Cadherin-11 inhibition may be key to potential treatment of some cancers
Inhibition of a molecule that occurs in some cancers with a poor prognosis as well as rheumatoid arthritis (RA) may lead to new treatments for both diseases.
Cadherin-11 is a molecule that helps cells stick together. It is over-produced in two very different diseases—some cancers derived from epithelium with a poor prognosis (including glioblastoma, some breast cancers, and prostate cancer) and rheumatoid arthritis. Inhibition of cadherin-11 may arrest cancer progression and also treat rheumatoid arthritis Oncotarget (2013;4).
"Our findings suggest that cadherin-11 is important for cancer progression as well as rheumatoid arthritis — for reasons we do not fully understand. Nevertheless, we are rapidly translating this discovery for use in the clinic," said Stephen Byers, PhD, professor and molecular oncologist at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. His research team found that cadherin-11 is over-expressed in 15% of breast cancers and in many glioblastomas. He believes the molecule also contributes to pancreatic cancer.
"Cadherin-11 expression is required for tumors to grow. If it is blocked, the cancers in cell line studies and in animals just stop growing—which is really quite striking," said Byers.
Byers and his team have developed a small molecule that binds to and inhibits cadherin-11 like the well-known arthritis drug celecoxib (Celebrex). Although celecoxib cannot be used as a single agent against cancer because it is too toxic at the level needed to inhibit cadherin-11, other molecules related to celecoxib work by a similar mechanism and may be less toxic.
Coauthor Michael Brenner, MD, of Harvard University in Cambridge, Massachusetts, has designed an antibody that can shut down cadherin-11 in rheumatoid arthritis. The Oncotarget study demonstrated that Brenner's antibody was also effective in animal models of tumors that produced cadherin-11.
The crystalline structure of cadherin-11 has been determined by co-author Lawrence Shapiro, PhD, of Columbia University in New York, New York. He is now working with Byers and Brenner to show how celecoxib and other inhibitors bind to cadherin-11.