Cancer breakthrough - first treatment to directly target tumor supply

For the first time, physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center in New York City have demonstrated in patients the ability of an antibody to directly target the blood supply of a wide variety of tumors, leaving healthy tissues unharmed.

The Phase I clinical trial tested an antibody called J591, targeted to the prostate specific membrane antigen (PSMA).

PSMA has been an attractive target for cancer drug development because it is not only present in high amounts in prostate cancers but it also is the only known molecular target present on tumor blood vessels but not normal blood vessels. The ability to target PSMA on blood vessels would provide a way to directly attack a tumor’s blood supply without affecting normal blood vessels.

"Anti-angiogenic" cancer therapies that focus on the tumor's blood supply are not new. However, other such treatments starve tumors of their blood supply indirectly, by reducing blood vessel growth signals. J591 may work in a new way, taking anti-angiogenic therapy to the next level by directly targeting PSMA on the cells of the tumor blood vessels and then zooming in for the kill.

The trial, which appears in the Feb. 10 issue of the Journal of Clinical Oncology, involved 27 cancer patients with a wide range of solid tumors -- including kidney, bladder, lung, breast, colorectal, pancreas and melanoma. All patients had widespread disease that had failed conventional treatments.

"Prior to this trial, we had laboratory data that indicated PSMA was present on tumor but not normal blood vessels," explains the study's senior author, Dr. Neil H. Bander, a urological cancer specialist at NewYork-Presbyterian/Weill Cornell and the Bernard and Josephine Chaus Professor of Urological Oncology at Weill Cornell Medical College. "We hypothesized that we could use an antibody to PSMA to specifically target tumor blood supply. This was a proof-of-principle trial to confirm -- or reject -- our hypothesis."

The research team used a radioactive tracer, attached to the antibody, to follow J591's progress throughout the body.

"We showed that J591 can directly target the tumor's blood vessels," Dr. Bander says. "That's an important first. It represents the difference between laying siege to a village vs. sending in troops with heavy artillery. Current anti-angiogenic approaches starve the blood vessels of growth signals, but with J591, one directly targets a lethal blow right at the tumor blood supply."

As its name implies, PSMA was first spotted in prostate cancers. However, in 1998, Dr. Bander's team found the antigen to be present in the blood vessels of a wide range of tumor types -- but not healthy vasculature. This finding has been subsequently verified by several research teams.

As expected, the antibody therapy left healthy tissue alone, resulting in very low levels of toxicity for patients. The relatively short, small trial did not turn up significant reductions in tumor volume, but Dr. Bander says the trial wasn't designed to do so.

"This was a proof-of-principle study designed purely to confirm that we could successfully target tumor vasculature without targeting normal tissue," he says. "Now that we have confirmed specific and accurate targeting, in subsequent studies we will arm the J591 antibody with drugs or radioactivity, and then we will assess tumor response. We are already using such armed antibodies in patients with prostate cancer and have been able to show significant anti-tumor activity."

The big news now is that J591, and compounds like it, could someday offer cancer patients a brand new weapon as they fight the disease. But Dr. Bander’s team doesn't expect that cancer patients would rely on PSMA-targeted therapies alone.

"In the future, we envision a multi-pronged attack on the tumor -- for example, combining therapies aimed directly at the malignant cells, along with therapies to both directly kill the tumor's blood supply as well as prevent it from re-growing," he says.

When it comes to fighting cancer, any new treatment option is always welcome, he adds. "With an antibody to PSMA like J591, we hope to open up a whole new front in the war against this disease."

This work was funded by grants from the U.S. National Institutes of Health, the U.S. Department of Army, the Cancer Research Institute, the David H. Koch Foundation, the Robert McCooey Cancer Research Fund, the Laurent & Alberta Gerschel Foundation, the Yablans Family Foundation, and BZL Biologics, Inc. Dr. Bander is a consultant to -- and owns stock in -- BZL Biologics, which has licensed the PSMA antibodies from Cornell.

Co-researchers include Drs. Matthew Milowsky, David Nanus, Lale Kostakoglu, Shankar Vallabhajosula and Stanley Goldsmith -- all of NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York City, and Dr. Jeffrey Ross and Christine Sheehan, both of the Albany Medical Center in Albany, NY.