As an associate professor in the section of Pediatrics-Hematology/Oncology and Bone Marrow Transplantation in the University of Colorado Anschutz School of Medicine, Masanori Hayashi, MD, is always looking for new ways to help patients, particularly those with rare cancers.
That’s why Hayashi, a member of the CU Anschutz Cancer Center, recently conducted research on the genetic causes of and potential new treatments for BCOR-CCNB3 sarcomas (BCS), a subtype of small cell sarcomas that represent a recently recognized group of solid tumors identified by rearrangements of the BCOR gene.
“It’s a rare sarcoma in pediatrics and young adults. The problem with these rare diseases is that sometimes people think they are similar to other cancers, though the treatment is very different,” says Hayashi, who presented on his research at the annual meeting of the American Association for Cancer Research in April. “This tumor has been called Ewing sarcoma-like, but it has a very different biology. My postdoc was able to make a cell line from a patient tumor, which gives us a unique opportunity to explore the biology of this disease.”
Hayashi and his research team began conducting experiments on the cell line, looking to find out how BCOR-CCNB3 sarcomas form.
“The BCOR gene is part of the epigenetic machinery, so we thought that the complex that BCOR is part of, which is called PRC 1.1, must be broken, and that’s how this disease happens,” he says. “That’s different from the paradigm of other diseases that are driven by genes that are fused together. These fusion genes usually turn on machinery that makes them cancerous, but in this instance, we thought it was a situation where the machinery is actually turning things off.”
Using an advanced epigenomic profiling technique called CUT&RUN (Cleavage Under Targets and Release Using Nuclease), which maps protein-DNA interactions to understand gene regulation in tumors, Hayashi and his team are looking at DNA binding in BCOR-CCNB3 sarcomas to see which genes are expressed and not expressed when the fusion gene is knocked down. Their hypothesis is that the fusion gene does not allow binding to the DNA, which changes the gene expression.
Hayashi hopes the research will change the treatment paradigm for the rare sarcoma, establishing it as a unique tumor type that requires its own specialized treatment.
“Survival rates for BCOR-CCNB3 seem to be similar or slightly better than Ewing sarcoma, but this disease keeps on smoldering, and it grows very slowly,” he says. “Clinically, we treat it the same way we treat Ewing sarcoma, but it’s a very different kind of disease. The survival numbers are a little bit hard to interpret.”
Other cancers are driven by BCOR fusions as well, he says, which means his research may have applications beyond this specific tumor type.
“Our hope is that we can identify genes that are differentially expressed, and those would probably be the same across multiple diseases that have BCOR alterations,” he says. “We want to find a new therapeutic target that targets all of these diseases.”
Hayashi says his research, as well as a growing body of research into rare cancers, spotlights a change in the way cancer is being studied and targeted.
“I think we’re transitioning from cancer as a monolith, where everything is the same, to thinking that each one has a different mechanism of action,” he says. “This is a chance to define this as a genetic group and try to come up with a genetic treatment, rather than basing treatment on where it arises from and what it looks like under the microscope.”