Pulmonary Cell News Volume 7.40 | Oct 11 2018

TOP STORY

Structure-Guided Combination Therapy to Potently Improve the Function of Mutant CFTRs

Scientists identified three small-molecule series that targeted defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain interfaces. Although individually these compounds marginally improved ΔF508-CFTR folding efficiency, function and stability, their combinations led to ~50–100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. [Nat Med] Abstract

(Ranked by impact factor of the journal)

PRKN-Regulated Mitophagy and Cellular Senescence during COPD Pathogenesis

Investigators showed parkin RBR E3 ubiquitin protein ligase (PRKN) overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PTEN induced putative protein kinase 1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. [Autophagy] Abstract

IL-17A-Associated IKK-α Signaling Induced TSLP Production in Epithelial Cells of COPD Patients

Inhibitor kappa kinase alpha (IKKα) silencing reduced thymic stromal lymphopoietin (TSLP) production in 16HBE cells stimulated with rhIL-17A and induced sputum supernatants from COPD patients. RhIL-17A increased the IKKα/acetyl-histone H3 immunoprecipitation in 16HBE cells. [Exp Mol Med] Full Article

Temporal Differentiation of Bovine Airway Epithelial Cells Grown at an Air-Liquid Interface

Researchers characterized the proliferation and differentiation of primary bovine bronchial epithelial cells grown at an air-liquid interface (ALI) at three-day intervals over a period of 42 days from the introduction of the ALI. [Sci Rep] Full Article

The Cysteinyl Leukotriene 3 Receptor Regulates Expansion of IL-25-Producing Airway Brush Cells Leading to Type 2 Inflammation

Airway brush cell expansion was attenuated in mice lacking either LTC₄ synthase, the biosynthetic enzyme required for cysteinyl leukotriene (CysLT) generation, or the epithelial cell receptor for leukotriene E4, CysLT3R. [Sci Immunol] Full Article

LUNG CANCER

Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer

Scientists report that LKB1 loss resulted in marked silencing of STING expression and insensitivity to cytoplasmic double strand DNA sensing. This effect was mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels, and reinforced by DNMT1 upregulation. [Cancer Discov] Abstract

IL-8-Induced O-GlcNAc Modification via GLUT3 and GFAT Regulates Cancer Stem Cell-Like Properties in Colon and Lung Cancer Cells

Researchers found that IL-8 was overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and was required for CSC properties, including tumor-initiating abilities. [Oncogene] Abstract

An HER3-Targeting Antibody-Drug Conjugate Incorporating a DNA Topoisomerase I Inhibitor U3-1402 Conquers EGFR Tyrosine Kinase Inhibitor-Resistant NSCLC

Investigators evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signaling. [Oncogene] Abstract

Inhibition of NF-κB Improves Sensitivity to Irradiation and EGFR-TKIs and Decreases Irradiation-Induced Lung Toxicity

Irradiation enhanced activation and expression of MET and therefore suppressed the sensitivity of lung cancer cells to irradiation or EGFR tyrosine kinase inhibitors (EGFR-TKIs). Inhibition of NF-κB by IMD 0354 or by p65 depletion reversed irradiation-induced MET activation and increased the sensitivity of lung cancer cells to irradiation, to EGFR-TKIs and to the combination thereof in vitro and in vivo. [Int J Cancer] Abstract

Long Non-Coding RNA AFAP1-AS1 Plays an Oncogenic Role in Promoting Cell Migration in Non-Small Cell Lung Cancer

The expression of lncRNA actin filament-associated protein 1-antisense RNA 1 (AFAP1-AS1) negatively correlated with CpG methylation status of its gene promoter, identified in both lung cancer cells and patient tissues, and treatment with DNA methyltransferase inhibitor decitabine significantly activated AFAP1-AS1 expression, strongly supporting that AFAP1-AS1 expression was tightly regulated by DNA methylation. [Cell Mol Life Sci] Abstract

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Acetylcholine Signaling System in Progression of Lung Cancers

The authors discuss the function of the acetylcholine-signaling proteins in the progression of lung cancer. The investigation of the role of cholinergic network in lung cancer will pave the way to novel molecular targets and drugs in this lethal malignancy. [Pharmacol Ther] Abstract

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G1 Therapeutics to Present Additional Data from Randomized Phase II Trial of Trilaciclib in Combination with Etoposide/Carboplatin

G1 Therapeutics, Inc. announced that new data from its randomized Phase II clinical trial of trilaciclib in combination with etoposide/carboplatin for treatment of first-line SCLC will be presented. [Press release from G1 Therapeutics, Inc. discussing research to be presented at the European Society for Medical Oncology (ESMO) 2018 Congress, Munich] Press Release

Insmed Presents New Data

Insmed Incorporated announced that the company presented data that provided additional insight into Mycobacterium avium complex (MAC) lung disease, a chronic and debilitating condition that can significantly increase patient morbidity and mortality. [Press release from Insmed Incorporated discussing research presented at IDWeek 2018 and at the CHEST Annual Meeting, San Antonio] Press Release

Bristol-Myers Squibb and Compugen Announce Clinical Collaboration to Evaluate Therapeutic Regimen in Advanced Solid Tumors

Bristol-Myers Squibb Company and Compugen announced the companies have entered into a clinical trial collaboration to evaluate the safety and tolerability of Compugen’s COM701, an investigational anti-PVRIG antibody, in combination with Bristol-Myers Squibb’s programmed death-1 immune checkpoint inhibitor Opdivo, in patients with advanced solid tumors. [Bristol-Myers Squibb Company] Press Release

Bellerophon Provides Update on INOpulse^® Phase IIb Clinical Program for Treatment of Pulmonary Hypertension Associated with Interstitial Lung Disease

Bellerophon Therapeutics, Inc. provided an update on the company’s ongoing Phase IIb randomized, double-blind, placebo-controlled clinical study evaluating INOpulse^® in patients with Pulmonary Hypertension associated with Interstitial Lung Disease, as well as updated interim results from the Pulmonary Arterial Hypertension Phase III trial, INOvation-1. [Bellerophon Therapeutics] Press Release

BerGenBio Enters Second Stage of Phase II Trial with Selective AXL Inhibitor Bemcentinib in Combination with KEYTRUDA^® in Patients with Advanced NSCLC

BerGenBio ASA announced that the first patient has been dosed in the second stage of the Phase II trial evaluating the company’s selective AXL inhibitor bemcentinib in combination with MSD’s anti-PD-1 therapy, KEYTRUDA^®, in patients with previously treated NSCLC whose disease is progressing. [BerGenBio ASA] Press Release

REVOLUTION Medicines Announces First Patient Dosed with RMC-4630 in Phase I Clinical Study in Patients with Advanced Solid Tumors

REVOLUTION Medicines, Inc. announced dosing of the first patient in a Phase I, open-label, monotherapy dose-escalation and expansion study of RMC-4630, the company’s lead investigational drug candidate targeting the enzyme SHP2. [Revolution Medicines] Press Release

UCLA Is Awarded $5 Million to Develop Tools to Detect Lung Cancer Earlier

Researchers from the UCLA School of Dentistry and the David Geffen School of Medicine at UCLA have been awarded $5 million over five years from the National Cancer Institute to develop liquid biopsy tools for testing individuals who could have lung cancer — the leading cause of cancer death in both U.S. men and women. [UCLA] Press Release

Synspira Receives U.S. FDA Orphan Designation for PAAG15A for the Treatment of Cystic Fibrosis

Synspira announced that it has been granted Orphan Designation by the United States FDA for poly glucosamine (PAAG15A), for the treatment of cystic fibrosis. Synspira is developing PAAG15A as SNSP113, a potential inhaled treatment to improve lung function in patients with cystic fibrosis. [Synspira] Press Release

Industry Partners Extensively Involved in Trials They Fund

Industry funders are usually involved in every stage of the clinical trials they support, and may try to downplay their involvement when trial results are reported, according to a study led by researchers in Denmark published in BMJ. The findings suggest that industry funders may be wielding greater influence over how trials are conducted and how results are published than currently realized. [The Scientist] Editorial

Argentina’s Scientists Struggle amid Slipping Peso and Rising Inflation

Researchers have struggled under austerity measures adopted by the government in 2014 and intensified in June by a financing agreement that Argentina signed with the International Monetary Fund. [Nature News] Editorial

NEW European Society for Medical Oncology (ESMO) 2019 Congress
September 27-October 1, 2019
Barcelona, Spain

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NEW Postdoctoral Position – Human Lung Organoid Research (Columbia University Medical Center)

Postdoctoral Research Fellow – Respiratory Epithelial Cell Biology (STEMCELL Technologies Inc.)

Research Associate – Lung Cancer (University of Cambridge)

Tenure Track or Early Career Investigator – Cell & Developmental Biology Center (National Heart, Lung & Blood Institute)

Postdoctoral Research Associate – Lung Cancer & Hypoxia Signaling (University of Illinois Cancer Center)

Postdoctoral Fellow – Vascular and/or Lung Biology (Yale University)

Postdoctoral Fellow – Sepsis and Pulmonary Injury Research (University of Maryland)

Research Fellow – Development of Occupational Diseases (CDC/National Institute for Occupational Safety and Health)

Faculty Investigators – Cancer Research (The University of Alabama at Birmingham)

Postdoctoral Position – Lung Diseases (German Research Center for Environmental Health)

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