Decoding EGFR’s skin toxicity

Rashes caused by EGFR inhibitors, are not “only” skin-deep. In the words of scientists from the Medical University of Vienna, they are “stigmatizing skin toxicities affecting patients’ quality of life and therapy adherence.” However, why EGFR inhibitors can lead to such debilitating skin side effects has been unclear. Now, the Vienna team demonstrated that EGFR signaling is required to keep intact the epithelial barrier during the initial outgrowth of hair from hair follicles. When EGFR signaling was blocked, microbiome bacteria were able to breach the epithelial barrier, setting off an immune response similar to that seen in atopic dermatitis. “Restoration of epidermal ERK signaling via prophylactic FGF7 treatment or transgenic SOS expression [rescued] the barrier defect in the absence of EGFR, highlighting a therapeutic anchor point,” the authors noted. They reported their findings in the Dec. 12, 2019, issue of Science Translational Medicine.

ALDH2 and Alzheimer’s

Investigators at Stanford University have provided new evidence linking Aldehyde dehydrogenase 2 deficiency (ALDH2*2) to an increased risk of Alzheimer’s disease (AD). Previous genomic analyses had suggested a possible connection between AD and the deficiency of ALDH2 deficiency, a condition better known for causing alcoholic flush, sometimes called Asian flush because the ALDH2*2 mutation is found mostly in East Asians. The team showed that mice homozygous for the ALDH2*2 mutation had higher levels of amyloid-b and neuroinflammation than their wild-type counterparts following alcohol exposure. “These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.” They reported their findings in the Dec. 11, 2019, issue of Acta Neuropathologica Communications.

Psychiatric risk genes can have distinct effects in different disorders

Researchers from multiple psychiatric consortia have published a new analysis of risk genes for eight psychiatric disorders The consortia performed a meta-analysis of previous genomic studies with more than 230,000 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome, and nearly half a million control subjects. They identified multiple new relationships between risk genes, and more than 100 genomic loci that were associated with more than one psychiatric disorder, “including 23 loci with… effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders.” More than 30 of the loci had not been associated with any of the individual disorders prior to the study. “These results highlight disparities between our clinically-defined classification of psychiatric disorders and underlying biology,” the authors wrote. “Future research is warranted to determine whether more genetically-defined influences on cross-diagnostic traits or subtypes of dissect may inform a biologically-informed reconceptualization of psychiatric [classification].” They reported their results in the Dec. 12, 2019, issue of Cell.

Getting, and keeping, antitumor T cells energized

Two separate research teams have reported new insights into the prerequisites for an antitumor T-cell response. Natural and CAR T-cell immune responses alike can lead to cures of even advanced cancers if they are sufficiently strong. But some tumors do not provoke a T-cell response in the first place, while in other cases, T cells mount an initial response that exhausts itself over time. In the Dec. 12, 2019, issue of Nature, researchers from Emory University have described an immune niche within tumors that is critical for a T-cell response to form. They identified a population of stem-like T cells directly within tumor niches that also contained antigen-presenting cells. The stem-like cells could retain their stem-like properties while giving rise to mature daughter cells. Those daughter cells had high levels of PD-1 expression, making them prone to shutdown by PD-L1 expressing tumor cells. The authors concluded that “these observations are not well explained by a model of T cell exhaustion whereby continuous antigen exposure leads to accumulation of checkpoint molecules, resulting in a decline of the T cell response.” Instead, they proposed that “stem-like cells require a region within the tumor that resembles the T cell zone of secondary lymphatic tissues, made up of dense areas of antigen-presenting cells. … The scarcity of these niches in tumors that rapidly progress after surgery suggests that tumors may be interfering with the formation or continued maintenance of immune niches and that this may be a novel mechanism of immune evasion requiring further investigation.” The report comes a week after Stanford investigators reported in the Dec. 5, 2019, issue of Nature that overexpression of the transcription factor c-JUN could prevent exhaustion in CAR T cells. “functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.

RAN protein is ALS target

The most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expansion in an intron of the protein C9orf72. However, there are multiple possibilities why this expansion could be toxic, and which one is the biggest problem has been unclear. Specifically, the intron expansion, which consists of the six base pairs GGGGCC, causes loss of function of the C9orf72 protein. The base pairs are also transcribed in both directions, and the resulting RNA is translated into six distinct dipeptides collectively known as RAN proteins. Researchers at the University of Florida have shown that those RAN proteins were both a driver of disease, and a potential therapeutic target. They generated RAN-protein targeting antibodies and showed those antibodies crossed the blood-brain barrier. The antibodies “improved behavior, decreased neuroinflammation and neurodegeneration, and increased survival of C9-500 ALS/FTD mice. … this study provides the first proof of principle data that human antibody therapy may be a viable therapeutic approach for C9orf72 ALS/FTD and possibly other RAN protein diseases.” They published their work in the Dec. 9, 2019, online issue of Neuron.

Fibrosis in the lung…

Scientists at the University of Texas Health Science Center at Tyler have identified a seven amino acid peptide that reduced the progression of idiopathic lung fibrosis (IPF) in mouse models. At a five-year survival rate of 20%, IPF has a worse prognosis than many cancers. There are both genetic and environmental risk factors, but many aspects of the disease remain poorly understood. One thing that is known, however, is that alveolar epithelial cell apoptosis precedes fibrosis. The researchers showed that a peptide of the caveolin-1 scaffolding domain consisting of seven amino acids improved survival in three separate mouse models of IPF by inhibiting apoptosis of alveolar epithelial cells. The team also developed a formulation of the peptide that was effective when delivered directly to the lungs via a nebulizer. They reported their results in the Dec. 11, 2019, issue of Science Translational Medicine.

… and in general

Researchers at University of California Los Angeles, in the meanwhile, have developed a new preclinical model of fibrosis in general. The authors wrote that “preclinical models that mimic the complex, progressive nature of the disease are lacking,” which in turn accounts for a lack of cures for the many different fibrotic diseases. The authors used iPS cells differentiated into multiple cell types to identify common fibrotic pathways across tissue types. Using their cell-based model they identified a compound, AA5, that targeted tissue repair agonists. The team validated their compound in ex vivo and in vivo models of ocular and lung fibrosis. They concluded that their model “recapitulates the common inflammation-driven progressive fibrosis seen across organs. … Our data suggest that approaching inflammation-driven fibrosis by targeting endogenous agonists of resolution may offer an attractive strategy to treat progressive fibrosis.” They reported their findings in the Dec. 10, 2019, issue of Cell Reports.

Unexpected Ibrance MOA

Scientists at the University of California, Santa Cruz, have demonstrated that the cyclin-dependent kinase inhibitor p27, when it formed a complex with CDK4 and cyclin D1, rendered CDK4 insensitive to the inhibitor Ibrance (palbociclib, Pfizer Inc.). In combination with estrogen receptor blockers, Ibrance significantly increases the progression-free interval in women with metastatic ER-positive breast cancer. In structural studies, the authors showed that unexpectedly, Ibrance did not bind to the activated complex of p27/CDK4/cyclin D1. Indeed, that complex was resistant to Ibrance due to structural changes induced by p27. Instead, Ibrance bound free CDK4 monomers as well as the related CDK6. An accompanying editorial stated that “Robust CDK6 activity can confer palbociclib resistance in CDK4-driven cancers, possibly because CDK6 assembles more efficiently than CDK4 into palbociclib-resistant trimers. Structures of CDK4 and CDK6 in complexes with the D-type cyclins are needed to understand differences in regulatory mechanisms and to improve drug development.” Paper and editorial appeared in the Dec. 13, 2019, issue of Science.

Macrophage activity backfires in S. aureus infection

Researchers at the University of North Carolina Chapel Hill have shown that macrophages can do more harm than good in bloodstream infections of Staphylococcus aureus. Serious infections of S. aureus that lead to feared complications like necrotizing fasciitis and sepsis usually begin as bloodstream infections. In the bloodstream, S. aureus is phagocytosed by neutrophils and macrophages. Previous work has shown that macrophages are inefficient at killing the S. aureus bacteria they phagocytose, making them a major reservoir for infections. In their experiments, the North Carolina investigators showed that reactive oxygen species generated by macrophages in their attempts to kill S. aureus resulted in “decreased respiration, lower ATP and increased antibiotic tolerance. We further show that respiratory burst induces antibiotic tolerance in the spleen during a murine systemic infection. These results suggest that a major component of the innate immune response is antagonistic to the bactericidal activities of antibiotics.” They published their work in the Dec. 9, 2019, online issue of Nature Microbiology.

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