Melanoma Puzzle
John Shabb, Ph.D., is working on a puzzle – the kind that brings scientists closer to understanding what is going wrong when cancer invades the body.
It began in the summer of 2005, when the associate professor of biochemistry and molecular biology set out for the University of Colorado at Boulder where he would spend the next 12 months, on sabbatical, gearing up to take his research in a whole new direction.
He joined the laboratory of renowned melanoma researcher and Howard Hughes Medical Institute (HHMI) investigator Natalie Ahn, Ph.D., where he “worked with a wonderful group of researchers” whose interests are in the area of signal transduction and its relationship to cancer progression.
“I’ve known her for quite a while,” Shabb says of Ahn whose background is in chemistry and biochemistry; her investigations are funded by HHMI and the National Institutes of Health. “I was there to pick their brains. They let me work on parts of their research.”
Biomedical investigators, such as Ahn and others, believe “there’s a molecular basis for melanoma cancer progression,” he explains. Melanoma is the most deadly form of skin cancer; it metastasizes (spreads) readily. And once it metastasizes, it is very difficult to treat.
“It’s important to study this disease. The need for better treatment is critical,” he says. The disease especially affects Caucasians, with a lifetime frequency of occurrence at one in 75.
In 1998, scientists discovered that almost two-thirds of all melanomas contain a specific activating mutation in B-Raf, he says. This protein kinase is a critical component in a signaling pathway that controls cell growth, migration and invasion.
“These are normal cellular processes at certain stages of a cell’s life cycle, but when they are no longer controlled, they become hallmarks of cancer progression,” he explains. “The signaling pathway that B-Raf initiates is turned off in normal melanocytes, a specialized pigment-producing cell in the skin, but is frequently turned on in the melanomas that arise from this cell type.”
In other words, the normal process of cell growth goes haywire, and leads to unregulated cell growth – which is cancer.
“The mutation appears to occur early on” in the progression of melanoma, but the underlying molecular consequences are poorly understood, says Shabb, who compares how he used to do research to proteomics, a new area of research, to putting a puzzle together.
“You may have a piece of the puzzle. You know everything there is to know about that piece: its size, its shape, color. But you may not know how it fits in the larger picture, how it functions in relation to all the other pieces,” he says. “That’s how much of biochemistry was done in the 20th century.”
Shabb is collaborating with his colleagues in Colorado to apply proteomics “to take a global look at the targets of B-Raf,” he says. “We try to look at all the pieces at the same time, rather than each element in isolation. This helps us find the molecular culprits of cancer progression much faster – and within the larger cellular context.”
The pathway to which B-Raf belongs has the potential to modify many components in a cancer cell. The old way of doing biochemistry would require looking at one modified component at a time to understand how it affects the cancer cell, he says. “You may have to look at many modified components before finding one that is important in cancer progression. That can take a long time.”
“We look at how all the pieces fit together, and how they interact with each other in order to find an understanding at the molecular level of how this disruption occurs,” he says. This study of the larger picture is called proteomics, an emerging field that holds promise for uncovering insights that will generate advancements in many areas of biomedical research.
Some drugs aimed at treating melanoma are undergoing clinical trials, he says. One of them, sorafenib, inhibits B-raf. Unfortunately so many normal cellular processes are affected by this protein, a drug like sorafenib may have undesirable side effects.
“This is a common problem in developing new drugs,” Shabb says.
For Shabb and his colleagues, this is “a whole new area of research in cancer progression and it’s very complex,” he says. Identification of downstream targets in this signaling cascade provides new and potentially more specific candidates for cancer chemotherapy.
The best weapons against melanoma, he says, are still preventive practices and early detection.
-Pamela D. Knudson
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