Finally, a Way to Drug KRAS
Roughly a third of all tumors have mutations in the protein RAS, but attempts to drug the enzyme have so far been unsuccessful. Now, a team from the University of California at San Francisco has identified small molecules that can bind one particular mutant of KRAS. That mutant has a cysteine in place of a glycine, and the molecules bound to the cysteine, which means they should not affect the wild-type protein. While the compounds reported in the current study did not completely block signaling and so would not be suitable as drugs, the authors said that “on the basis of these data and our understanding of the biochemical mechanism of the inhibitors, we are confident that our findings can serve as the starting point for drug-discovery efforts” targeting KRAS. The findings were published in the Nov. 22, 2013, issue of Nature.
Cilia Again Linked to Obesity
Researchers from the Mount Sinai School of Medicine and the Israeli Clalit Health Services Group have identified a recessive mutation that leads to morbid obesity in individuals with two copies. The mutation is in the gene for the ciliary protein CEP19. The authors identified the mutation by sequencing an Israeli family prone to morbid obesity. They confirmed the gene’s effects in animal studies. Knockout mice lacking the gene were also morbidly obese and had impaired insulin signaling and metabolic syndrome. The results are the third findings linking ciliary proteins to obesity, though the molecular underpinnings of the link remain unclear, partly due to the fact that the functions of cilia themselves are only beginning to be understood. The authors published their study in the Nov. 21, 2013, online edition of the American Journal of Human Genetics.
Pseudogenes May Just Be Genes
Researchers from the Swedish Karolinska Institutet have developed a new method to identify parts of the genome that make proteins, and they used it to identify almost 100 new protein-coding loci in the human genome, as well as several dozen in the mouse genome. Less than 2 percent of the human genome appears to code for proteins, with the rest being partly dedicated to regulatory functions and partly having no identified function yet. Many of the new protein-coding sequences are parts of so-called pseudogenes, which were thought to not code for proteins. Beyond the specific proteins the authors identified, their method allows the identification of protein-coding sequences throughout entire large genomes. The authors said they hope it will be broadly applicable to identify protein-coding sequences in organisms with large genomes without having to first winnow down candidate regions. Their findings appeared in the Nov. 17, 2013, issue of Nature Methods.
Mice Like It Hot, Tumors Like It Cool
Scientists at the Roswell Park Cancer Institute have shown that the standard temperature in animal colonies impairs the ability of mice to fight off tumors, systematically biasing the results of studies on the immune system and cancer. The National Research Council’s (NRC’s) official Guide for the Care and Use of Laboratory Animals requires mice to be housed at temperatures between 20 and 26 degrees Celsius, which is below the thermoneutral range, meaning that mice have to use energy to keep their body temperature at a normal levels. In their work, the authors compared animals housed at the temperatures required by the NRC to those housed at a thermoneutral temperature, namely, 30 to 31 degrees. They found that xenografted tumors grew more slowly in immunocompetent (but not immunosuppressed) mice housed under thermoneutral conditions, and that such animals had fewer immunosuppressive cells and more killer T cells. The authors said their findings both “underscore the fact that investigating mouse models under a single set of environmental temperature conditions may lead to a misunderstanding of the antitumor immune potential” and “highlight the need for additional study to determine how systemic metabolic stress modulates the functions of immune effector cells, particularly in tumor-bearing mice, and whether cancer therapies, including immunotherapy, are impacted by housing temperature.” They were published in the Nov. 18, 2013, issue of the Proceedings of the National Academy of Sciences.
Flu Mutates All the Time, but Not Everywhere
Researchers from the Dutch Erasmus Medical Center and the British University of Cambridge have shown that over the 35 years from 1968 to 2003, most changes in the hemagglutinin protein of the flu virus that led to antigenic drift occurred in only seven amino acids, all of them near the HA protein’s receptor binding site. Hemagglutinin is one of the two proteins that determines the antibody response to a given strain. To date, it is necessary to develop a new flu vaccine every year by predicting which of many circulating strains are likely to become an issue during the next flu season. The findings suggest that such predictions can focus heavily on a few amino acids. They were published in the Nov. 22, 2013, issue of Science.
MiR Blocker Raises Good Cholesterol
A team including scientists from Santaris Pharma A/S has demonstrated that blocking an entire family of microRNAs (miRNAs) using antimir technology improved the levels of HDL “good” cholesterol in obese monkeys, and was safe over a period of more than three months. MiRNAs have been implicated in many diseases, but targeting them has been challenging because there are many miRNAs that share a core targeting sequence but are otherwise different from each other. The authors had previously shown that it was possible to knock down an entire family by targeting its shared core sequence. In follow-up experiments, they showed that pharmacologically blocking the miR-33 family increased expression of the genes normally inhibited by miR-33 and improved the blood fat profile in obese and insulin-resistant monkeys. The authors published their results in the Nov. 21, 2013, issue of Science Translational Medicine.
Predicting – and Preventing – Relapse
Scientists from the Mayo Clinic have gained new insights into the factors driving relapse at a cellular level. Many patients end their cancer treatment with minimal residual disease – microscopic tumors that are too small to be detected, but can survive for years or even decades before causing a full-blown relapse. The authors monitored mice with transplanted tumors to see whether there were molecular warnings when a tumor was close to recurrence. They found that such tumors stimulated a substantial innate immune response, and tumors that recurred did so because they were able to evade that immune response. The authors also found that if they promoted recurrence by administering vascular endothelial growth factor (VEGF) to mice with minimal residual disease, the animals responded significantly better to both first-line treatments and oncolytics than animals that were already in full-blown recurrence when treatment began. “These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment,” the authors wrote. Their work appeared in the Nov. 17, 2013, issue of Nature Medicine.
Kinase Activity Differs Between, Not Within, CRPC
Researchers from the University of California at Los Angeles have shown that patients with metastatic castration-resistant prostate cancer (CRPC) follow the “Anna Karenina” principle: they are each unhappy in their own way. The authors looked at the pattern of phosphorylation in soft tissue metastases in autopsy tissues of patients who died from metastatic CRPC, as well as primary tumors before any treatment and cell line-derived xenografts. They found that while kinase activation patterns were different from patient to patient, they tended to be the same across different metastases in the same patient, suggesting that the origin of the tumor played a bigger role than the organ microenvironment of the metastases. They also found that xenografted cell lines had a very different kinase activation pattern from primary tumors. “The observation that similar kinase activities are present in most if not all anatomically disparate metastatic lesions from the same patient suggests that CRPC patients may benefit from individualized, targeted combination therapies,” the authors said. Their work appeared in the Nov. 18, 2013, advance online edition of the Proceedings of the National Academy of Sciences.
Take Two Ibuprofen and Remember My Number
Researchers at Louisiana State University Health Science Center have shown that the memory effects of medical marijuana are due to the activation of the enzyme COX-2. Marijuana is used medically, and its active ingredient, tetrahydrocannabinol (THC), is being developed for therapeutic purposes. But among its side effects are memory problems. In their work, the authors showed that treatment with THC activated COX-2 in synapses, and that activation led to the removal of glutamate receptors, which are important for the formation and storage of new memories. Blocking COX-2 prevented THXC’s effects on memory. The authors said that “these results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.” COX-2 is inhibited by the generic painkiller ibuprofen. The findings appeared in the Nov 21, 2013, issue of Cell.
Woolly Mammoth Bacteria?
Researchers from the Danish University of Copenhagen and the Norwegian University of Tromso have shown that bacteria can take up and incorporate DNA sequences from dead and even extinct organisms, which may be a heretofore unrecognized form of bacterial evolution. Short sequences of often-damaged DNA are ubiquitous in the environment, as they are released from dying cells and organisms. In their studies, the researchers showed that sequences from woolly mammoth bone – a species that has been extinct for tens of thousands of years – were taken up by the bacterium Acinetobacter baylyi. The authors concluded that “damaged and degraded DNA may be a previous unrecognized driver of bacterial evolution with implications for evolutionary theory.” Their work appeared in the Nov. 18, 2013, issue of the Proceedings of the National Academy of Sciences.
– Anette Breindl, Science Editor