1G8 antibody signals prostate cancer cells to stop growing and die

Oct 17 2005

Researchers at UCLA's Jonsson Cancer Center have uncovered the mechanism by which an antibody blocks the growth of prostate cancer in animal models, a discovery that could pave the way for development of a new molecularly targeted therapy.

The antibody, called 1G8 and discovered by UCLA scientists, signals the prostate cancer cells to stop growing and die, said Dr. Robert E. Reiter, a Jonsson Cancer Center researcher and professor of urology. The antibody proved effective in several different animal models of prostate cancer, Reiter said, indicating that is could be a potent cancer fighter.

The research appears in the Oct. 15 issue of Cancer Research, a peer-reviewed journal published by the American Association for Cancer Research.

The 1G8 antibody binds to prostate stem cell antigen or PSCA, a cell surface protein discovered by Reiter that is found in about 95 percent of early stage prostate cancers and about 87 percent of prostate cancers that have spread to the bones. PSCA also is found in bladder and pancreatic cancers, Reiter and his team previously discovered, so a new targeted therapy developed from the antibody may also prove effective in battling those cancers.

"The big question with antibodies has been, how do they work?" said Reiter, senior author of the study. "Do antibodies recruit the immune system to kill the cancer or do they send a signal that tells the cancer cells to stop growing? This study shows how the antibody works, so we'll know how to apply it in the clinical setting."

The 1G8 antibody has two parts, one that binds with PSCA and one that binds with macrophages, the immune system's killer cells. Reiter and his team fragmented the antibody, separating the part that binds to PSCA and testing it alone in the animal models to see how it affected the prostate cancer cells. Even without engaging an immune response, the antibody blocked the growth of the prostate cancer cells.

"The fragments we created were unable to bind to the immune system, but they retained the same activity the whole antibody showed, so we proved that 1G8 must work by signaling the cancer cells to stop growing and die," Reiter said. "That's important because it provides a lot more information about what PSCA does and how antibodies work. It also suggests that PSCA is a very good target for therapy and that our antibody, in particular, is extremely active and binds to a region on the cell surface protein that may be an optimal target for a new treatment."

Molecularly targeted therapies are the new wave of cancer therapy, homing in on what is broken or mutated in the cancer cells and leaving the healthy cells alone. Because they only target the cancer cells, these therapies typically cause few side effects, if any, and are much easier for patients to tolerate.

The next step, Reiter said, is to test the 1G8 antibody in human clinical trials, probably in about a year.

This study is the result of years of laboratory research and is part of the Jonsson Cancer Center's Specialized Program of Research Excellence in prostate cancer, a National Cancer Institute-funded program to discover new and better ways to prevent, detect and treat prostate cancer.

"This work from start to finish is a UCLA discovery, true translational research that will go from the lab bench to the patient bedside," Reiter said.

Prostate cancer will strike more than 232,000 men in the United States this year alone, killing more than 30,350. Prostate cancer is the second leading cause of cancer death in men, according to the American Cancer Society.

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