A Research Strategy for Rare Cancers

Researchers at St. Jude Children's Research Hospital have developed a strategy to identify drugs showing promise against rare cancers, and they've used that strategy to find drugs that are likely to be effective against ependymoma, a rare, treatment-resistant brain tumor. The search for treatments against rare cancers is often done by testing hit-or-miss treatments – a situation that is problematic, but especially in rare cancers, where getting enough patients for a clinical trial is difficult. In their paper, the authors described using a combination of high-throughput screening, kinomewide binding assays and in vivo efficacy studies to identify several potential approaches to treating ependymoma – including 5-fluorouracil, which is a workhorse chemotherapy but had not been tested in this particular cancer and, as an early generation cancer drug, would not likely be formally tested in a clinical trial. The authors said that beyond its specific implications for ependymoma, "the approach described here should significantly advance the efficiency and speed with which we discover and develop treatments for rare cancers and cancer subtypes." The findings appeared in the Sept. 13, 2011, Cancer Cell.

Same or Different?

Induced pluripotent stem cells may offer the versatility of embryonic stem cells without the ethical issues. Or, may not. Trying to answer that question, researchers from the University of Wisconsin at Madison compared the entire protein expression profiles of both cells by using mass spectrometry to compare four embryonic stem cell lines to four iPS cell lines. Overall, both cell types were quite similar, and in some measurements, there were greater differences between different ES cell lines than between a given ES cell and iPS cell line. But the authors found what they called "subtle but reproducible" differences between ES and iPS cells overall, often at the level of their regulation – some proteins, for example, were expressed in similar amounts but showed different levels of phosphorylation, which would lead to different activity levels in cells. The authors concluded, "iPSCs retain residual regulation characteristic of the cells from which they were derived," although they also noted that considerable technical rigor was necessary to detect even the minor differences their study uncovered. Their work appeared in the Sept. 11, 2011, online issue of Nature Methods, and they have created a Stem Cell-Omics Repository, or SCOR, website and public database.

Blood Pressure Risk Genes Discovered

More than a billion people worldwide suffer from high blood pressure, and that makes them all more susceptible to heart disease and stroke. Two groups of scientists, one from the International Consortium for Blood Pressure Genome-Wide Association Studies and one from the University of Leicester, published two studies last week that identified 16 new risk variants for high blood pressure and confirmed another 12 previously identified genes. The authors calculated an overall risk score for each individual based on their pattern of SNPs, and found that higher risk scores were significantly correlated with blood pressure-related organ damage and clinical cardiovascular disease, but not kidney disease. For their studies, the authors looked mainly at individuals of European descent. But they did confirm several risk variants in populations of East Asian, South Asian and African descent, and found that the variants affecting blood pressure were, by and large, similar across different ethnic groups. The papers appeared in the Sept. 11, 2011, online editions of Nature and Nature Genetics, respectively.

Killing Two Addictions with One Kinase

Smoking and alcohol addiction are frequently a package deal, and abstaining alcoholics smoke at a higher rate than the general population, partly because many subjectively feel that smoking helps them stay off booze – although it should be noted that in animal studies, smoking increases alcohol consumption. But whatever the details, nicotine and alcohol addiction seem to share underlying mechanisms. Now, researchers at the Ernest Gallo Clinic and Research Center, which is affiliated with the University of California at San Francisco, have identified an enzyme, protein kinase C epsilon, that might be a target for treating both addictions. The authors found that PKC epsilon knockout mice did not appear to get addicted to nicotine-containing water, as normal mice will. They also did not show a preference for areas of their cage where they had gotten alcohol. The kinase appeared to affect dopamine signaling in reward areas of the brain. The authors concluded that PKC epsilon "could be a target for the treatment of comorbid nicotine and alcohol addictions." Their work appeared in the Sept. 12, 2011, early online edition of the Proceedings of the National Academy of Sciences.

Osteoblasts: Not Seeding Their Own Destruction?

Bone is alone among the organs in that it has a cell dedicated to its constant destruction: osteoclasts, which destroy bone and act in concert with bone-building osteoblasts to control overall bone mass. Osteoclasts become activated through a signaling molecule called RANK ligand, or RANKL, and osteoblasts conveniently produce such RANKL, so scientists have assumed that the osteoblast-produced RANKL is what activates osteoclasts. But two separate research teams, one from the University of Arkansas and one from the Japanese Tokyo Medical and Dental University, showed that another cell type actually produces most of the RANKL that leads to osteoclast formation. By selectively deleting the RANKL gene from different cell types, the authors were able to show that, in mice, when osteoblasts do not produce RANKL, osteoclasts still formed. But when two other cell types, chondrocytes and osteocytes, could not produce RANKL, the mice soon developed osteopetrosis, or excessive bone. Both studies appeared in the Sept. 11, 2011, issue of Nature Medicine.

Cellular Detour Could Solve CF Problem

Cystic fibrosis most often stems from a point mutation in a chloride channel; ironically, the channel still works, but cells are unable to transport it to the surface, making the issue of whether it works a moot point until now. Last week, however, researchers from the Korean Yonsei University School of Medicine reported that they were able to get cells to transport the defective protein to the cell surface via an alternate route, the so-called GRASP pathway. Transgenic mice with the mutated version of the chloride channel have intestinal disease, retarded growth and usually die before a year of age; but those symptoms could be greatly improved in animals that also overexpressed GRASP protein. The findings, the authors wrote, "offer a potential therapeutic strategy for the treatment of cystic fibrosis and perhaps diseases stemming from other misfolded proteins." Their work was published in the Sept. 8, 2011, issue of Cell.

Cutting Trauma's Second Act

In the U.S., and many other developed nations, trauma, or serious injury due to either violence or an accident, is the leading cause of death in those younger than 45. Only about half of all trauma deaths, though, are due to blood loss or direct organ damage that is too great to survive. The other half occur later, due to infections and septic shock that ultimately lead to organ failure. There currently is no good way to predict who is at risk for late complications of trauma. But scientists from Princeton University found a gene expression signature that may help identify such at-risk patients. The team looked at the changes in gene expression over the course of four weeks in nearly 170 patients after they experienced blunt-force trauma, and identified several genes whose expression levels changed soon after the initial accident in patients that later developed late-term complications. The authors hope their findings will prove useful in identifying both patients at risk for trauma complications and therapeutic targets for preventing such complications. Their work appeared in the Sept. 13, 2011, online edition of PLoS Medicine.

Approved Drugs May Fight Prions . . .

Researchers from New York University identified several compounds showing early stage promise against prion diseases, which currently have no effective treatments. The scientists first screened several groups of compounds in cell culture and found they decreased the levels of misfolded prion proteins in cell lines. Some of the compounds were chosen because previous work had shown they cross the blood-brain barrier easily and bind to amyloid plaques, which also are aggregated proteins and whose structures are likely to be similar to clumped prion proteins; others were chosen for their similarity to a drug that can bind prion proteins, though it does not protect animals or humans from prion disease. In mice, all four compounds prolonged the asymptomatic period of prion infection and lessened cell damage even once symptoms occurred. The authors concluded that "these four compounds can be considered, with further development, as candidates for prion therapy." Two of the drugs, the antidepressant trimipramine and the antipsychotic fluphenazine, already are FDA-approved. The experiments were published in the Sept. 13, 2011, online edition of PLoS ONE.

. . . And Cancer-Associated Epilepsy

Patients with brain tumors frequently suffer from seizures, and researchers from the University of Alabama at Birmingham have discovered both how those seizures develop and how they might be treated. The seizures develop because tumor cells secrete large amounts of the excitatory neurotransmitter glutamate, and they apparently do so via a cysteine-glutamate transporter that imports cysteine into the tumor cells and exported glutamate. Chronic hyperstimulation of neurons next to the tumor cells led to abnormal activity and, ultimately, epilepsy. The team treated the mice with the drug sulfasalazine, which blocks the transporter and is used to treat rheumatoid arthritis and Crohn's disease. At doses equivalent to those used in Crohn's therapy, the drug reduced the number of seizures that mice with gliomas had. The authors suggested that sulfasalazine "should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma in humans." The work appeared in the Sept. 11, 2011, issue of Nature Medicine.

– Anette Breindl, Science Editor