Antibody Approach Directly Targets Tumor Blood Supply

The phase I clinical trial, performed by investigators from at New York-Presbyterian Hospital/Weill Cornell Medical Center (New York, NY, USA), evaluated an antibody called J591, targeted to the prostate-specific membrane antigen (PSMA). PSMA has been a promising target for cancer drug development because it is not only present in high amounts in prostate tumors 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 narrowing in for the kill.

The study, which was published in the February 10, 2007, issue of the Journal of Clinical Oncology, involved 27 cancer patients with a broad 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,” explained the study's senior author, Dr. Neil H. Bander, a urologic cancer specialist at New York-Presbyterian/Weill and professor of urologic 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 investigators 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 commented. "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 seen 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 discovery 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 comparatively short, small trial did not reveal significant reductions in tumor volume, but according to Dr. Bander, the trial was not 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 said. "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.”

What is really exciting is that J591, and compounds like it, could someday offer cancer patients a brand new weapon as they fight the disease, according to the researchers. But Dr. Bander's team does not 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,” Dr. Bander stated. When it comes to fighting cancer, any new treatment option is always welcome, he added. "With an antibody to PSMA like J591, we hope to open up a whole new front in the war against this disease.”


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