Dec 6, 2004 — Researchers at the Albert Einstein College of Medicine of Yeshiva University have devised an ingenious therapy for melanoma, the increasingly common skin cancer that kills nearly 8,000 Americans each year and has so far resisted all treatment efforts when it has spread to other parts of the body. The research is described in the October 12 issue of the Proceedings of the National Academy of Sciences.
The anti-melanoma strategy involves “piggybacking” a radiation-emitting isotope onto an antibody that binds to melanin, the pigment that gives skin its color. Carried deep into the tumor by the blood, the antibodies target the melanin released by dying cells—a hallmark of melanoma tumors. Once the antibodies latch onto these melanin particles, their radioactive cargoes zap and destroy melanoma tumor cells nearby. The radiation doesn’t affect healthy, melanin-containing cells in the skin, eyes or elsewhere in the body, since melanin in these cells is tucked away in tiny compartments and therefore not accessible to the melanin-binding antibodies.
The findings show how basic research in one area of medicine can yield unexpected benefits for an entirely different field.
“We certainly didn’t set out to find a cure for melanoma,” says Dr. Arturo Casadevall, senior author of the paper and chief of the Division of Infectious Diseases at Einstein. Instead, the advance emerged from his study of Cryptococcus, a fungus that can cause fatal infections in people with weakened immune systems.
Previous studies had shown that disease-causing Cryptococcus strains produce melanin when grown in the laboratory. Seeking a way to find out if these fungi produce melanin in “real life,” Dr. Casadevall made antibodies to melanin and used them to study whether disease-causing Cryptococcus made melanin during infection. The antibodies revealed melanin’s presence in the tissues of infected animals, suggesting that Cryptococcus may owe its virulence to melanin production — and giving Dr. Casadevall an idea.
“Fungal melanin and human melanin are very similar, so we decided to see if our antibody would also bind to human melanin, and it did,” Dr. Casadevall recalls. “Knowing that aggressive melanoma tumors release copious amounts of melanin, we realized that our melanin antibody might help against melanoma if we could somehow combine it with a therapeutic agent.”
The solution — piggybacking a radioisotope onto the antibody — was suggested by the study’s lead author, Dr. Ekaterina Dadachova, an assistant professor in Einstein’s Department of Nuclear Medicine, who has collaborated with Dr. Casadevall since arriving at Einstein at the end of 2000.
To test the therapy’s effectiveness, the researchers injected human melanoma cells into mice, creating melanoma tumors in the animals. Then the researchers combined the antibody with the isotope 188-Rhenium and administered the therapy intravenously to half the animals, with the remaining mice serving as untreated controls. Over the next 30 days, no deaths occurred among the treated mice, whose tumors had not grown since the day the therapy was given; by contrast, melanoma tumors grew aggressively in the control mice, all but one of which had died after 20 days.
“This type of treatment, called radioimmunotherapy, was recently approved for use against non-Hodgkins lymphoma, a ‘semi-liquid’ cancer that is quite sensitive to radiation,” says Dr. Dadachova. “But solid tumors such as melanomas are much more resistant to radiation and to all other anti-cancer treatments, so our success in this study is especially gratifying.”
Dr. Casadevall notes that their treatment is likely to be particularly effective against the most aggressive cases of melanoma. “The more aggressive the tumor, the more melanin it will likely release, increasing the number of targets for the antibody,” he says. “Furthermore, melanin released from tumor cells doesn’t get degraded, so the therapy’s effectiveness may actually increase with increasing numbers of treatment cycles as the melanin from dying tumor cells accumulates in the tissue. This is the opposite of what often occurs in cancer chemotherapy, where tumors may eventually develop resistance to the treatment.”
The Einstein investigators are hoping to proceed to clinical trials soon.