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Archive - 2013

January 26th

Telomerase Mutation a Driver Mutation in Melanoma

Approximately ten percent of all cases of malignant melanoma are familial cases. The genome of affected families tells scientists a lot about how the disease develops. Professor Dr. Rajiv Kumar of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) together with Professor Dr. Dirk Schadendorf from Essen University Hospital studied a family in which 14 family members were affected by malignant melanoma. The scientists analyzed the genomes of family members and found an identical mutation in the gene for telomerase, an enzyme often called the “immortality enzyme,” in all persons studied. Telomerase protects the ends of chromosomes from being lost in the process of cell division and, thus, prevents that cell from aging and dying. The inherited gene mutation leads to the formation of a binding site for protein factors in the controlling region of the telomerase gene, causing it to become overactive. As a result, mutated cells overproduce telomerase and hence become virtually immortal. The results were published online in Science on January 24, 2013. This spectacular finding of the family analysis prompted the scientists to also look for mutated telomerase genes in non-inherited (sporadic) melanoma, which is much more common than the familial variant. In most of the tissue samples of melanomas of all stages they found alterations in the telomerase gene switch, which the researchers clearly identified as typical consequences of sun exposure. Even though these mutations were not identical to those found in the melanoma family, they had the same effect: overactive telomerase. "We don't believe that the telomerase gene in melanoma is mutated by pure chance, but that it is a so-called driver mutation that drives carcinogenesis," says Dr. Kumar.

January 17th

Novel Technique Reveals Dynamics of Telomere DNA Structure

Biomedical researchers studying aging and cancer are intensely interested in telomeres, the protective caps on the ends of chromosomes. In a new study, scientists at the University of California-Santa Cruz used a novel technique to reveal structural and mechanical properties of telomeres that could help guide the development of new anti-cancer drugs. Telomeres are long, repetitive DNA sequences at the ends of chromosomes that serve a protective function analogous to that of the plastic tips on shoelaces. As cells divide, their telomeres get progressively shorter, until eventually the cells stop dividing. Telomeres can grow longer, however, through the action of an enzyme called telomerase, which is especially active in cells that need to keep dividing indefinitely, such as stem cells. Researchers have also found that most tumor cells show high telomerase activity. Dr. Michael Stone, an assistant professor of chemistry and biochemistry at UC-Santa Cruz, said his lab is particularly interested in the folding and unfolding of a DNA structure at the tail end of the telomere, known as a G-quadruplex, because it plays a key role in regulating telomerase activity. "Most cancer cells use telomerase as one mechanism to maintain uncontrolled growth, so it is an important target for anti-cancer therapeutics," Dr. Stone said. "The G-quadruplex structures of telomere DNA inhibit the function of the telomerase enzyme, so we wanted to understand the mechanical stability of this structure." Xi Long, a graduate student in Dr. Stone's lab, led the project, which involved integrating two techniques to manipulate and monitor single DNA molecules during the unfolding of the G-quadruplex structure.

Potential New Treatment for Gastrointestinal Cancers Discovered

Researchers have identified a complex of proteins that promotes the growth of some types of colon and gastric cancers, and shown that medications that block the function of this complex have the potential to be developed into a new treatment for these diseases. The complex of proteins, known as mTorc1 (mammalian target of rapamycin complex 1), has previously been implicated in the development of some other cancers, but this is the first time it has been shown to promote the growth of colon and gastric cancers that are associated with inflammation. Dr Stefan Thiem and Associate Professor Matthias Ernst from the Walter and Eliza Hall Institute’s Cell Signalling and Cell Death division made the discovery with colleagues while at the Melbourne-Parkville Branch of the Ludwig Institute for Cancer Research. Associate Professor Ernst is a Ludwig Institute Member. Their findings were published online on January 16, 2013 in the Journal of Clinical Investigation. Cancers of the digestive system are a significant cause of death in Australia. Colon (or bowel) cancer causes more than 4,000 deaths annually – more than any other cancer except lung cancer – while more than 1,000 Australians die from gastric (or stomach) cancer each year. Associate Professor Ernst said many types of colon and gastric cancer are associated with chronic inflammation. “We have previously shown that the immune system’s inflammatory response can promote the growth of tumors,” he said.

January 16th

Possible Role for Huntington’s Gene Discovered

About 20 years ago, scientists discovered the gene that causes Huntington’s disease, a fatal neurodegenerative disorder that affects about 30,000 Americans. The mutant form of the gene has many extra DNA repeats in the middle of the gene, but scientists have yet to determine how that extra length produces Huntington’s symptoms. In a new step toward answering that question, MIT biological engineers have found that the protein encoded by this mutant gene alters patterns of chemical modifications of DNA. This type of modification, known as methylation, controls whether genes are turned on or off at any given time. The mutant form of this protein, dubbed “huntingtin,” appears to specifically target genes involved in brain cell function. Disruptions in the expression of these genes could account for the neurodegenerative symptoms seen in Huntington’s disease, including early changes in cognition, says Dr. Ernest Fraenkel, an associate professor of biological engineering at MIT. Dr. Fraenkel’s lab is now investigating the details of how methylation might drive those symptoms, with an eye toward developing potential new treatments. “One could imagine that if we can figure out, in more mechanistic detail, what’s causing these changes in methylation, we might be able to block this process and restore normal levels of transcription early on in the patients,” says Dr. Fraenkel, senior author of a paper describing the findings in this week’s (January 15, 2013) issue of PNAS. Lead author of the paper is Christopher Ng, an MIT graduate student in biological engineering. Other authors are MIT postdoc Ferah Yildirim; recent graduates Yoon Sing Yap, Patricio Velez, and Adam Labadorf; technical assistants Simona Dalin and Bryan Matthews; and Dr. David Housman, the Virginia and D.K. Ludwig Professor of Biology.

January 14th

Researchers Identify Gene Fusion for Rare Cancer

It started with a 44-year-old woman with solitary fibrous tumor, a rare cancer seen in only a few hundred people each year. By looking at the entire DNA from this one patient's tumor, researchers have found a genetic anomaly that provides an important clue to improving how this cancer is diagnosed and treated. Researchers at the University of Michigan Comprehensive Cancer Center sequenced the tumor's genome through a new program called MI-ONCOSEQ, which is designed to identify genetic mutations in tumors that might be targeted with new therapies being tested in clinical trials. The sequencing also allows researchers to find new mutations. In this case, an unusual occurrence of two genes - NAB2 and STAT6 - fusing together. This is the first time this gene fusion has been identified. "In most cases, mutations are identified because we see them happening again and again. Here, we had only one case of this. We knew NAB2-STAT6 was important because integrated sequencing ruled out all the known cancer genes. That allowed us to focus on what had been changed," says lead study author Dan R. Robinson, research fellow with the Michigan Center for Translational Pathology. Once they found the aberration, the researchers looked at 51 other tumor samples from benign and cancerous solitary fibrous tumors, looking for the NAB2-STAT6 gene fusion. It showed up in every one of the samples. Results were published online January 13, 2013 in Nature Genetics. "Genetic sequencing is extremely important with rare tumors," says study co-author Scott Schuetze, M.D., associate professor of internal medicine at the U-M Medical School. "Models of rare cancers to study in the laboratory are either not available or very limited.

January 14th

Antibodies Shown to Have Protective Role Against Ebola Virus in Vaccine Study

Researchers at the NIH and Oregon Health & Science University (OHSU) have found that an experimental vaccine elicits antibodies that can protect nonhuman primates from Ebola virus infection. Ebola virus causes severe hemorrhagic fever in humans and nonhuman primates, meaning that infection may lead to shock, bleeding, and multi-organ failure. According to the World Health Organization, Ebola hemorrhagic fever has a fatality rate of up to 90 percent. There is presently no licensed treatment or vaccine for Ebola virus infection. Several research groups have developed experimental vaccine approaches that protect nonhuman primates from Ebola virus and the closely related Marburg virus. These approaches include vaccines based on DNA, recombinant adenovirus, virus-like particles, and human parainfluenza virus 3. But how these vaccine candidates confer protection is an area that is still being explored: Do they activate immune cells to kill the invading virus? Or do they elicit antibodies that block infection? In the current study, scientists at NIH's National Institute of Allergy and Infectious Diseases and OHSU's Vaccine & Gene Therapy Institute built on earlier work with an experimental vaccine composed of an attenuated vesicular stomatitis virus carrying a gene that codes for an Ebola virus protein. They observed how cynomolgus macaques responded to a challenge of Ebola virus before and during treatment with the vaccine and in conjunction with depleted levels of immune cells. Their results showed that important immune cells—CD4+ T cells and CD8+ T cells—had a minimal role in providing protection, while antibodies induced by the vaccine appeared to be critical to protecting the animals.

Knee Cartilage Repair Success Seen in Clinical Trial of New Material

In a small study, researchers reported increased healthy tissue growth after surgical repair of damaged cartilage if they put a “hydrogel” scaffolding into the wound to support and nourish the healing process. The squishy hydrogel material was implanted in 15 patients during standard microfracture surgery, in which tiny holes are punched in a bone near the injured cartilage. The holes stimulate patients’ own specialized stem cells to emerge from bone marrow and grow new cartilage atop the bone. Results of the study, published in the January 9, 2013 issue of Science Translational Medicine, are a proof of concept that paves the way for larger trials of the hydrogel’s safety and effectiveness, the researchers say. “Our pilot study indicates that the new implant works as well in patients as it does in the lab, so we hope it will become a routine part of care and improve healing,” says Jennifer Elisseeff, Ph.D., Jules Stein Professor of Ophthalmology and director of the Johns Hopkins University School of Medicine’s Translational Tissue Engineering Center (TTEC). Damage to cartilage, the tough-yet-flexible material that gives shape to ears and noses and lines the surface of joints so they can move easily, can be caused by injury, disease, or faulty genes. Microfracture is a standard of care for cartilage repair, but for holes in cartilage caused by injury, it often either fails to stimulate new cartilage growth or grows cartilage that is less hardy than the original tissue. Tissue engineering researchers, including Dr. Elisseeff, theorized that the specialized stem cells needed a nourishing scaffold on which to grow, but demonstrating the clinical value of hydrogels has “taken a lot of time,” Dr. Elisseeff says.

Scientists Find New Way to Boost Common Cancer Drugs

Shutting down a specific pathway in cancer cells appears to improve the ability of common drugs to wipe those cells out, according to new research from scientists at Fox Chase Cancer Center, published in the January 2013 issue of Cancer Discovery. "Ideally, this research will eventually enable scientists to find drugs that disrupt this pathway and boost the impact of current therapies," says Igor Astsaturov, M.D., Ph.D., Attending Physician in the Department of Medical Oncology at Fox Chase. "That's the long-term plan." The new approach appears to enhance the tumor-killing ability of a commonly prescribed class of drugs that includes cetuximab (Erbitux), used to treat colorectal and head and neck cancers. These drugs work by blocking the activity of the epidermal growth factor receptor (EGFR), which sits on the cell surface and senses cues from the environment, telling cancer cells to grow and divide, says Dr. Astsaturov. "The whole mantra of modern day oncology is to suppress these inputs." Although EGFR inhibitors succeed in killing cancer cells, some malignant cells still find ways to evade the drug, and become resistant to treatment. Consequently, many researchers are actively looking for ways to kill these surviving cancer cells, annihilating tumors completely. In 2010, Dr. Astsaturov and his colleagues identified a pathway in the cell that, when blocked, completely suppressed EGFR activity. Interestingly, the pathway consists of a series of enzymes that, when working in concert, synthesize new molecules of cholesterol, an essential component of the cell membranel. This pathway is particularly important to cancer cells, which are constantly dividing and therefore need to produce more cholesterol for the new cells.