An international research team reports that a molecule that helps cells stick together is significantly overproduced in two very different diseases, rheumatoid arthritis and a variety of cancers including breast and brain tumors. The scientists, who made the discovery also found candidate drugs to inhibit the molecule, cadherin-11, one of which is already in a clinical trial.
The study (“Cadherin-11 in poor prognosis malignancies and rheumatoid arthritis: common target, common therapies”), published in Oncotarget, was led by investigators at Georgetown University Medical Center, and included collaborators from Harvard and Columbia Universities, Mayo Clinic, and Queen's University in Belfast, Northern Ireland.
“CDH11 knockdown and antibodies effective in RA slowed the growth of basal-like breast tumors and decreased proliferation and colony formation of breast, glioblastoma, and prostate cancer cells,” wrote the investigators. “The repurposed arthritis drug celecoxib, which binds to CDH11, and other small molecules designed to bind CDH11 without inhibiting COX-2 preferentially affect the growth of CDH11 positive cancer cells in vitro and in animals. These data suggest that cadherin-11 is important for malignant progression, and is a therapeutic target in arthritis and cancer with the potential for rapid clinical translation.”
“Our findings suggest that cadherin-11 is important for cancer progression as well as rheumatoid arthritis for reasons we do not fully understand,” says the study's senior investigator, Stephen Byers, Ph.D., a professor and molecular oncologist at Georgetown Lombardi Comprehensive Cancer Center. “Nevertheless, we are rapidly translating this discovery for use in the clinic.”
Dr. Byers and his Georgetown colleagues, Shahin Assefnia, D.V.M., Siva Dakshanurthy, Ph.D., and Jaime Guidry Auvil, Ph.D., have found that cadherin-11 is overexpressed in 15% of breast cancers and in many glioblastomas. He believes the molecule also contributes to pancreatic cancer.
“What most of these cancers all have in common is cadherin-11 and a poor prognosis, with no effective therapies,” Dr. Byers says. “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.”
The Georgetown team has developed a small molecule agent to shut down cadherin-11 in cancer, and, by screening drugs now on the market, found that the well-known arthritis drug Celebrex acts in a similar way. While it is unlikely that Celebrex could be used as a single agent against cancer because it would be too toxic at the level needed to impair cadherin-11, a Celebrex-related molecule works the same way and may potentially be less toxic. Co-author Michael Brenner, M.D., at Harvard University, has designed an antibody that can shut down cadherin-11 in rheumatoid arthritis. The Oncotarget study demonstrated that Brenner's antibody worked in animal models of tumors that made cadherin-11.
It was by chance that he and Dr. Brenner were working on the same molecule at the same time and came to know of each other's work. Coincidentally, co-author Lawrence Shapiro, Ph.D., at Columbia, was building a crystal structure of cadherin-11 and is now working with Drs. Byers and Brenner to show how the molecule binds to Celebrex and other small molecule drug cadherin-11 inhibitors.
This close collaboration led Drs. Byers, Brenner and Shapiro to apply for a grant last year from the National Cancer Institute's Provocative Questions project. They proposed answering the question related to the connection between drugs, such as anti-inflammatory agents, that can protect against cancer and other conditions.