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Archive - 2012

September 29th

Combination of Targeted Treatment Drugs Delays Resistance in Melanoma Patients

Combined treatment with two drugs targeting different points in the same growth-factor pathway delayed the development of treatment resistance in patients with BRAF-positive metastatic malignant melanoma. The results of a phase I/II study of treatment with the kinase inhibitors dabrafenib and trametinib were published online on September 29, 2012 in the New England Journal of Medicine (NEJM) and are being released online to coincide with a presentation at the European Society for Medical Oncology meeting in Vienna. "We investigated this combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy," says Keith Flaherty, M.D., of the Massachustts General Hospital (MGH) Cancer Center, lead author of the NEJM report and principal investigator of the study. "We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone." In approximately half of patients with metastatic melanoma, tumor growth is driven by mutations that keep the BRAF protein – part of the MAPK cell growth pathway – constantly activated. In recent years, drugs that inhibit BRAF activity have rapidly halted and reversed tumor growth in about 90 percent of treated patients, but most patients' response is temporary, with tumor growth resuming in six or seven months. Investigations into how this resistance emerges have suggested that the MAPK pathway gets turned back on through activation of MEK, another protein further down the pathway. Based on promising results of animal studies, the current investigation was designed to test whether inhibiting both the BRAF and MEK proteins could delay treatment resistance.

New, Rabies-Related Virus Caused Death in the Congo

An isolated outbreak of a deadly disease known as acute hemorrhagic fever, which killed two people and left one gravely ill in the Democratic Republic of Congo in the summer of 2009, was probably caused by a novel virus scientists have never seen before. Described online on September 27, 2012 in the open-access journal PLoS Pathogens, the new microbe has been named Bas-Congo virus (BASV) after the province in the southwest corner of the Congo where the three people lived. It was discovered by an international research consortium that included scientists from the University of California, San Francisco (UCSF) and the University of California, Davis, Global Viral, the Centre International de Recherches Médicales de Franceville in Gabon, the Institut National de Recherche Biomédicale, Kinshasa in the Democratic Republic of the Congo, Metabiota, and others. “Known viruses, such as Ebola, HIV, and influenza, represent just the tip of the microbial iceberg,” said Joseph Fair, Ph.D., a co-author and vice president of Metabiota. “Identifying deadly unknown viruses, such as Bas-Congo virus, gives us a leg up in controlling future outbreaks.” “These are the only three cases known to have occurred, although there could be additional outbreaks from this virus in the future,” said Charles Chiu, M.D., Ph.D., an assistant professor of laboratory medicine at UCSF and director of the UCSF-Abbott Viral Diagnostics and Discovery Center, who spearheaded the UCSF effort to identify the virus. Dr. Chiu and his team continue to work on new diagnostics to detect the virus so that health officials in the Congo and elsewhere can quickly identify it should it emerge again. One odd characteristic of the Bas-Congo virus, Dr.

September 28th

Genome Sequence of Endangered Puerto Rican Parrrot

The international open-access journal GigaScience (a BGI and BioMed Central journal) has announced the publication, on September 28, 2012, of a unique study providing the genome sequence of the critically endangered Puerto Rican Parrot (Amazona vittata) by Dr. Taras Oleksyk and colleagues at the University of Puerto Rico-Mayaguez. The sequencing and analysis of the genome of the only surviving native parrot in U.S. territory provide numerous benefits for avian genetics, conservation studies, and evolutionary analyses. What is remarkable here, and highlighted in an accompanying commentary by Dr. Steven J. O'Brien of St. Petersburg State University, is that it shows how accessible genomic technology has become. With the human genome project taking a consortium of the leading international genome centers a decade and $3 billion USD to carry out, just over a decade later the genome of the Puerto Rico parrot was assembled at a small institution in Puerto Rico, and completely funded by the community. Money was raised in a variety of creative ways, including student organized art and fashion shows (see:, social-networking sites, and private donations from Puerto Rican citizens wanting to promote research on their local wildlife. This project serves as a signal that work on large-scale whole-genome projects is becoming more democratized, and opens the door for more creative input from outside the large genome centers. Dr.

September 26th

Comprehensive Genomic Analysis Sheds New Light on Subtypes of Breast Cancer

Comprehensive genomic analysis of breast tumors has revealed four main subclasses of breast cancer, each of which has extensive genetic heterogeneity, said an international consortium of scientists in The Cancer Genome Atlas Network that includes scientists from the Baylor College of Medicine (BCM), and from 90 other institutions around the world. The result were published in an open article online on September 23, 2012 in Nature. "In the last 10 years, new technologies have allowed us to look at these tumors at a variety of different levels," said Dr. Chad Creighton, an associate professor in the National Cancer Institute-designated Dan L. Duncan Cancer Center at BCM, who worked on the analysis of the various genomic datasets, which included, for all genes, the sequence, expression, copy number, and any epigenetic silencing. Dr. Lawrence Donehower, professor of molecular virology and microbiology at BCM, concentrated on analysis involving a particular tumor suppressor gene called p53. "We took all these data and used them together to identify these four basic subtypes of tumors that we’ve known about for some time," said Dr. Creighton. "Among other things, this study aimed to get at the fundamental question of just how many subtypes of breast cancer there are, because that can determine treatment." "This is one of the largest multi-institutional and multi-platform efforts of this kind to date," said Dr. Donehower. For this report, members of the consortium evaluated tumors and tissue samples from 825 patients with breast cancer. Of these, 510 tumors from 507 patients underwent sequencing of the whole exome (the protein-coding portion of the genome) and identified 30,626 somatic mutations.

September 25th

Cilia-Based Gene Therapy Restores Sense of Smell in Mice

A team of scientists from Johns Hopkins and other institutions report that restoring tiny, hair-like structures to defective cells in the olfactory system of mice is enough to restore a lost sense of smell. The results of the experiments were published online on September 2, 2012 in Nature Medicine, and are believed to represent the first successful application of gene therapy to restore this function in live mammals. An expert in olfaction, Randall Reed, Ph.D., professor of molecular biology and genetics and co-director of the Center for Sensory Biology at the Johns Hopkins Institute for Basic Biomedical Sciences, cautions that researchers are still years away from applying the same therapy in people, and that if and when it comes, it will likely be most effective for those who suffer from anosmia (lack of smell) due to inherited genetic disorders. “But our work has already contributed to a better understanding of the cellular factors involved in anosmia, and that will give us insights into other neurological disorders, as well,” he says. The mice used in the current study carried a genetic mutation that destroyed the production of a protein critical for the functioning of cilia in the cells responsible for smell, called olfactory sensory neurons. These specialized cells each display several of the protruding, hair-like structures that contain receptors for odorants. Without functional cilia, the cells become a broken link in the chain of events necessary for proper odor detection in the environment, the researchers explained. Beginning with a common cold virus, which readily infects the cells of the nasal cavity, researchers replaced some of the viral genes with a corrected version of the defective cilia gene.

Mechanism That Leads to Non-Familial Parkinson's Disease Identified

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson's disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson's and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published online on September 25, 2012 in Nature Communications. Studies of rare, familial (heritable) forms of Parkinson's show that a protein called alpha-synuclein plays a role in the development of the disease. People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson's. Another key feature of Parkinson's is the presence of excess alpha-synuclein aggregates in the brain. As the vast majority of patients with Parkinson's do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson's nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease. Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson's. "It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits," said study leader Asa Abeliovich, M.D., Ph.D., associate professor of pathology and neurology at CUMC.

Researchers ID Protein That Suppresses Breast Cancer Metastases

A receptor protein suppresses local invasion and metastasis of breast cancer cells, the most lethal aspect of the disease, according to a research team headed by scientists from The University of Texas MD Anderson Cancer Center. Reporting online on September 23, 2012 in Nature Medicine, the team described using high-throughput RNA sequencing to identify the leukemia inhibitory factor receptor (LIFR) as a novel suppressor of breast cancer metastasis, the spread of the disease to other organs. "Based on our findings, we propose that restoring the expression or the function of key metastasis suppressors like LIFR could be used to block breast cancer metastasis," said lead investigator Li Ma, Ph.D., assistant professor in MD Anderson's Department of Experimental Radiation Oncology. "Lack of clinically proven prognostic markers and therapeutic agents for metastasis are major barriers for eradicating breast cancer deaths," Dr. Ma said. "Although many metastasis-promoting genes have been identified, they have not been translated into clinical practice. The exceptions are the HER2- and VEGF-targeting agents, which have shown measurable, but moderate, benefit in the clinic." Only a few genes have been established as metastasis suppressors, Dr. Ma said, and many researchers believe that such genes play only a minor role in metastasis. The investigators in this study, however, found that LIFR is "highly relevant in human tumors." While 94 percent of normal human breast tissues show high LIFR expression, LIFR is downregulated or lost in a significant fraction of patients with ductal carcinoma in situ (DCIS) or invasive breast cancer, and loss of LIFR closely correlates with poor clinical outcomes. Dr.

September 24th

First-Ever Treatment for Premature Aging Disease Shows Promise in Clinical Trial

Results of the first-ever clinical drug trial for children with progeria, a rare, fatal "rapid-aging" disease, demonstrate the efficacy of a farnesyltransferase inhibitor (FTI), a drug originally developed to treat cancer. The clinical trial results, achieved only six years after scientists identified the genetic cause of progeria, included significant improvements in weight gain, bone structure and, most importantly, the cardiovascular system, according to The Progeria Research Foundation (PRF) and Boston Children's Hospital. The study results were published online in an open article on Septermber 24, 2012 in PNAS. Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated aging in children. All children with progeria die of the same heart disease that affects millions of normal aging adults (atherosclerosis), but instead of occurring at 60 or 70 years of age, these children may suffer heart attacks and strokes as early as age 5 years, with the average age of death at 13 years. "To discover that some aspects of damage to the blood vessels in progeria can not only be slowed by the FTI called lonafarnib, but even partially reversed within just 2.5 years of treatment is a tremendous breakthrough, because cardiovascular disease is the ultimate cause of death in children with progeria," said Leslie Gordon, M.D., Ph.D., lead author of the study, medical director for the PRF, and mother of a child with progeria. In addition, Dr. Gordon is a staff scientist at Boston Children's Hospital and Harvard Medical School, and an associate professor at Hasbro Children's Hospital and Alpert Medical School of Brown University.

New Peptide-Enclosed Vesicles Have Potential for Targeted Drug Delivery

For the first time, researchers at Kansas State University and Jikei University in Japan have designed and created a bounded vesicle formed entirely of peptides -- molecules made up of amino acids, the building blocks of protein. The vesicle could serve as a new drug delivery system to safely treat cancer and neurodegenerative diseases. The study, led by Dr. John Tomich, professor of biochemistry at Kansas State University, was published on September 18, 2012 in the journal PLoS ONE, and a patent for the discovery is pending. The peptides are a set of self-assembling branched molecules made up of naturally occurring amino acids. The chemical properties of the peptides create a vesicle that Dr. Tomich describes as a bubble: It's made up of a thin membrane and is hollow inside. Created in a water solution, the bubble is filled with water rather than air. The peptides -- or bubbles -- can be made in a solution containing a drug or other molecule that becomes encapsulated as the peptides assemble, yielding a trapped compound, much like a gelatin capsule holds over-the-counter oral remedies. The peptide vesicles could be delivered to appropriate cells in the body to treat diseases and minimize potential side effects. "We see this as a new way to deliver any kind of molecule to cells," Dr. Tomich said. "We know that in certain diseases subpopulations of cells have gone awry, and we'd like to be able to specifically target them instead of attacking every cell, including healthy ones." The finding could improve gene therapy, which has the potential to cure diseases by replacing diseased cells with healthy ones. Gene therapy is being tested in clinical trials, but one of the biggest challenge is how best to deliver the genes.

Back Pain Gene Identified

Researchers at King’s College London have for the first time identified a gene linked to age-related degeneration of the intervertebral discs in the spine, a common cause of lower back pain. Costing the UK an estimated £7billion a year due to sickness leave and treatment costs, the causes of back pain are not yet fully understood. Until now, the genetic cause of lower back pain associated with lumbar disc degeneration (LDD) was unknown, but the largest study to date, published online on September 19, 2012 in the journal Annals of Rheumatic Diseases, has revealed an association with the PARK2 gene. Mutations in this gene are already known to cause a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinson disease. The researchers, funded by the Wellcome Trust and Arthritis Research UK, say more research into this surprising association needs to be carried out in order to fully understand how it is triggered, but this new finding could ultimately pave the way towards developing new treatments in the future. LDD is a common age-related trait, with over a third of middle-aged women having at least one degenerate disc in the spine. Discs become dehydrated, lose height and the vertebrae next to the discs develop bony growths called osteophytes. These changes can cause or contribute to lower back pain. LDD is inherited in between 65 – 80 per cent of people with the condition, suggesting that genes play a key role. Scientists compared MRI images of the spine in 4,600 individuals with genome-wide association data, which mapped the genes of all the volunteers. They identified that the gene PARK2 was implicated in people with degenerate discs and could affect the speed at which they deteriorate. The researchers say the results show that the gene may be switched off in people with LDD.