Metastatic melanoma is the leading cause of skin cancer deaths in the United States because once has spread - metastasized - life expectancy for patients is dramatically shortened.

Melanoma diagnosis and treatment has progressed a lot and the future looks even brighter but the current reference therapy for patients diagnosed with metastatic melanoma is Dacarbazine (DTIC), which is associated with relatively poor patient outcomes.

In a new study, researchers found that standard treatments for metastatic melanoma are not effective against a growth factor protein called Nodal. The study also showed that combination therapies incorporating anti-Nodal antibodies with DTIC are a promising alternative. Previous research in the Hendrix laboratory showed that Nodal, which is critical for human embryonic development, re-emerges in metastatic melanoma.

Katharine Hardy, PhD, a post-doctoral fellow at Ann&Robert H. Lurie Children's Hospital of Chicago, led the effort by treating three different melanoma cell lines with DTIC. The group discovered that Nodal-expressing cells not only remained after the therapy, but their numbers actually increased. "Remarkably, the residual populations of tumor cells that were largely unaffected by DTIC were Nodal positive," said investigator Mary J.C. Hendrix, PhD. 

The next step was to test whether a combination of anti-Nodal and DTIC therapy would be more successful combating the Nodal. "We found that using a lower concentration of the DTIC with a low concentration of an anti-Nodal antibody induced cell death and decreased cell growth synergistically," Hendrix said. "Tumor cells are very dependent on this growth factor, and when you take it away, they die."

At any time, 20 to 30 percent of melanoma tumor cells express Nodal, according to the study. Their power to increase cell proliferation can even spread to nearby cells that don't produce the growth factor.

The researchers have begun to investigate whether other melanoma therapies on the market affect Nodal, and, if they don't, to determine if the therapies work in conjunction with anti-Nodal antibodies, in a similar manner to the DTIC study. In the same paper, they performed initial experiments testing a therapy that inhibits B-RAF, a mutation found in a portion of melanoma tumors. It did not work against Nodal, but the combination strategy did. 

If the scientists can develop an anti-Nodal antibody that works in humans, the combination treatment could lead to better outcomes for patients with metastatic melanoma, a disease with an overall median survival of only six to nine months.

"Nodal is still a relatively new observation - made right here at Northwestern University and Stanley Manne Children's Research Institute, and it's a very powerful growth factor that represents a promising cancer stem cell target," Hendrix said.

Hendrix is President and Scientific Director of Stanley Manne Children's Research Institute, Professor at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Children's Research Fund Professor and William G. Swartchild, Jr. Distinguished Research Professor. The first author is Katharine M. Hardy, PhD, a former senior postdoctoral fellow in the Hendrix laboratory, with co-authors Luigi Strizzi, MD, PhD, director, Experimental Biomarker Studies, Senior Research Scientist, Cancer Biology and Epigenomics Program at the research institute, and Naira V. Margaryan, DVM, PhD, Research Scientist and director of the Research Histology Core Facility at the research institute; Kanika Gupta, Howard Hughes Medical Institute NU Bioscientist Program, Weinberg College of Arts and Sciences, Northwestern University; George F. Murphy, MD, Professor of Pathology at Harvard Medical School and Brigham & Women's Hospital, Boston; and Richard A. Scolyer, BMedSci, MBBS, Consultant Pathologist and Co-director of Research, Melanoma Institute Australia, Senior Staff Specialist of Tissue Pathology and Diagnostic Oncology at the Royal Prince Alfred Hospital, Sydney, and Clinical Professor at The University of Sydney.

Published in  published in Molecular Cancer Research. Funded  by National Institutes of Health (NIH) and National Cancer Institute (NCI) grants and the Eisenberg Research Scholar Fund, as well as a gift from the Robert Kris family. Murphy and Scolyer contributed the melanoma patient samples used in this study.