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.

Combatting the EZH2 Enzyme

Chemotherapy has been the standard cancer treatment method for lung cancer, but it is known to cause problems, including harming healthy cells and not killing all cancer cells. These cells are often changed as a result of the chemotherapy, making them more difficult to treat with standard methods. As a result, these cells evade further treatment, causing the cancer to return. More recently, immunotherapy with checkpoint inhibitors have become the mainstay of first line and follow on therapy in various types of lung cancers.  

A recent study by Dr. Gaetano Gargiulo at the Helmholtz Association in Germany has discovered a potential way to treat cells that have been altered by chemotherapy treatment. His research was recently published in the Journal of Experimental Medicine and focused on non-small cell lung cancer (NSCLC), the most common type of lung cancer, which includes several subtypes.

While chemotherapy is often successful in stopping cells from dividing in NSCLC patients, aggressive cancer cells can survive the treatment and end up altered as a result. These remaining cells are dangerous because they have changed in a way that can leave doctors unsure as to what type of cancer they are dealing with and how to best treat it.

Dr. Gargiulo’s team investigated an enzyme, called Enhancer of Zeste 2 (EZH2), that promotes lung cancer. They treated test mice with drugs that inhibited EZH2, and soon found that it caused the cancer cells to become more aggressive due to inflammation in the cells. Instead of seeing this as a problem, researchers saw an opportunity to outsmart the cancer. The researchers encouraged the cells to become inflamed and then ambushed them by giving the mice an anti-inflammatory drug, leaving the aggressive cells exposed and vulnerable to treatment.

Early tests suggest this could be a potential strategy to explore in treating lung cancer patients. Gargiulo made a point of noting that making cancer more aggressive can be very dangerous, and researchers must be cautious when pursuing this experimental path.