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Archive - Oct 24, 2012


12-Gene Chemokine Signature May Be Associated with Better Survival in Metastatic Melanoma

Researchers at the Moffitt Cancer Center in Tampa, Florida have discovered a unique immune gene signature that can predict the presence of microscopic lymph node-like structures in metastatic melanoma. The presence of these immune structures, the researchers said, appears to be associated with better survival and may indicate the possibility of selecting patients for immunotherapy based solely on the immune-related makeup of their tumors as an approach to personalized medicine. The full text of the study appeared online on October 24, 2012 in Scientific Reports, a journal from the Nature Publishing Group. In this study, the researchers analyzed a 12-chemokine gene expression signature across nearly 15,000 distinct solid tumors of different types, including metastatic melanoma. Chemokines are powerful immune system molecules known to be important in lymph node formation and function during development. The 12-chemokine gene expression signature was found to remarkably predict the presence of microscopic lymph node-like structures within some melanomas and was also associated with better overall survival of these patients. The researchers speculate that the lymph nodal structures they identified are active and playing an important positive role in a self-elicited (endogenous) anti-tumor response – initially locally and then systemically. They also anticipate that their findings in melanoma may extend to other solid tumors, such as those of colorectal, lung, and ovarian origin.

Nobel Prize Winner Discovers New Target for Cancer Research

In a new paper published online on October 24, 2012 in Nature, BioFrontiers Institute scientists at the University of Colorado-Boulder, Drs. Tom Cech and Leslie Leinwand, described a new target for anti-cancer drug development that is located at the ends of our DNA. Researchers in the two scientists' laboratories collaborated to find a patch of amino acids that, if blocked by a drug docked onto the chromosome end at this location, may prevent cancerous cells from reproducing. The amino acids at this site are called the "TEL patch" and once modified, the end of the chromosome is unable to recruit the telomerase enzyme, which is necessary for growth of many cancerous cells. "This is an exciting scientific discovery that gives us a new way of looking at the problem of cancer," Dr. Cech said. "What is amazing is that changing a single amino acid in the TEL patch stops the growth of telomeres. We are a long way from a drug solution for cancer, but this discovery gives us a different, and hopefully more effective, target." Dr. Cech is the director of the BioFrontiers Institute, a Howard Hughes Medical Investigator and winner of the 1989 Nobel Prize in chemistry. Co-authors on the study include postdoctoral fellows Drs. Jayakrishnan Nandakumar and Ina Weidenfeld; University of Colorado undergraduate student Caitlin Bell; and Howard Hughes Medical Institute Senior Scientist Dr. Arthur Zaug. Telomeres have been studied since the 1970s for their role in cancer. They are constructed of repetitive nucleotide sequences that sit at the ends of our chromosomes like the ribbon tails on a bow. This extra material protects the ends of the chromosomes from deteriorating, or fusing with neighboring chromosome ends. Telomeres are consumed during cell division and, over time, will become shorter and provide less cover for the chromosomes they are protecting.

Large-Scale Sequencing Study of Pancreatic Cancer Reveals Genetic Clues

A large-scale study that defines the complexity of underlying mutations responsible for pancreatic cancers in more than 100 patients was published online in Nature on October 24, 2012. The analysis represents the first report from Australia’s contribution to the International Cancer Genome Consortium (ICGC), which brings together the world's leading scientists to identify the genetic drivers behind 50 different cancer types. Pancreatic cancer has the highest mortality rate of all the major cancers and is one of the few for which survival has not improved substantially over the past 40 years. It is the fourth-leading cause of cancer death. Professor Sean Grimmond, from the Institute for Molecular Bioscience (IMB) at The University of Queensland, and Professor Andrew Biankin, from The Kinghorn Cancer Centre at Sydney’s Garvan Institute of Medical Research / St. Vincent's Hospital, led an international team of more than 100 researchers that sequenced the genomes of 100 pancreatic tumors and compared them to normal tissue to determine the genetic changes that lead to this cancer. “We found over 2,000 mutated genes in total, ranging from the KRAS gene, which was mutated in about 90 per cent of samples, to hundreds of gene mutations that were only present in 1 or 2 per cent of tumors,” Professor Grimmond said. “So while tumors may look very similar under the microscope, genetic analysis reveals as many variations in each tumor as there are patients. This demonstrates that so-called ‘pancreatic cancer’ is not one disease, but many, and suggests that people who seemingly have the same cancer might need to be treated quite differently.” Professor Biankin said such individual genetic diagnoses and treatments represent the future of healthcare.

Scientists ID Two Receptor Families Used by Dengue Virus to Penetrate Cells

By demonstrating that it is possible to inhibit viral infection in vitro by blocking the bonding between the Dengue virus and TIM and TAM receptors, researchers have opened the way to a new antiviral strategy. Their work was published online in Cell Host & Microbe on October 18, 2012. The Dengue virus circulates in four different forms (four serotypes). It is transmitted to humans by mosquitoes. It is a major public health problem. Two billion people throughout the world are exposed to the risk of infection and 50 million cases of Dengue fever are recorded by the WHO every year. The infection is often asymptomatic, or causes influenza-like symptoms, but its most serious forms can lead to fatal haemorrhagic fevers. At present, there is no preventive vaccine or efficient antiviral treatment for these four Dengue serotypes. So it is of vital importance that new therapeutic strategies be developed. Ali Amara's team at INSERM, together with colleagues, performed genetic screening in order to identify cell receptors used by the virus to penetrate target cells. The researchers have determined the important function played by the TIM receptors (TIM-1, 3, 4) and TAM receptors (AXL and TYRO-3) in the penetration process of the four Dengue serotypes. Mr. Amara's team has succeeded in demonstrating that the expression of these two receptor families makes cells easier to infect. In addition, the researchers observed that interfering RNA or antibodies that target the TIM and TAM molecules considerably reduced the infection of the cells targeted by the Dengue virus. The TIM and TAM molecules belong to two distinct families of transmembrane receptors that interact either directly (TIM) or indirectly (TAM) with phosphatidylserine, an "eat-me" signal that allows the phagocytosis and the elimination of these apoptopic cells.

New T Cell Treatment Targets Advanced Melanoma in Mouse Model

Cancers arise in the body all the time. Most are nipped in the bud by the immune response, not least by its T cells, which detect telltale molecular markers—or antigens—on cancer cells and destroy them before they grow into tumors. Cancer cells, for their part, evolve constantly to evade such assassination. Those that succeed become full-blown malignancies. Yet, given the right sort of help, the immune system can destroy even these entrenched tumors. In the October 22, 2012 issue of the Journal of Experimental Medicine, researchers led by Jedd Wolchok, M.D., Ph.D., of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York describe one way in which that might be achieved. The paper relates how the cancer drug cyclophosphamide (CTX) and OX86—an antibody that activates a molecule named OX40 on T cells—were combined with a cutting-edge therapy known as adoptive T cell transfer to eradicate advanced melanoma tumors in mice. Dr. Wolchok and his colleagues had previously shown that CTX and OX86 treatment caused the regression of such tumors. Now they wanted to see if adding T cell transfer to the mix would further improve outcomes. T cell transfer is an investigative immunotherapy in which T cells that target tumors are isolated from patients, manipulated, expanded, and then transfused back into those patients. A variety of T cells are of relevance to this approach. One is the CD8+ T cell, which can directly kill diseased and cancerous cells. Another is the CD4+ T cell, whose general role is to orchestrate the immune assault. It comes in several varieties — examples are the T helper 1 (Th1) and T helper 2 (Th2)—each of which elicits a distinct sort of immune response. And then there is the regulatory T cell, which keeps a lid on the last two responses.