression and causing tumors to develop.

Researchers found the ncBAF complex is essential for synovial sarcoma and rhabdoid tumors to maintain cell division and growth. Researchers believe that disrupting ncBAF could be the key to treating these tumors, deeming it a “synthetic lethal target.”

Kadoch and her colleagues further focused on the BRD9 subunit of the ncBAF complex, noting that there are current treatments under investigation focused on blocking BRD9. Researchers are also working on protein degraders that are designed to eliminate BRD9 in cells. Kadoch hopes her team’s findings will assist other researchers as they work on blocking the BRD9 protein and fighting cancer.

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