Moneyball for drugs

The PrOCTOR score, a composite score taking into account multiple features of drug candidates and their targets, could be used to predict whether a drug was likely to fail in clinical trials for efficacy reasons. Guidelines for which properties make chemicals drug-like, such as Lipinski's Rule of Five, have improved toxicity predictions, but they are collectively error-prone in their prediction of both toxicity and tolerability. Researchers from Weill Cornell Medical College used characteristics of both drugs and targets to come up with the PrOCTOR (predicting the odds of clinical trial outcomes) score, which consists of "10 molecular properties, 34 target-based properties and four drug-likeness rule features." The authors said the approach "has the potential to impact the preclinical drug development pipeline by quantifying how likely a given compound is to have manageable toxicity in clinical trials. . . . PrOCTOR may also help flag drugs for increased post-approval surveillance of adverse effects and toxicity. Perhaps even more importantly, the model will help design better drugs by providing insights about how various chemical and target-based properties can contribute to or help avert toxicity." The team published the study in the Sept. 15, 2016, online issue of Cell Chemical Biology.

Pick a peptide, any peptide

Researchers have developed computational methods that allowed them to design stable peptides with precisely determined shapes. Peptides combine the specificity of biologics with a size that is closer to small molecules than whole proteins, allowing them to enter cells. However, it has been hard to design peptides with a specific shape, because the principles that govern protein shapes are not well understood and there are an enormous number of potential amino acid combinations for even relatively short peptides. In their experiments, a team from the University of Washington developed a set of algorithms that included both naturally occurring and unnatural amino acids and peptide backbone shapes. They used their algorithms to predict the shapes of different peptides. The researchers validated their predictions by synthesizing some of those peptides and comparing structural data to the predicted structures, and found the synthesized peptides to be "nearly identical to the computational design models. The computational design methods and stable scaffolds presented here provide the basis for development of a new generation of peptide-based drugs." They published their results in the Sept. 15, 2016, issue of Nature.

New hypertension risk genes

The good news about genetic risk factors for hypertension is that more than 60 of them have been identified. The bad news is that collectively, those 60 explain less than 5 percent of the genetic risk for hypertension. Multi-institutional consortia of several hundred researchers each have published two new meta-analyses that used different tools to identify an additional 44 risk genes. The studies point to potential new targets for developing hypertension drugs. A third of the U.S. population has hypertension, but currently, between limited efficacy and limited adherence, many cannot control their hypertension using available medications. The team used two different chips for their work, one exome chip and one focused on cardiometabolic single nucleotide polymorphisms (SNPs). They identified targets that included endothelial cells, which play an important role in constricting blood vessels, and norepinephrine synthesis. The authors wrote their "large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk." They published their studies in the Sept. 12, 2016, online issue of Nature Genetics.

Don't touch that tag

By inhibiting an interaction partner of N-Myc, researchers were able to slow the growth of neuroblastoma xenografts in mouse models. Like many oncogenes, Myc is a transcription factor, a class of proteins that is collectively hard to drug. Like many transcription factors, it is constantly produced and degraded under normal conditions, and trouble often starts when the degradation process goes awry and the transcription factor starts accumulating. A team from Columbia University showed that in the case of N-Myc, a form of Myc that is active in neuroblastomas, ubiquitin-specific protease 7 (USP7 or HAUSP) was responsible for removing a degradation marker. In cell culture and animal experiments, inhibiting HAUSP activity destabilized N-Myc, and ultimately tumor cells. In patients, high expression of HAUSP correlated with a poor prognosis. "Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors," the authors concluded. They reported their findings in the Sept. 12, 2016, online issue of Nature Medicine.

Metals weigh down antitumor T cells

Metallothioneins, a group of proteins with multiple roles in metal binding and redox reactions, may play a role in T-cell exhaustion, a phenomenon in which activated T cells become unable to fight infections or tumor cells, leading to immune escape. Unleashing T cells in tumor patients still fails more often than it works, and there are multiple mechanisms of failure, including ionic brakes. Researchers from the Broad Institute, Harvard Medical School and the Brigham and Women's Hospital have shown that metallothionein plays a role in activated but dysfunctional T cells. Markers of exhaustion have been hard to distinguish from markers of activation, since exhaustion is the product of chronic activation. By using single cell analyses, the team was able to specifically distinguish the activation from exhaustion gene expression programs in T cells. They found that metallothionein activation, which influences zinc and copper metabolism, was a specific marker of exhaustion, and that tumors grew slower in metallothionein-deficient mice in spite of relatively high amounts of checkpoint blockers, including PD-1, on tumor-infiltrating lymphocytes. "Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact," the authors wrote. They published their findings in the Sept. 8, 2016, print issue of Cell.

Channeling antitumor energy

Potassium ions that were released by dying tumor cells inhibited antitumor T cells, and treating mice with T cells that overexpressed potassium channels improved tumor clearance and survival in mouse models of melanoma. Some tumors have antitumor T cells within them but nevertheless progress. The mechanisms preventing such T cells from mounting an effective antitumor response remain poorly understood. In their work, the authors from Oregon Health and Sciences University showed that high levels of extracellular potassium impaired the function of antitumor T cells within the tumor microenvironment. The T cells took up the potassium, and lowering intracellular potassium levels by engineering them to overexpress a channel through which potassium could be pumped out improved their function. "These results uncover an ionic checkpoint that blocks T cell function in tumors and identify potential new strategies for cancer immunotherapy," the authors wrote. Their work appeared in the Sept. 15, 2016, issue of Nature.

T1D linked to IL6

T cells from individuals with type 1 diabetes were more responsive to interleukin-6, a cytokine that plays a role in many autoimmune diseases. There is a clinical study of the effects of IL-6-blocking monoclonal antibody Actemra (tocilizumab, Roche Holding AG) underway in type 1 diabetes patients, and the authors from the Benaroya Research Institute at Virginia Mason in Seattle wanted to understand the molecular underpinnings of how IL-6 affects T cells in diabetes, as well as compare it to other autoimmune diseases where IL-6 plays a role. They found that IL-6, but not other cytokines, enhanced STST3 signaling in the T cells in type 1 diabetes patients. Transcriptome analysis showed novel potential targets related to inflammation and homing. "Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6-targeted therapeutic intervention such as the one that is being currently tested," the authors concluded. Their work appeared in the Sept. 14, 2016, issue of Science Translational Medicine.

Biobanking tumor diversity

Researchers have developed a culturing method that allowed them to preserve the heterogeneity of breast tumors in a mix of patient-derived xenografts and short-term culturing methods. Considering how widely cell lines are used on cancer research, classical cell lines are quite poorly predictive of the clinical success of most cancer drugs. One reason is that tumor heterogeneity is not preserved in cell lines, but is a critical determinant of the response to drugs. A team from the British Cambridge University has developed a biobank of more than 80 patient-derived tumor xenografts, which could be explanted and cultured, using methods that preserved heterogeneity through repeated cycles of xenografts and culturing. The researchers said that "the biobank represents a powerful resource for preclinical breast cancer pharmacogenomic studies . . . including identification of biomarkers of response or resistance." The team published its biobank, which is publicly accessible, in the Sept. 15, 2016, online issue of Cell.

Move over, Miro

The mitochondrial membrane protein Miro played a role in removing dysfunctional mitochondria, and the Parkinson's disease (PD) risk mutation LRRK2G2019S slowed down that removal by preventing an interaction between Miro and LRRK. Mitochondrial dysfunction is at the core of neuronal death in PD, and the authors used induced pluripotent stem (iPS) cells to investigate the role of Miro, which had previously been linked to PD risk. They showed that Miro anchors mitochondria to microtubules. Miro was normally degraded in order to remove dysfunctional mitochondria, and that degradation occurred through an interaction with LRRK and was prevented by the LRRK2G2019S mutation. The authors from Stanford University noted that "the clinical manifestations of patients bearing LRRK2G2019S are indistinguishable from those of idiopathic PD. Thus, understanding the pathogenic pathway of mutant LRRK2 will yield insights into the disease mechanisms that are broadly applicable to both familial and sporadic forms of PD." Their findings appeared in the Sept. 8, 2016, online issue of Cell Stem Cell.