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Archive - Oct 22, 2011

Coupling of Two Proteins Promotes Glioblastoma Development

Two previously unassociated proteins known to be overly active in a variety of cancers bind together to ignite and sustain malignant brain tumors, a research team led by scientists at The University of Texas MD Anderson Cancer Center reports in the cover story of the October 18, 2011 issue of Cancer Cell. This research is the first to connect FoxM1 to a molecular signaling cascade that regulates normal neural stem cells, said senior author, Dr. Suyun Huang, associate professor in MD Anderson's Department of Neurosurgery. "When FoxM1 binds to beta-catenin, we found that it also supports the self-renewal and differentiation of glioma- initiating cells, cancer stem cells thought to drive glioblastoma multiforme," Dr. Huang said. Glioblastoma multiforme is the most common and lethal form of brain tumor. Glioma- initiating cells are prime suspects in the disease's resistance to treatment and ability to reoccur. The scientists established the relationship between FoxM1 and beta-catenin in a series of cell line experiments and then confirmed their findings in mouse models of human glioblastoma and in an analysis of human tumors. FoxM1 and beta-catenin separately have so far largely evaded targeting by drugs. Dr. Huang and her team are focusing on the details of the connection between the two proteins in search of small molecules that might block their binding. "Our study might lead to the development of a new class of small-molecule anti-cancer drugs, including but not necessarily limited to glioblastoma multiforme," Dr. Huang said. Much preclinical work remains to be done before such a drug can be identified and brought to clinical trial. FoxM1 was previously known solely as a transcription factor – a protein that binds to the DNA in a gene's promoter region to prompt the gene's expression of messenger RNA that is processed into a protein.

Common 3-Drug Regimen for Idiopathic Pulmonary Fibrosis Found Harmful

The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, has stopped one arm of a three-arm multi-center, clinical trial studying treatments for the lung-scarring disease idiopathic pulmonary fibrosis (IPF) for safety concerns. The trial found that people with IPF receiving a currently used triple-drug therapy consisting of prednisone, azathioprine, and N-acetylcysteine (NAC) had worse outcomes than those who received placebos, or inactive substances. "These findings underscore why treatments must be evaluated in a rigorous manner," said Dr. Susan B. Shurin, acting director of the NHLBI. "This combination therapy is widely used in patients with IPF, but has not previously been studied in direct comparison to a placebo for all three drugs." The interim results from this study showed that compared to placebo, those assigned to triple therapy had greater mortality (11 percent versus 1 percent), more hospitalizations (29 percent versus 8 percent), and more serious adverse events (31 percent versus 9 percent) and also had no difference in lung function test changes. Participants randomly assigned to the triple- therapy arm also remained on their assigned treatment at a much lower rate (78 percent adherence versus 98 percent adherence). "Anyone on some combination of these medications with questions or concerns should consult with their health care provider and not simply stop taking the drugs," said Dr. Ganesh Raghu, professor of medicine at the University of Washington, Seattle, and a co-chair of this IPF study.

CK1 Enzyme May Be New Target for the Treatment of Cancer

Researchers from the New York University (NYU) Cancer Institute, a National Cancer Institute (NCI)-designated cancer center at NYU Langone Medical Center, and collaborators have identified a cell cycle-regulated mechanism behind the transformation of normal cells into cancerous cells. The study shows the significant role that protein networks can play in a cell leading to the development of cancer. The study results, published in the October 21, 2011 issue of the journal Molecular Cell, suggest that inhibition of the CK1 (casein kinase 1) enzyme may be a new therapeutic target for the treatment of cancer cells formed as a result of a malfunction in the cell's mTOR signaling pathway. In the study, NYU Cancer Institute researchers examined certain multi-protein complexes and protein regulators in cancer cells. Researchers identified a major role for the multi-protein complex called SCFβTrCP . This complex assists in the removal from cancer cells of the recently discovered protein DEPTOR, an inhibitor of the mTOR (mammalian Target of Rapamycin) pathway. SCF (Skp1, Cullin1, F-box protein) ubiquitin ligase complexes are responsible for the removal of unnecessary proteins from a cell. This degradation of proteins by the cell's ubiquitin system controls cell growth and prevents malignant cell transformation. Researchers show that inhibiting the ability of SCFβTrCP to degrade DEPTOR in cells can result in blocking the proliferation of cancer cells. In addition, researchers discovered that the activity of CK1, a protein that regulates signaling pathways in most cells, is needed for SCFβTrCP to successfully promote the degradation of DEPTOR. "Low levels of DEPTOR and high levels of mTOR activity are found in many cancers, including cancers of the breast, prostate, and lung," said senior study author Dr.