Going For Jugular In Melanoma

Melanoma

It's increasingly believed among scientists that nearly every cancer contains small populations of highly dangerous cells " cancer stem cells " that can initiate a cancer, drive its progression, and create endless copies of themselves. On the theory that targeting these cells might be an effective therapeutic strategy, researchers around the world have begun isolating stem cells from various kinds of cancers. Now, for the first time, researchers at Children's Hospital Boston and Brigham and Women's Hospital (BWH) have found a strategy that selectively targets cancer stem cells for destruction, successfully halting one of the deadliest cancers " melanoma " in mice.

The findings, reported in a cover article in the January 17, 2008, issue of Nature, also add credence to the hypothesis that stem cells drive cancer progression.

Melanoma is a highly aggressive and difficult-to-treat cancer because it is resistant to virtually all drugs. In 2007, an estimated 59,940 cases were diagnosed in the U.S., with about 8,110 deaths, according to the National Cancer Institute, and the percentage of people developing melanoma in the U.S. has more than doubled in the past 30 years. Melanoma usually grows initially as a flat brown to black spot that can be removed surgically if recognized early, but once a three-dimensional nodule develops, it gains the ability to metastasize and becomes deadly.

Markus Frank, MD, a researcher in the Transplantation Research Center of Children's and BWH, in collaboration with George Murphy, MD, chief of Dermatopathology at BWH, isolated melanoma stem cells and found that they have, on their surface, a special protein that helps shuttle toxic agents out of the cell. Previously, the Children's-BWH laboratory of Frank and Natasha Frank, MD (who is also in the Division of Genetics at Children's and BWH) discovered and cloned this protein, known as ABCB5, and showed that it renders melanoma cells resistant to chemotherapy drugs.(1) In the new paper, they show that ABCB5 is unique to the subpopulation of melanoma stem cells.

But most strikingly, Frank and colleagues were able to leverage ABCB5 " normally a protector " to bring about the destruction of these highly virulent stem cells in mice bearing human melanomas. They injected the mice with monoclonal antibodies that bound only to cells with the ABCB5 protein " namely, melanoma stem cells. The antibodies stimulated an immune response against the stem cells that led to cell death and significantly inhibited melanoma growth as compared with untreated mice.

"This study lays the groundwork for a possible treatment, showing that targeting stem cells may be a viable strategy in cancer," says Frank. "Until this study, no evidence had been provided."

"The study also shows that melanomas are 'smart,' in that their virulence is hidden within small sub-populations that are difficult to identify and difficult to destroy as a result of expressing proteins like ABCB5," adds Murphy. "Now, the distinct possibility exists that such cells actually can be outsmarted. Hopefully, this will lead to new ways of treating metastatic disease, since our existing treatments don't work well."

Frank and colleagues, including the paper's first author, Tobias Schatton, PharmD, of the Transplantation Research Center, are pursuing further studies aimed at eventually bringing this finding to the clinic. They are studying various alternative ways of inhibiting ABCB5, such as human monoclonal antibodies (the one used in this study was raised in a mouse) or small inhibitory RNA molecules.

They are also closely studying the melanoma stem cell, now that they've isolated it, using gene-expression studies and proteomic studies to understand what makes it tick. "This could yield other targets in the cell," says Frank. "However, I favor ABCB5 " it's not just a marker or beacon on the cell, but it relates to the cell's ability to develop drug resistance."

Frank adds that a cancer stem cell could try to outsmart treatments that target ABCB5 by making less of the protein, but since ABCB5 is so essential to the cell's ability to survive chemotherapy, this is unlikely to happen. ABCB5 might also be a useful marker of a tumor's virulence, indicating the need for aggressive treatment, Murphy notes.

These ongoing studies are supported by the Specialized Program in Research Excellence (SPORE) in Skin Cancer, a Dana Farber Harvard Cancer Center-wide translational research grant based at the BWH and funded through the National Cancer Institute/National Institutes of Health.

"It is gratifying to see this exciting work move closer to clinical applications, thanks to the collaboration between Drs. Frank and Murphy and the involvement of our patients with melanoma," says study co-author Thomas Kupper, MD, SPORE Director and Chair of Dermatology at the BWH. "Effective treatments for advanced melanoma are desperately needed."