Recently, scientists from the Dana-Farber Cancer Institute have discovered new drug targets for two malignant cancers. It is expected to develop new therapies for the treatment of synovial sarcoma and malignant rods-shaped tumors. Related research result was published in the Nature Cell Biology.
The researchers say that these two cancers depend on a new molecular called ncBAF, which plays a key role in regulating gene activity, consisting of multiple specific protein subunits. Biologically or chemically inactivating components of ncBAF may specifically impair proliferation of synovial sarcoma and malignant rod-shaped tumor cancer cell lines. Dr. Cigall Kadoch said that this is an important research result they have achieved in the treatment of stubborn invasive cancer. In that study, they have identified a new type of cancer-specific target, which is expected to be used in the future to develop new anticancer therapies.
Synovial sarcoma is a rare soft-tissue cancer. Young people are of high risk. Malignant rod-shaped tumors are also a very rare type of tumor. They usually occur in children under 2 years of age. Both types of cancer affect the patient’s brain, kidney, and other body organs. Recently, researchers have discovered a molecular machine called chromatin remodeling complex in the occurrence and maintenance of cancer. These complexes are a kind of protein cluster structure, which can change the way DNA is packaged, thus helping to regulate gene switches, each of which consists of multiple protein subunits.
In this study, the researchers focused on the SWI/SNF family complex, which contains three types of complexes, cBAF, PBAF, and ncBAF. Two weeks ago, researchers just published an article in Cell for the first time reporting the assembly sequence of these complexes, namely modular organization. And more importantly, these chromatin remodeling devices can “travel” to multiple sites in the cellular DNA genome and regulate gene expression to produce key proteins required for cells at multiple time points. It is estimated that 20% of human cancers are associated with mutations in genes encoding chromatin remodeling complex subunits that cause the destruction of gene expression and induce tumors.
In the current study, the researchers found that the ncBAF complex differs from the other two complexes in a variety of ways, including regions that act on the genome, and because the ncBAF complex contains two subproteins: BRD9 and GLTSCR1. These two subunits are not components of other complexes, and the ncBAF complex also lacks the subunits possessed by other complexes. The researchers point out that the function of ncBAF is essential for synovial sarcoma and malignant rod-shaped tumors to maintain cell division and growth. Because of its importance for these cancers, ncBAF is often referred to as “synthetic lethal target”, that is, the ability to interfere with ncBAF may be a reliable method for treating related tumors.
Now, Kadoch and colleagues are very interested in studying the function of the subunit BRD9 in the ncBAF complex, because small molecular probes can block the activity of BRD9, and researchers can also design an experimental formulation called a protein degrader to eliminate BRD9 from cells. Finally, researcher Kadoch said that in the future they hope to develop new targeted therapies for the treatment of these two types of cancer through in-depth clinical trials.
Brittany C. Michel, Andrew R. D’Avino, Seth H. Cassel, et al. A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nature Cell Biology (2018) doi:10.1038/s41556-018-0221-1
Mashtalir N, D’Avino AR, Michel BC, et al. Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes. Cell. 2018 Oct 18. pii: S0092-8674(18)31244-3. doi: 10.1016/j.cell.2018.09.032