YOUR HEALTH :
The Promise of RNAi
A Quantum Leap Toward New Treatments for Deadly Skin Cancers
Dr. Michael R. Green, University of Massachusetts Medical School
In 2008, nearly 62,500 people in the United States were diagnosed with melanoma, and the great risk is that this dreaded form of cancer will metastasize and become a death sentence—as it did for almost 8,500 Americans last year.
Melanocytes—the pigment-producing cells in your skin—can develop into either moles or melanoma cells. If you have a mole (that does not bear the signs of cancer), you lucked out because of defenses that have evolved over millennia to help prevent you from developing melanoma. Instead of growing into a cancer, your melanocytes stopped dividing and you ended up with a small benign lesion or mole.
Michael Green, M.D., Ph.D., a Howard Hughes Medical Institute (HHMI) Investigator and University of Massachusetts Medical School (UMMS) researcher, and his colleagues wanted to understand why some melanocytes divide uncontrollably and turn into melanoma cells and others go into hibernation as a result of the body’s natural protection mechanism and become moles.
Now, thanks to their breakthrough, this life-saving answer may be close at hand.
To understand these processes, Dr. Green’s team of researchers set out to identify genes involved in melanoma prevention. They conducted a genome-wide survey by inserting small bits of RNA—the molecule that carries out DNA’s instructions for making proteins—into cells to selectively turn off different genes.
Photo: Dr. Michael Green with graduate students Ryan Serra and Ling Lin.
This method takes advantage of RNA interference (RNAi), a mechanism for blocking gene activity, which has been central to groundbreaking research at UMMS. Scientists realize that if RNAi is used to shut down disease-causing genes, then development of a new class of treatments may result.
Dr. Green and his team identified 17 genes that are required to keep a melanocyte from becoming a melanoma cell. One of these genes, called IGFBP7, stood out because it was actually a secreted protein. Secreted proteins don’t stay inside their cells—they move into the blood and on to other cells. The team discovered that IGFBP7, when added to melanocytes cultured in the lab, caused these cells to stop dividing, much like what happens to melanocytes in a mole. But when it was added to cultured melanoma cells, they got an unexpected and exciting result: IGFBP7 caused these cells to “commit suicide.” Dr. Green and his team went on to show that injecting IGFBP7 into mice could stop the growth of melanoma in these small lab animals.
These findings raise the intriguing possibility that IGFBP7 could be used as a treatment for melanoma in humans. But Dr. Green doesn’t think the possibilities end there.
“The ultimate goal of these studies is to see if IGFBP7 can also be used to treat people who have metastatic melanoma, which is currently untreatable,” Dr. Green said. Malignant melanoma is treatable if caught in the early stages, but it’s the more advanced, metastatic melanoma that is untreatable and has a poor prognosis.
In addition to melanoma and other cancers, RNAi-based therapeutics might be able to silence genes involved in neurodegenerative diseases—such as ALS, infectious diseases, as well as autoimmune diseases such as diabetes—by controlling abnormal cell division and protein production within cells.
Dr. Michael R. Green, University of Massachusetts Medical School
RNAi was discovered by UMass faculty member and 2006 Nobel Laureate and National Academy of Sciences member Craig Mello and Andrew Fire of the Carnegie Institution of Washington (now at Stanford University). Prior to this landmark discovery, researchers used chemical methods to shut down genes, a task that took a great deal of laboratory time and slowed research.
The RNA interference (RNAi) Institute (see sidebar)
When Dr. Green and his colleagues wanted to perform a genome-wide survey for their melanoma research, they used a plasmid library, housed at the UMMS RNAi Core Facility. They knew that a small change in BRAF—a protein instrumental to cell division—can cause melanocytes to stop growing.
“We were looking for genes that, when turned off, would allow cells to overcome the growth arrest and begin dividing, as they would in cancer,” Dr. Green said. “In our libraries we have small RNAs that allow us to turn off, one by one, every single human gene.”
“At UMass Medical School we pride ourselves on having excellent research facilities,” he said. “Most universities do not have such an extensive resource.”
Moving Forward
Dr. Green hopes that through collaboration with other world-class UMass researchers and the use of the comprehensive resources available at UMMS, he can soon advance his research into the clinical phase.
The Drug Development Group (DDG) at the National Cancer Institute (NCI), which is interested in developing promising lead compounds into clinical trials, is currently working with Dr. Green and his team to move through the required pre-clinical phase.
During the pre-clinical phase, researchers must produce the protein according to Good Manufacturing Practices (GMP) standards and perform a series of toxicology studies to show that treatment is safe for clinical trials.
If treatment proves successful, researchers believe the IGFBP7 protein could be used against other forms of cancer with an activated BRAF mutation, such as colon cancer.
“If this becomes an effective treatment, a large fraction of the people who die from melanoma and colon cancer might be cured,” Dr. Green said. “To my knowledge, we’re the only research institution that’s discovered this protein and its effects and the only laboratory or university that is trying to turn it into a medicine to treat melanoma.”
For more information:
To learn more about Dr. Green’s research or to support research at the UMass Medical School, please contact the UMass Memorial Foundation at 508-856-5520, giving@umassmed.edu, or http://www.umassmed.edu/foundation.
If you have a question or concern about a mole or something on your skin, please see your doctor.
To locate a physician at UMass Medical Center, call 800-431-5151 or visit http://www.umassmemorial.org.
Thriving Research Community Attracts Leading Researchers to UMass Medical School
RNA interference (RNAi), gene silencing by double-stranded RNA, was uncovered in 1998 by Nobel Laureate Craig C. Mello, Ph.D., HHMI Investigator and the Blais University Chair in Molecular Medicine at UMass Medical School, in collaboration with Andrew Fire, Ph.D., of the Carnegie Institution of Washington (now at Stanford University). Since their discovery, the technology of RNAi has been widely adopted. Scientists realize that if RNAi is used to shut down disease-causing genes, then development of a new class of therapeutics can result.
UMMS is in the process of establishing the RNA interference (RNAi) Institute to capitalize on its expertise in the field of RNAi-based gene silencing. The institution’s scientists, who represent the world’s largest critical mass of talent, are mobilized to continue development of powerful RNAi technologies. The vision for the Institute emphasizes clinical and translational research and, ultimately, developing the next generation of therapeutics. A cornerstone of the University’s life sciences initiative, the RNAi Institute works in conjunction with the Center for Stem Cell Biology and Regenerative Medicine and the Gene Therapy Center to combat diseases on a genetic level. Together, these centers form the UMMS Advanced Therapeutics Cluster (ATC).
The Advanced Therapeutics Cluster is attracting leading researchers from across the country. Within the past year, Victor Ambros, Ph.D.—a National Academy of Sciences member in whose Harvard University lab Dr. Mello completed his doctorate research in the 1980s—left Dartmouth Medical School to join UMMS. In 1993, Dr. Ambros identified microRNAs—very short RNA strands that regulate the production of proteins for specific genes—a discovery for which he was named a co-recipient of the 2008 Lasker Award for Basic Medical Research. Since then, he has identified genes for several microRNAs involved in animal development, and he is currently working to understand the role of these strands in human disease.
In 2008, Melissa Moore, Ph.D., an HHMI Investigator and professor of Biochemistry & Molecular Pharmacology, joined UMMS from Brandeis University. Dr. Moore is interested in pre-mRNA splicing, or modification of RNA after transcription. This work aids in understanding protein development and could have clinical applications in the future.
“The strength of RNAi as a technology is that, first and foremost, it is amazing biology. The extraordinary depth of RNAi biology research at UMass Medical School makes us a unique place to translate RNAi into a human therapy. And the breadth of research interests here means that partnerships between clinicians and basic researchers form naturally, based on mutual enthusiasm for using RNAi to transform medicine,” said Phillip D. Zamore, Ph.D., HHMI Investigator, Gretchen Stone Cook Chair in Biomedical Sciences, and professor of Biochemistry & Molecular Pharmacology.
RNAi Core Facility
UMMS also houses a world-class, extensive library of plasmids—DNA molecules independently capable of replicating within a cell. Each plasmid contains what’s called a small hairpin RNA—an RNA that’s directed against the product of a gene. A hairpin RNA can knock out the function of any gene in the genome.
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