SUMMIT trial shows mutation, location both matter
Data from the phase II SUMMIT basket trial of HER tyrosine kinase inhibitor neratinib (Puma Biotechnology Inc.) in patients with HER2 or HER3-mutated tumors across multiple anatomical locations have shown that targeting HER2 can have therapeutic value in tumors beyond breast cancer, but also reaffirmed that for most targeted therapies, the anatomical location as well as the molecular mutation play a role. Researchers from Memorial Sloan-Kettering Cancer Center reported the results of the trial, concluding that "efficacy in HER2-mutant cancers varied as a function of both tumor type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumors that contain kinase domain missense mutations." Their findings appeared in the Jan. 31, 2018, online issue of Nature.
Mutant Huntingtin destabilizes chromosomes
Huntington's disease (HD), though it is a neurodegenerative disease that becomes symptomatic only in middle age, appears to have a neurodevelopmental component. Mutant Huntingtin gene has a stretch of glutamine-encoding CAG in it that is much shorter in regular cells. But many things remain unclear about how that leads to toxicity decades later in specific types of neurons. Researchers from the Rockefeller University engineered human embryonic stem cells with various lengths of triplet expansions, and discovered that the cells had chromosomal instability and developed forebrain cells with multiple cell nuclei "at an abundance directly proportional to CAG repeat length," leading them to conclude that "disrupted neurogenesis during development is an important, unrecognized aspect of HD pathogenesis." They also discovered that knockout cells lacking both copies of Huntingtin had the same chromosomal instability, leading them to conclude that "HD represents a genetic dominant-negative loss of function, contrary to the prevalent gain-of-toxic-function hypothesis. The consequences of developmental alterations should be considered as a new target for HD therapies." Their work appeared in the Jan. 29, 2018, online issue of Development.
Genes between a rock and a hard place
Tradeoffs between the risk of cancer and of degenerative diseases occur at all levels from genes to epidemiology, researchers from the Institute for Experimental Medicine at the German University of Kiel have reported. Aging is the primary risk factor for a number of diseases, but individuals are most strongly at risk for different age-related diseases at different ages. As people age from their sixties into their eighties, their relative risk of cancer declines as the risk of degenerative diseases increases. The team looked at the transcriptional signatures of different tissues in different species at different ages, and found that this epidemiology was reflected in the transcriptomes and "on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa, the authors wrote. "These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing." Their work appeared in the Jan. 30, 2018, online issue of Nature Communications.
Microbiome has role in familial colon cancer
Patients with familial adenomatous polyposis (FAP) were more likely than control individuals to have bacterial biofilms in their colons that contained two bacterial strains that produce genotoxins, enterotoxigenic Bacteroides fragilis and colibactin-producing Escherichia coli. Researchers from Johns Hopkins University investigated the microbiome of individuals with FAP because while almost all individuals with FAP ultimately develop colon cancer as the result of a mutant tumor suppressor, the onset of disease varies widely even within families with the same mutation. Using a mix of clinical data and animal models, the authors found that "co-colonization with ETBF and pks+ E. coli, found in more than half of FAP patients (in contrast to less than 25 percent of controls), promotes enhanced carcinogenesis" through both mucus degradation and IL-17 production." The team published its results in the Feb. 2, 2018, issue of Science.
IBS risk gene has role in junctions
Researchers have identified how variants in the gene C1orf106 affect the risk of irritable bowel syndrome (IBS). IBS is an autoimmune disease marked by chronic inflammation, but C1orf106 is expressed at low levels in immune cells and is found at higher levels in intestinal epithelial cells. A team from the Broad Institute and Massachusetts General Hospital showed that its role in those cells is to promote the formation of tight junctions, which protect the intestines from intestinal bacteria. Mice lacking C1orf106 exhibited "defects in the intestinal epithelial cell barrier, a phenotype observed in IBD patients that confers increased susceptibility to intestinal pathogens. Furthermore, the IBD risk variant increases C1orf106 ubiquitination and turnover with consequent functional impairments." That work appeared in the Feb. 2, 2018, issue of Science.
Functional link between aggregates, proteasome
Protein aggregates and proteasome dysfunction are common features of neurodegenerative disorders. Researchers at the German Center for Neurodegenerative Diseases and the Max Planck Institute for Biochemistry have gained new insights into the link between the two. The team looked at amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), both of which are most commonly caused by an expansion in the gene C9orf72 that leads to protein aggregation. The team investigated the nature of those aggregates using electron microscopy, and found that they consisted of "densely packed ribbons" that recruited proteasome complexes. Complexes near the aggregates were stabilized, which was indicative of degradation being stalled within them. "Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes," the authors wrote. They published their study in the Feb. 1, 2018, issue of Cell.
Looking at males' half-full autoimmune glass
Women are much more likely than men to develop autoimmune disease, and "while most studies have focused on what causes the damaging inflammation in females, there is also much to be learned by studying the factors that confer protection to males." So wrote the authors of a paper doing exactly that, by looking at a mouse model of multiple sclerosis. The team, from Northwestern University, showed that when mice were exposed to myelin basic protein, that set off an autoimmune response in females. In males, that autoimmune response was prevented because such exposure induced the production of the anti-inflammatory cytokine interleukin-33 (IL-33). The proinflammatory response in female mice could be reversed by treating them with IL-33. The authors also showed that testosterone directly induced the expression of IL-33 in mast cells, and concluded that "IL-33 therapy has the potential to prevent disease progression by blocking damaging inflammation as well as promoting myelin and neuronal repair in MS and other diseases of the CNS." Their work appeared in the Jan. 29, 2018, issue of the Proceedings of the National Academy of Sciences.
Cure globally, treat locally
Scientists have developed an approach for testing the ability of locally administered immune enhancing agents to systemically eradicate tumors, and shown that "combination of a TLR ligand and an anti-OX40 antibody can cure multiple types of cancer and prevent spontaneous genetically driven cancers." OX40 is a T-cell checkpoint, but OX40 signaling activates T cells rather than inhibiting them, as is the case with PD-1. The researchers from Stanford University tested multiple combination treatments on mouse models xenografted with the same tumor at two separate anatomical sites. If treatment at one site was able to evoke a systemic immune response, the tumor at the other site subsequently shrank. The team showed that stimulating innate immune receptors with TLR9 agonists led to the expression of OX40 on T cells. When the animals were then treated with an OX40 agonist antibody, it triggered a T-cell response to the antigens of the injected tumor. The authors said their approach, called in situ vaccination, "does not require knowledge of the tumor antigens," though "potential drawbacks include reliance on adequate immune infiltrates and the availability of a suitable injectable site of tumor." Their findings were published in the Jan. 31, 2018, issue of Science Translational Medicine.
Mice, monkeys, men and molehills?
A paper published by researchers from the University of Pennsylvania reported toxicity concerns when an adeno-associated virus (AAV)-based vector was used to deliver the gene for the survival of motor neuron (SMN) protein in primate and piglet models of spinal muscular atrophy. The team reported liver and neuronal toxicity in both animal models after treatment with "a dose similar to that employed in the SMA clinical trial" of AVXS-101. Others were less worried. An analyst note from Jefferies Inc.'s Biren Amin and Kelly Shi noted that Avexis' own preclinical data showed no such toxicity, nor has any unexpected toxicity been observed in its clinical trials. Amin and Shi concluded that the toxicity observed by the Penn team, which was published online in Human Gene Therapy on Jan. 30, 2018, "could be unique to [the] Penn construct," which tested a different AAV variant than the one used in the clinical trial.
Some like it hot
Mitochondria are the powerhouses of the cell, producing the energy currency ATP. Researchers from the French INSERM Institute have used heat-sensitive fluorescent reporter dyes to show that in doing so, they also produce enough heat to run at temperatures roughly 10 degrees Celsius above the rest of the body. Further studies showed that various mitochondrial enzymes worked best at temperatures near 50 degrees Celsius. The authors were cautious in their conclusions, noting that "in view of their potential consequences, these observations need to be further validated and explored by independent methods" to exclude artefacts. Nevertheless, they noted that "organisms survive across a wide range of temperatures . . . and their enzymes and membranes have adapted to function accordingly," and suggested that "our study prompts a critical re-examination of the literature on mitochondria." Their work appeared in the Jan. 25, 2018, issue of PLoS Pathogens.