
JACKSONVILLE, Fla. — June 20, 2012. A molecule widely believed to fight many forms of cancer actually helps deadly thyroid tumors grow, and cancer therapies now being tested in humans might boost the activity of this newly revealed bad guy, researchers at Mayo Clinic in Florida say. Their findings are published online this month in the Journal of Cell Science. The study found that in anaplastic thyroid cancer, the Forkhead transcription factor, FOXO3a, is not the helpful tumor suppressor everyone thought it was, but, instead, is a lethal promoter of tumor growth. When FOXO3a was silenced in laboratory models of human anaplastic thyroid cancer, the cells grew slowly, but when it was added, they grew much faster. "This result is exactly the opposite of what we expected," says senior author John A. Copland, Ph.D., a Mayo cancer biologist. "We were more than surprised. We were concerned." FOXO3a is known as a suppressor of tumor growth because it responds to all forms of cell stress, including that produced in cancer, by turning on genes inside the nucleus that trigger the cell's death. Cancer, in turn, is known to shut down FOXO3a by sending it out of the nucleus and into the cell's cytoplasm, where it is degraded. The molecule that ships FOXO3a out of the nucleus is Akt, which tries to keep cancer cells alive. The research team used an Akt blocker — similar to the ones now being used in human cancer clinical trials — expecting to increase nuclear FOXO3a and suppress cancer growth in anaplastic thyroid cancer. They were trying to find a treatment for one of the deadliest known cancers, which accounts for just 2 percent of thyroid cancer cases in the U.S. but is responsible for about 40 percent of thyroid cancer deaths. "The issue we are grappling with is that there are no effective treatments for this cancer. These tumors are so aggressive because there are so many genetic abnormalities," says study co-author Robert Smallridge, M.D., a Mayo endocrinologist who treats thyroid cancer patients. "We are studying what drives this cancer and how it can be treated." The study showed that FOXO3a remained in the nucleus, with the use of an Akt inhibitor, and that instead of helping to kill cancer cells, FOXO3a was accelerating their growth. This raises concern about the use of Akt inhibitors since one of the mechanisms is to cause FOXO3a to remain active in the nucleus. "We discovered a biological switch that turns FOXO3a from a good guy into a bad actor, but we don't know what that is yet, or in which cancers that might happen," says lead researcher Laura Marlow, a Mayo biologist. "Cancer researchers, including those testing Akt inhibitors, should know that FOXO3a has pro-cancer activity as well as anti-cancer properties," Dr. Copland says. "Concern should be raised that an Akt inhibitor will enhance retention of FOXO3a in the nucleus, causing FOXO3a to remain active.
JACKSONVILLE, Fla. — June 6, 2012. Using a new and powerful approach to understand the origins of neurodegenerative disorders such as Alzheimer's disease, researchers at Mayo Clinic in Florida are building the case that these diseases are primarily caused by genes that are too active or not active enough, rather than by harmful gene mutations. VIDEO ALERT: Video resources of Nilufer Ertekin-Taner, M.D., Ph.D., discussing the study are available here. In the June 7 online issue of PLoS Genetics, they report that several hundred genes within almost 800 brain samples of patients with Alzheimer's disease or other disorders had altered expression levels that did not result from neurodegeneration. Many of those variants were likely the cause. "We now understand that disease likely develops from gene variants that have modest effects on gene expression, and which are also found in healthy people. But some of the variants — elevating expression of some genes, reducing levels of others — combine to produce a perfect storm that leads to dysfunction," says lead investigator Nilufer Ertekin-Taner, M.D., Ph.D., a Mayo Clinic neurologist and neuroscientist. "If we can identify the genes linked to a disease that are too active or too dormant, we might be able to define new drug targets and therapies," she says. "That could be the case for both neurodegenerative disease as well as disease in general." Dr. Ertekin-Taner says no other lab has performed the extent of brain gene expression study conducted at Mayo Clinic's Florida campus. "The novelty, and the usefulness, of our study is the sheer number of brain samples that we looked at and the way in which we analyzed them. These results demonstrate the significant contribution of genetic factors that alter brain gene expression and increase risk of disease," she says. This form of data analysis measures gene expression levels by quantifying the amount of RNA produced in tissue and scans the genome of patients to identify genetic variants that associate with these levels. Mayo researchers measured the level of 24,526 transcripts (messenger RNA) for 18,401 genes using cerebellar autopsy tissue from 197 Alzheimer's disease patients and from 177 patients with other forms of neurodegeneration. The researchers then validated the results by examining the temporal cortex from 202 Alzheimer's disease patients and from 197 with other pathologies. The difference between these samples is that while the temporal cortex is affected by Alzheimer's disease, the cerebellum is relatively spared. From these analyses, the researchers identified more than 2,000 markers of altered expression in both groups of patients that were common between the cerebellum and temporal cortex. Some of these markers also influenced risk of human diseases, suggesting their contribution to development of neurodegenerative and other diseases regardless of their location in the brain. They identified novel expression "hits" for genetic risk markers of diseases that included progressive supranuclear palsy, Parkinson's disease, and Paget's disease, and confirmed other known associations for lupus, ulcerative colitis, and type 1 diabetes. "Altered expression of brain genes can be linked to a number of diseases that affect the entire body," Dr. Ertekin-Taner says.
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