Rush University Medical Center in Chicago is leading a nationwide phase 3 clinical trial to determine whether a promising vaccine for advanced melanoma can effectively treat the deadly skin cancer. An earlier phase 2 trial of the experimental drug involving 50 patients with metastatic melanoma had what were referred to as “stunning results.” Eight patients recovered completely and four partially responded to the vaccine, according to the researchers. “Very few treatment options exist for patients with advanced melanoma, none of them satisfactory, which is why oncologists are so excited about the results we found in our phase 2 study,” said Dr. Howard Kaufman, associate dean of Rush Medical College and director of the Rush Cancer Program. Dr. Kaufman is leading the phase 3 study. The vaccine being tested is called OncoVEX, initially developed to combat herpes virus. Researchers discovered accidentally that the vaccine attacked cancerous tissue when it was inadvertently placed in a Petri dish of tumor cells. The vaccine includes an oncolytic virus, a reprogrammed virus that has been converted into a cancer-fighting agent that attacks tumor cells while leaving healthy cells undamaged. OncoVEX also carries biological agents that boost the immune response to melanoma. The vaccine is injected directly into lesions that can be felt or seen, with or without ultrasound. The procedure is generally done in a physician’s office. “What really surprised, and encouraged, us was that the vaccine worked not just on the cells we injected, but on lesions in other parts of the body that we couldn’t reach,” Dr. Kaufman said in commenting on the phase 2 results. “In other words, the vaccine prompted an immune response that was circulated through the bloodstream to distant sites.
Researchers at the University of Massachusetts Medical School and colleagues have discovered a critical step for blood vessel growth in zebrafish embryos, providing new insight into how vascular systems develop and offering a potential therapeutic target for preventing tumor growth, which depends on vascularization. The researchers have identified a novel microRNA-mediated genetic pathway responsible for new blood vessel growth (angiogenesis) in zebrafish embryos. The work provides new insights into how vascular systems use the forces of existing blood flow to initiate the growth of new vessels. Focusing on the development of the fifth and sixth aortic arches in the zebrafish, senior author Dr. Nathan Lawson described how the forces exerted by blood flow on endothelial cells are a critical component for expressing a microRNA that triggers new vessel development. In the early stages of development, when blood flow is present in the aortic vessels, but the vascular linkages between the two arches have yet to be established, the stimulus provided by active blood flow leads to expression of an endothelial-cell specific microRNA (mir-126). In turn, this microRNA turns on vascular endothelial growth factor (VEGF), a chemical signal produced by surrounding cells that normally stimulates angiogenesis. Thus, blood flow allows the endothelial cells to respond to VEGF by growing into new blood vessels. However, when blood flow in the aortic arches was restricted, mir-126 failed to be expressed. In the absence of this microRNA, new blood vessels were unable to develop due to a block in VEGF signaling. “We have known for over a hundred years that blood flow makes new vessels grow,” said Dr. Lawson. “But we never really knew how cells in a growing vessel interpreted this signal.
In a mouse model, scientists have discovered that alpha-cells in the pancreas, which do not produce insulin, can convert into insulin-producing beta-cells, advancing the prospect of regenerating beta-cells as a cure for type 1 diabetes. The research team, led by senior author Dr. Pedro L. Herrera of the University of Geneva, demonstrated that beta-cells will spontaneously regenerate after near-total beta-cell destruction in mice and the majority of the regenerated beta-cells are derived from alpha-cells that had been reprogrammed, or converted, into beta-cells. Using a unique model of diabetes in mice, in which nearly all of the beta-cells are rapidly destroyed, the researchers found that if the mice were maintained on insulin therapy, beta-cells were slowly and spontaneously restored, eventually eliminating the need for insulin replacement. Alpha-cells normally reside alongside beta-cells in the pancreas and secrete a hormone called glucagon, which works in opposition to insulin to regulate the levels of sugar in the blood. Alpha-cells are not attacked by the autoimmune processes that destroy beta-cells and cause type 1 diabetes. Dr. Andrew Rakeman, the Juvenile Diabetes Research Foundation (JDRF) Program Manager in Beta-Cell Therapies and who was not involved in the research, said that the breakthrough in Dr. Herrera’s work is the demonstration that alpha-to-beta-cell reprogramming can be a natural, spontaneous process. “If we can understand the signals that are triggering this conversion, it will open a whole new potential strategy for regenerating beta-cells in people with type 1 diabetes,” he said. “It appears that the body can restore beta-cell function either through reprogramming alpha-cells to become beta-cells or, as previously shown by others, by increasing growth of existing beta cells.
“Personalized Medicine 3.0–Targeting Cancer” is a one-day conference and networking opportunity for health and industry professionals, educators, and scientists. The conference will focus on cancer–using genomic information to characterize tumors precisely and ensure the use of the most effective treatment regimens for individual patients with the fewest side effects. The organizers note that personalized medicine is poised to transform healthcare over the next several decades, and that it offers both the possibility of improved health outcomes and the potential to make healthcare more cost-effective. The conference will be held in San Francisco at San Francisco State University from 9 am to 7 pm on Tuesday, May 25, 2010. The two previous annual conferences on personalized medicine have been enormous successes and similar results are expected for this third conference. The organizers urge you to register early as space is limited and the registration fee is $249 until April 15, 2010. Registration includes a light breakfast, lunch, and a networking reception at the end of the day. Registration details and a preliminary program are available at the conference web site (personalizedmedicine.sfsu.edu/), as are additional details on the conference.
In the largest genome-wide study of brain aneurysms ever conducted, an international team led by researchers at the Yale School of Medicine has identified three new genetic variants that increase a person’s risk for developing this deadly disease. “These findings provide important new insights into the causes of intracranial aneurysms and are a critical step forward in the development of a diagnostic test that can identify people at high risk prior to the emergence of symptoms,” said Dr. Murat Gunel, senior author of the report. “Given the often-devastating consequences of the bleeding in the brain, early detection can be the difference between life and death.” The new study, the second by Yale researchers published within the last 15 months, brings to five the number of regions of the genome that have been found to contribute to the nearly 500,000 cases of this devastating disorder diagnosed annually worldwide. The researchers searched across the entire genome for changes in the genetic code that were shared more often by aneurysm patients than by unaffected individuals. The researchers determined that if persons carry all of the risk variants discovered by the Yale-led team, they are five to seven times more likely to suffer an aneurysm than those individuals who carry none. While these findings have transformed the understanding of the genetic risks for intracranial aneurysms, considerable work remains to be done, the researchers noted. “These five findings explain about 10 percent of genetic risk of suffering an aneurysm,” Dr. Gunel said. “This is 10 percent more than we understood just a couple of years ago, but there is a long way to go.”
A second study, in a different mouse model, has shown that the pharmacological agent rapamycin, which has previously been shown to extend life span in mice, may prevent Alzheimer’s disease in humans. A bacterial product first isolated from the soil on Easter Island, rapamycin is already approved by the U.S. Food & Drug Administration to prevent organ rejection in transplant patients. The first of the two Alzheimer’s studies, was published online on February 23, 2010 in the Journal of Biological Chemistry (A. Caccamo et al.), and showed that rapamycin curbed the effects of Alzheimer’s in one mouse model. The new study, published on April 1 in PLoS ONE, showed similar effects in a completely different mouse model of Alzheimer’s. Both reports came from the University of Texas Health Science Center at San Antonio and collaborating institutions. The second report showed that administration of rapamycin improved learning and memory in a strain of mice engineered to develop Alzheimer’s. The improvements in learning and memory were detected in a water maze activity test that is designed to measure learning and spatial memory. The improvements in learning and memory correlated with lower damage in brain tissue. “Rapamycin treatment lowered levels of amyloid-beta-42, a major toxic species of molecules in Alzheimer’s disease,” said senior author Dr. Veronica Galvan. “These molecules, which stick to each other, are suspected to play a key role in the early memory failure of Alzheimer’s.”
The first genome of a songbird (the male zebra finch), has been sequenced and has revealed secrets of the relatively rare ability to communicate through “learned vocalizations.” This ability has been documented in just a few other animals, including other songbirds, parrots, hummingbirds, bats, whales, and humans. The ability is lacking in chickens, the only other bird to have had its genome sequenced, and is also absent in female zebra finches. The current research indicates that the ability seems to depend, in part, on the extensive involvement of non-coding RNAs (ncRNAs). A major reason the researchers decided to study the zebra finch genome was the male bird’s ability to learn complex songs from its father. At first, a fledgling male finch makes seemingly random sounds, much like the babble of human babies. With practice, the young bird eventually learns to imitate its father’s song. Once the bird has mastered the family song, it will sing that song for the rest of its life and pass the song on to the next generation. Though female finches do perceive and remember songs, researchers suggest that their inability to learn songs may be due to differences in sex hormones, as well as chromosomal sex differences affecting the brain. The chicken and zebra finch genomes are similar in many ways. Both have approximately one billion DNA base pairs–roughly one-third the size of a human genome. However, researchers discovered that some genes associated with vocal behavior have undergone accelerated evolution in the finch. For example, they found a disproportionately high number of ion channel genes among the 49 genes in the finch genome that are suppressed, or turned off, in response to song. Human ion channel genes have been shown to play key roles in many aspects of behavior, neurological function, and disease.
Contrary to conventional wisdom that the symptoms of Down syndrome are likely caused by an overabundance of certain proteins due to the additional copy of chromosome 21, scientists at Ohio State University and collaborators have found evidence that at least some of the symptoms may actually be associated with underexpression of a certain protein or proteins due to the presence of five microRNA genes on chromosome 21. MicroRNAs bind to messenger RNA and cause the inhibition of protein synthesis for that messenger RNA. Computer analysis revealed over 1,600 proteins that were potential targets of the five microRNAs on chromosome 21, all of which could cause problems in Down syndrome because they would be underexpressed. Based on other evidence, the researchers selected one of the protein genes (for methyl-CpG-binding protein 2, known as MeCP2) for further study. Among the reasons for selecting this gene was that it is known to be mutated in Rett syndrome, an inherited cognitive disorder. The researchers used just two of the five microRNAs on chromosome 21 for the experiments in this study, miR-155 and miR-802, to match the only microRNAs available in the genetically engineered mouse model of Down syndrome. First, the researchers made copies of the relevant microRNAs. In human brain cell lines, they manipulated levels of those two molecules to show the inverse relationship with MeCP2. If the microRNAs were overexpressed, the level of the MeCP2 protein went down. When the microRNAs were underexpressed, the protein levels went up.
A two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer, according to a team of scientists at The University of Texas M.D. Anderson Cancer Center and INCELL Corporation. The drug regimen, tested so far in mouse models and on human colon cancer tissue in the laboratory, appears to address a problem with chemopreventive drugs–they must be taken continuously long term to be effective, exposing patients to possible side effects, said senior author Dr. Xiangwei Wu, associate professor in M.D. Anderson’s Department of Head and Neck Surgery. “This combination can be given short term and periodically to provide a long-term effect, which would be a new approach to chemoprevention,” Dr. Wu said. The team found that a combination of Vitamin A acetate (RAc) and TRAIL, (tumor necrosis factor-related apoptosis-inducing ligand), kills precancerous polyps and inhibits tumor growth in mice that have deficiencies in a tumor-suppressor gene. That gene, adenomatous polyposis coli (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all human colon cancers, Dr. Wu said. Early experiments with APC-deficient mice showed that the two drugs combined or separately did not harm normal colon epithelial cells. Separately, they showed no effect on premalignant polyps. RAc and TRAIL together killed premalignant polyps, causing programmed cell death known as apoptosis. RAc, researchers found, sensitizes polyp cells to TRAIL. The scientists painstakingly tracked the molecular cascade caused by APC deficiencies, and found that insufficient APC sensitizes cells to TRAIL and RAc by suppressing a protein that blocks TRAIL. Before human clinical trials can be considered, Dr.
When levels of free protein p85 were increased in the livers of severely obese, diabetic mice, researchers at Children’s Hospital Boston-Harvard Medical School and the University of Tokyo saw improved glucose tolerance and reduced blood glucose levels. The effect lies in the influence of p85 on the transcription factor XBP-1 (X-box binding protein 1), the scientists said. Under the influence of p85, XBP-1 normally moves to the nucleus and turns on genes for numerous chaperone proteins, which reduce stress on the endoplasmic reticulum (ER) by aiding and stabilizing the folding of proteins that are produced there and then dispatched to do their jobs in the cell. In previous work, the authors had shown that the brain, liver, and fat cells of obese mice have increased stress in the ER. In the presence of obesity, the ER is overwhelmed and its operations break down. This so-called “ER stress” activates a cascade of events that suppress the body’s response to insulin, and is a key link between obesity and type 2 diabetes. Until now, however, researchers haven’t known precisely why obesity causes ER stress to develop. Senior author Dr. Umut Ozcan and colleagues have now shown that XBP-1 is unable to function properly in obese mice. Instead of traveling to the cell nucleus and turning on chaperone genes, XBP-1 becomes stranded. Probing further, the researchers found the reason: XBP-1 fails to interact with p85, which is part of an important protein (phosphotidyl inositol 3 kinase or PI3K) that mediates insulin’s effect of lowering blood glucose levels. Dr. Ozcan’s group identified a new complex of p85 proteins in the cell, and showed that normally, when stimulated by insulin, p85 breaks off and binds to XBP-1, helping it get to the nucleus.