"There are currently no drugs for advanced metastatic melanoma that have any effect on long term survival," says David Curley, an M.D.-Ph.D. student at the University of Vermont (UVM) College of Medicine, who recently co-authored a study in the journal Nature Genetics with scientific colleagues at the University of California, San Francisco (UCSF). Part of Curley's Ph.D. dissertation project was the development of novel mouse models of melanoma.
"There has not been a major advance in the treatment of metastatic melanoma in the last 25 years," says Martin McMahon, Ph.D., senior co-author of the study and Efim Guzik Distinguished Professor in Cancer Biology at the UCSF. "While other cancers are more common, it is the rate of increase and the often aggressive course of the disease that worries people who study melanoma."
Melanoma is a type of skin cancer that develops from pigment cells called melanocytes. Curley, with collaborators at UCSF, focused on the most common genetic mutation in melanoma — a gene that can cause normal cells to become cancer cells called BRAF. BRAF mutation is not the only genetic alteration observed in human melanoma. It is often found in combination with the silencing of PTEN, an important tumor-suppressor gene.
The UCSF group engineered a mouse that, at a time of the researchers' choosing, turned on the BRAF oncogene. The UVM group, led by Curley's mentor and former UVM assistant professor of pathology Marcus Bosenberg, M.D., Ph.D., created a mouse that, at the time of their choosing, lost a tumor suppressor gene commonly lost in humans with melanoma (PTEN tumor suppressor). By combining activation of the BRAF gene with deletion of the PTEN suppressor gene, the collaborators were able to generate a mouse model of malignant melanoma.
"This was the first model where the mice grow their own primary tumors that very rapidly spread to the same organs that human melanoma normally spreads to," says Curley. "This model is also the first to use the BRAF and PTEN genes."
Next, the researchers studied the impact of a combination of two different drugs that target the pathways commonly altered in human melanoma on mouse melanoma. These two small molecule inhibitors — one, an experimental therapy supplied by Pfizer Inc., and the other, a drug called Rapamycin — were given orally and were able to halt the growth of the melanoma tumors in the mice, as long as they remained on these therapies.
"It is our hope that these models will be widely used to develop new treatments for this deadly cancer as well as to study the mechanisms by which melanoma is formed and spreads to other organs," says Curley.
The scientists emphasized that although they engineered mice with very specific genetic alterations, it is possible that human melanoma is genetically more complex than the model they have generated.
The work, which was supported by McMahon's Diana Ashby Award of The Melanoma Research Foundation, a UC Discovery grant in partnership with Genentech, Inc., and the National Institutes of Health, was an integral collaboration between McMahon's laboratory at UCSF and Bosenberg's laboratory at UVM. The studies at UVM were primarily conducted by Curley, and the work at UCSF was primarily carried out by a post-doctoral fellow, David Dankort, Ph.D. Additional co-authors of the paper were Robert Cartlidge and Anthony Kamezis of the UCSF Helen Diller Family Comprehensive Cancer Center, Betsy Nelson and William Damsky, Jr., of the UVM College of Medicine, and Mingjian You and Ronald DePinho of the Dana-Farber Cancer Institute and Harvard Medical School.
Curley received his undergraduate degree from the University of Massachusetts Amherst. From 1998 to 2001, while an undergrad, he worked as a Howard Hughes Medical Institute summer research associate in Dr. Gary Gilliland's lab at Harvard Medical School/Brigham and Women's Hospital. While working in Dr. Gilliland's lab, he studied the molecular genetics of leukemia and small molecule inhibitors. Following graduation, he joined the lab full time as a research technician and worked there for two years before coming to the UVM College of Medicine as an M.D.-Ph.D. student in 2003. He hopes to pursue a career as an academic oncologist following the completion of his medical training.