Immunized from bad memories

A team from Virginia Commonwealth University has shown that treating mice with the multiple sclerosis drug Gilenya (fingolimod, Novartis AG) helped them to forget fearful memories. In the treatment of multiple sclerosis, Gilenya appears to work by influencing immune cell trafficking. But it is becoming increasingly clear that Gilenya has a variety of effects in the central nervous system. In their studies, the authors showed that the activated form of Gilenya is a histone deacetylase (HDAC) inhibitor, and that when mice were treated with the drug, it accumulated in brain areas important for learning and memory. And, through effects on HDACs, affected gene expression programs that are tied to learning. Such animals had deficits in some types of learning, and were more easily able to forget fear-associated memories, suggesting that Gilenya's activated form "may be a useful adjuvant therapy to facilitate extinction of aversive memories." The findings appeared in the May 25, 2014, issue of Nature Neuroscience.

Kinky antibodies more stable

On evolutionary timescales, sharks were the first organisms to develop antibodies. And those antibodies are especially stable, because sharks have high levels of urea in their bloodstream to prevent osmotic water loss. Urea, in turn, tends to denature proteins, and so shark blood proteins are more stable than those of evolutionary latecomers. Now, researchers at the St. Jude Children's Research Hospital have gained structural insights into those antibodies, and used those insights to engineer human antibodies for increased stability and secretion efficiency. Shark antibodies lacked the hinge region of human antibodies, relying instead on a kink to position its different domains. The researchers published their work in the May 19, 2014, issue of the Proceedings of the National Academy of Sciences.

Organoids recapitulate driver mutations

Scientists from Stanford University have reported that organoid cultures of different gastrointestinal tumors accurately modeled what is known about cancer progression in the organs they were meant to model. Organoids, 3-D miniature models of organs containing multiple tissue types, have been developed in the hopes of combining biological realism with the ease of access that in vitro systems can offer. In their work, the authors set out to put that biological realism to the test. They found that when they compared the effects of mutations on organoids developed from colon, stomach and pancreas, the mutations that were necessary to lead to uncontrolled growth of the tissues in vitro and tumor formation in vivo mirrored those that have been seen clinically for the respective tumor types. The authors concluded that "these studies demonstrate the general utility of a highly tractable primary organoid system for cancer modeling and driver oncogene validation in diverse gastrointestinal tissues." Their work appeared in the May 25, 2014, issue of Nature Medicine.

Drugging Myc

In order to fuel their relentless growth, cancer cells need to increase not only the amount of proteins they synthesize, but also the amount of DNA and RNA nucleotides. Researchers from the University of California at San Francisco have discovered an enzyme that couples the rate of both processes, and is controlled by the oncogene Myc. The enzyme, phosphoribosyl-pyrophosphate synthetase 2 (PRPS2), was not critical for cellular function in normal cells. But in cells overexpressing Myc, it coordinated protein and nucleic acid synthesis. In Myc-overexpressing cells, blocking PRPS2 was a synthetic lethal, driving the cells to apoptosis. Myc-driven tumors could not be initiated or maintained if PRPS2 was silenced in inducible knockout mice. "Together, these studies identify a translationally anchored anabolic circuit critical for cancer cell survival and an unexpected vulnerability for 'undruggable' oncogenes, such as Myc," the authors summarized. Their work appeared in the May 22, 2014, issue of Cell.

Keeping insulin around

Logic suggests that raising insulin levels through stabilizing insulin should lead to improved glucose control. But in practice, mice lacking IDE, the enzyme that degrades insulin, have impaired glucose control. Now, scientists from Harvard University have developed a pharmacological IDE inhibitor that they used to probe IDE's role more specifically than knockout mice could. In their studies, they showed that in both lean and obese mice, IDE regulated not just insulin, but also glucagon and amylin, two hormones that control blood sugar levels. When mice were fed glucose, acute treatment with IDE improved their blood sugar levels. "These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type 2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation," the authors concluded. Their work appeared in the May 22, 2014, issue of Nature.

Liver has immune system role

The liver is thought of as mainly a metabolic organ, detoxifying the bloodstream from its owners various vices. But scientists from the Swiss University of Bern have discovered that it also serves to keep gut bacteria in check. Blood exiting the gut circulation passes through the liver, and the authors showed that as it does so, commensal microbes that have hitched a ride are cleared in the liver by immune system cells. In animal models of liver damage, such clearance was impaired, leading to an increased immune response to commensals. The team noted that "liver disease is markedly increasing in incidence in the developed world, secondary not only to alcohol abuse and viral infections but also to progressive hepatic fatty changes and damage arising from metabolic syndrome," and so "understanding the impact of liver function and dysfunction on host-microbial mutualism is highly relevant to human health." They reported their discoveries in the May 22, 2014, issue of Science Translational Medicine.

Targeting oncogenic drivers in lung cancer

Researchers from the Memorial Sloan-Kettering Cancer Center have investigated the clinical benefit of testing lung cancer patients for the genetic makeup of their tumors and selecting targeted therapies accordingly. Their study has also brought important insights into the frequency of different driver mutations in lung cancer, and the conduct of clinical trials. The authors tested the tumors of roughly 1,000 lung cancer patients for the presence of different oncogenic mutations, and treated them with targeted therapy where it was available for the driver mutations they identified, either in the form of FDA-approved medications or in clinical trials. Individuals who received such targeted treatments lived longer than those receiving only chemotherapy, though the authors cautioned that "randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival." The work also showed that multicenter trials are both feasible and efficient to test drugs for diseases that are due to many different mutations occurring in a few percent of patients each. The study appeared in the May 21, 2014, online edition of the Journal of the American Medical Association.

How prostate cells get MIFed

The relationship between human papillomavirus and cervical cancer is more famous, but prostate cancer, too, is associated with a sexually transmitted infection – in this case, by the parasite trichomonas vaginalis. Now researchers from the University of California at Los Angeles have deciphered the molecular link between t. vaginalis infection and aggressive prostate cancer. In their studies, the authors showed that t. vaginalis produced a secreted protein that had similarities to the human protein, macrophage migration inhibitory factor (MIF). Exposure to the t. vaginalis MIF led to increased proliferation and migration of prostate cancer cells, as well as increased inflammation in prostate tissue. "This study demonstrates that a specific parasite-derived protein can mimic its human homolog to increase inflammation and cell proliferation, which, in turn, may result in the promotion and progression of prostate cancer," the authors said. The work appeared in the May 19, 2014, online edition of the Proceedings of the National Academy of Sciences.

Stroma's good points

Tumor stroma, which makes up the bulk of many tumors, but is not made of the actual tumor cells themselves, provides a support system to tumor cells. But two separate research teams, one from the M.D. Anderson Cancer Center and one from Columbia University and the University of Pennsylvania, have demonstrated that stroma also plays a restraining role in pancreatic cancer. Both teams found that when they blocked the formation of stromal cells, pancreatic cancers grew more quickly and were more aggressive. Specifically, the effect appeared to be due to a lack of sonic hedgehog (Shh), giving new insights into the function of this protein and providing a possible explanation for the failure of Shh antagonists in clinical trials. (See BioWorld Today, Jan. 30, 2012.) The work "underscores the need for caution" in stroma targeting. The papers appeared back to back in the May 22, 2014, issue of Cancer Cell.

No ESKAPE from new antibacterial

Researchers from the Canadian University of British Columbia have developed a peptide that could block signaling important for biofilm formation. When bacteria band together in biofilms, they become resistant to many antibiotics, and biofilms cause roughly two-thirds of all human infections and are prominent on medical devices, as well as in chronic infections. In their studies, the team screened for peptides with anti-biofilm activity and showed that the immunomodulatory protein IDR1018 had such anti-biofilm activity. The peptide was active against the ESKAPE pathogens, (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species), which the authors said have been "identified by the Infectious Diseases Society of America as the most recalcitrant and resistant organisms in our society. The strategy presented here represents a significant advance in the search for new agents that specifically target bacterial biofilms. The authors said their work "represents a new approach against biofilm-related drug resistance." They published their study in the May 22, 2014, issue of PLoS Pathogens.

By Anette Breindl, Science Editor