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Archive - Mar 25, 2011

FDA Approves BMS Drug for Late-Stage Melanoma

The U.S. Food and Drug Administration today (March 25, 2011) approved Yervoy (ipilimumab) to treat patients with late-stage (metastatic) melanoma, the most dangerous type of skin cancer. Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the United States during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute. “Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient’s life,” said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment." Yervoy is a monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen or CTLA-4. CTLA-4 may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells. Yervoy may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors. The drug is administered intravenously. Yervoy’s safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed. The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone.

Existing Asthma Drug May Prove Useful in Treating Alzheimer’s

A drug used to treat asthma has been shown, in a transgenic mouse model, to help reduce the formation of amyloid beta, a peptide in the brain that is implicated in the development of Alzheimer's disease, according to researchers at Temple University's School of Medicine. The researchers published their findings, "Pharmacologic Blockade of 5-Lipoxygenase Improves the Amyloidotic Phenotype of an AD Transgenic Mouse Model," in the American Journal of Pathology. In previous studies, the Temple researchers discovered that 5-lipoxygenase, an enzyme long known to exist in the brain, controls the activation state of gamma secretase, another enzyme that is necessary and responsible for the final production of amyloid beta. When produced in excess, amyloid beta causes neuronal death and forms plaques in the brain. The amount of these amyloid plaques in the brain is used as a measurement of the severity of Alzheimer's. In the current study, led by Dr. Domenico Praticò, an associate professor of pharmacology in Temple's School of Medicine, the researchers tested the drug Zileuton, an inhibitor of 5-lipoxygenase typically used to treat asthma, in a transgenic mouse model of Alzheimer's disease. At the end of the treatment they found that this drug, by blocking the 5-lipoxygenase, reduced gamma secretase's production of amyloid beta and the subsequent build up of amyloid plaques in the brain by more than 50 percent. Dr. Praticò said that gamma secretase is present throughout the body and, despite its role in the development of amyloid plaques, plays a significant role in numerous important functions. Direct inhibitors of gamma secretase are known, he said, but blocking the enzyme completely may cause problems such as the development of cancer.

Researchers ID Possible Powerful New Colon Cancer Marker

A research team at the University of Colorado Cancer Center has identified an enzyme that could be used to diagnose colon cancer earlier. It is possible that this enzyme also could be a key to stopping the cancer. Colon cancer is the third most common cancer in Americans, with a one in 20 chance of developing it, according to the American Cancer Society. This enzyme biomarker could help physicians identify more colon cancers and do so at earlier stages when the cancer is more successfully treated. The research was led by Dr. Vasilis Vasiliou, professor of molecular toxicology at the University of Colorado School of Pharmacy, and published in the February 11, 2011 issue of Biochemical and Biophysical Research Communications. Dr. Vasiliou’s laboratory specializes in understanding the role of enzymes called aldehyde dehydrogenases in drug metabolism, metabolic diseases, cancer, and normal and cancer stem cells. Dr. Vasiliou’s team studied colon cancers from 40 patients and found a form of aldehyde dehydrogenase known as ALDH1B1 present in every colon cancer cell in 39 out of the 40 cases. The enzyme, which is normally found only in stem cells, was detected at extraordinarily high levels. “Other potential colon cancer biomarkers have been identified in the past, but none thus far are present in such a high percent of the cancer cells and virtually none are overexpressed like this one,” says Dr. David Orlicky, associate professor of pathology at the CU medical school and a member of the research team. This finding is particularly timely as it was recommended recently at the Human Genome 2011 annual meeting that a chemical analysis for biomarkers should always accompany genotyping in early detection of colon cancer, said Dr. Vasiliou, who attended the meeting in Dubai.

Clue to Mechanism by Which Certain Gene Mutations Cause Familial Parkinson’s

Researchers at the Mount Sinai School of Medicine and collaborating institutions have discovered a way that mutations in a gene called LRRK2 may cause the most common inherited form of Parkinson's disease. The study, published online on March 1, 2011, in the journal PLoS ONE, shows that upon specific modification called phosphorylation, LRRK2 protein binds to a family of proteins called 14-3-3, which has a regulatory function inside cells. When there is a mutation in LRRK2, 14-3-3 is impaired, leading to Parkinson's. This finding explains how mutations lead to the development of Parkinson's, providing a new diagnostic and drug target for the disease. Using one-of-a-kind mouse models developed at the Mount Sinai School of Medicine, Dr. Zhenyu Yue, Associate Professor of Neurology and Neuroscience, and his colleagues, found that several common Parkinson's disease mutations—including one called G2019S—disturb the specific phosphorylation of LRRK2. This impairs 14-3-3 binding to varying degrees, depending on the type of mutation. "We knew that the LRRK2 mutation triggers a cellular response resulting in Parkinson's disease, but we did not know what processes the mutation disrupted," said Dr. Yue. "Now that we know that phosphorylation is disturbed, causing 14-3-3 binding to be impaired, we have a new idea for diagnostic analysis and a new target for drug development." Dr. Yue's team also identified a potential enzyme called protein kinase A (PKA), responsible for the phosphorylation of LRRK2. Although the exact cellular functions disrupted by these changes are unclear, the study provides a starting point for understanding brain signaling that contributes to the disease.

Potential Non-Insulin Treatment of Type 1 Diabetes Investigated

Researchers at the University of Texas Southwestern Medical Center have discovered a hormone pathway that potentially could lead to new ways of treating type 1 diabetes independent of insulin, long thought to be the sole regulator of carbohydrates in the liver. Results of this new study are published in the March 25, 2011 issue of Science. Another hormone, fibroblast growth factor 19 (FGF19), has insulin-like characteristics beyond its role in bile acid synthesis. Unlike insulin, however, FGF19 does not cause excess glucose to turn to fat, suggesting that its activation could lead to new treatments for diabetes or obesity. “The fundamental discovery is that there is a pathway that exists that is required for the body, after a meal, to store glucose in the liver and drive protein synthesis. That pathway is independent of insulin,” said Dr. David Mangelsdorf, chairman of pharmacology at UT Southwestern. Naturally elevating this pathway, therefore, could lead to new diabetes treatments outside of insulin therapy. The standard treatment for type 1 diabetes, which affects about 1 million people in the U.S., involves taking insulin multiple times a day to metabolize blood sugar. Dr. Mangelsdorf and Dr. Steven Kliewer, professor of molecular biology and pharmacology at UT Southwestern, are co-senior authors of the study. Dr. Kliewer has been studying the hormone FGF19 since he discovered its involvement in metabolism about eight years ago. Fibroblast growth factors control nutrient metabolism and are released upon bile acid uptake into the small intestine. Bile acids, produced by the liver, break down fats in the body. In this work, researchers studied mice lacking FGF15 – the rodent FGF19 hormone equivalent. These mice, after eating, could not properly maintain blood concentrations of glucose and normal amounts of liver glycogen.