Thirty years ago, Gail Sonenshein was studying cancer in immune cells when she read an article in the New York Times that would shape the rest of her career. The article described a new residency program in women’s health, part of an effort to improve treatment and outcomes for women at a time when most medical knowledge came from exclusively studying men.
“I woke up the next day and thought, well, I don’t see patients but I care about women’s health and I can do something about that,” said Sonenshein, who is now a professor of developmental, molecular, and chemical biology at Tufts University School of Medicine. “I decided to convert my whole lab over to breast cancer research.”
Since then, Sonenshein has directed all her efforts toward a better understanding of breast cancer and women’s health as a whole. She co-launched a women’s health research program at Boston Medical Center and served as its first director. She is developing tests to find evidence of carcinogen exposure in blood samples, and is working on a promising diagnostic and treatment for the most aggressive forms of breast cancer based around a protein called ADAM8.
Sonenshein, who is also a professor at the Graduate School of Biomedical Sciences, and her colleagues discovered that the protein ADAM8 is on the surface of breast cancer cells and facilitates both the growth and spread of these cancers in mice. They recently developed antibodies that recognize and bind exclusively to ADAM8. Using an assay based on these antibodies, they showed that one third of all breast cancers express ADAM8 and that high levels of ADAM8 are associated with worse patient outcomes.
The work, published recently in Cancer Cell International, could help identify which cancers require more aggressive treatments. Sonenshein and her colleagues are also using these antibodies to develop treatments that would inhibit ADAM8, slowing or stopping the growth and spread of cancers with the worst prognoses.
“The most aggressive solid tumors are high in ADAM8,” Sonenshein said. “So if we can get this into the clinic and if it works as we hope, it’s going to be a big deal.”
Antibodies for ADAM8
When Sonenshein’s lab first identified ADAM8 as a potential target, they found that it affects cancers through two different mechanisms. One section of ADAM8, the metalloproteinase domain, helps new blood vessels form, which brings oxygen and nutrients to the cancer to help it grow larger. Another section, the disintegrin domain, modifies the outside of cancerous cells in a way that allows them to enter blood vessels and travel to other parts of the body.
This second part, the ability of a cancer to spread, is typically the most dangerous. Tumors that grow but don’t spread are usually easier to treat or remove. But Sonenshein found that most treatments in development against ADAM8 were only targeting the metalloproteinase domain—the piece that helps a cancer grow.
“If you target the growth, the cancer will be small but it can still spread, and it’s the spread that can kill you,” Sonenshein said.
Moreover, these treatments were not specific enough. They used small molecule inhibitors, which go inside a protein’s structure, and ended up impacting many proteins with metalloproteinase parts, not just ADAM8. Sonenshein and her team decided to take a different approach using antibodies.
As a proof of concept, the team started with a commercially available antibody that binds well to ADAM8 in mice and determined that tumors grew more slowly and didn’t spread as well when the researchers used the antibody to inhibit ADAM8. But the commercially available antibodies still had a 5% to 10% chance of interacting with other proteins in the same family, so the researchers made plans to develop their own.
by: Laura Castañón
published on Medical Xpress