A Probe-Free Occupancy Assay to Assess a Targeted Covalent Inhibitor of Receptor Tyrosine-Protein Kinase erbB-2.

Establishing target engagement is fundamental to effective target-based drug development. It paves the way for efficient medicinal chemistry design and definitive answers about target validation in the clinic. For irreversible targeted covalent inhibitor (TCI) drugs, there is a unique opportunity to establish and quantify the target engagement or occupancy.

MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System.

Quantifying O-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases.

Detection of gene fusions using targeted next-generation sequencing: a comparative evaluation.

Background: Gene fusions represent promising targets for cancer therapy in lung cancer. Reliable detection of multiple gene fusions is therefore essential.

Methods: Five commercially available parallel sequencing assays were evaluated for their ability to detect gene fusions in eight cell lines and 18 FFPE tissue samples carrying a variety of known gene fusions.

Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial.

Background: The multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC).

Patients And Methods: Patients received FOLFOX6 with cetuximab (500 mg/m) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO).

KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors - TORC1/2 Inhibition as Salvage Strategy.

Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of or , favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients-adding further complexity to the scope of resistance.

Impact of RAS mutation subtype on clinical outcome-a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer.

Mutated RAS onco-proteins are key drivers across many cancers. The distribution of somatic RAS mutations varies between cancer entities. Retrospective analyses have associated some RAS mutations with distinct clinical outcomes.

Plant diversity maintains multiple soil functions in future environments.

Biodiversity increases ecosystem functions underpinning a suite of services valued by society, including services provided by soils. To test whether, and how, future environments alter the relationship between biodiversity and multiple ecosystem functions, we measured grassland plant diversity effects on single soil functions and ecosystem multifunctionality, and compared relationships in four environments: ambient conditions, elevated atmospheric CO, enriched N supply, and elevated CO and N in combination. Our results showed that plant diversity increased three out of four soil functions and, consequently, ecosystem multifunctionality.

Rapid and Highly Sensitive Detection of Therapeutically Relevant Oncogenic Driver Mutations in EBUS-TBNA Specimens From Patients With Lung Adenocarcinoma.

Background: First-line afatinib treatment prolongs overall survival in patients with metastatic non-small-cell lung cancer (NSCLC) harboring exon 19 deletion of epidermal growth factor receptor (EGFRdelEx19) mutations. In contrast, Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations are negative predictors for benefit from EGFR-targeting agents. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well-established for lung cancer diagnosis and staging.

Papilloma of the Fallopian Tube: A Rare Gynecologic Neoplasm Harboring a BRAF (c.1799T>A) Mutation (V600E).

Papillomas of the fallopian tube are exceedingly rare benign tumors, and only very few cases have been reported in the literature. Clinically, they may present as a mass lesion or occur without symptoms. Histomorphologically, they are papillary tumors covered by nonatypical epithelium with occasional ciliated or goblet cells growing in the lumen, and they are most frequently located in the infundibular region of the fallopian tube.

Phosphorylation of p70 Ribosomal Protein S6 Kinase β-1 is an Independent Prognostic Parameter in Metastatic Colorectal Cancer.

Background: Deregulation of signal transduction pathways plays a critical role in oncogenesis of colorectal cancer (CRC) and directly affects sensitivity to targeted therapies. Against this background we developed a comprehensive biomarker profiling program including markers of downstream signaling to study their association with clinical outcomes.

Patients And Methods: A prospectively studied cohort of 160 patients with metastatic CRC was included.

Comprehensive Biomarker Analyses in Patients with Advanced or Metastatic Non-Small Cell Lung Cancer Prospectively Treated with the Polo-Like Kinase 1 Inhibitor BI2536.

Background: Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established.

Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC.

Curcumin induces G2/M arrest, apoptosis, NF-κB inhibition, and expression of differentiation genes in thyroid carcinoma cells.

Purpose: The therapy of unresectable advanced thyroid carcinomas shows unfavorable outcome. Constitutive nuclear factor-κB (NF-κB) activation in thyroid carcinomas frequently contributes to therapeutic resistance; the radioiodine therapy often fails due to the loss of differentiated functions in advanced thyroid carcinomas. Curcumin is known for its anticancer properties in a series of cancers, but only few studies have focused on thyroid cancer.

High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified Patients with ROS1-Positive Metastatic Lung Cancer.

Objectives: Chromosomal rearrangements involving ROS1 define a rare entity of lung adenocarcinomas with exquisite sensitivity to molecularly targeted therapy. We report clinical outcomes and genomic findings of patients with ROS1-positive lung cancer who were prospectively identified within a multiplex biomarker profiling program at the West German Cancer Center.

Methods: Standardized immunohistochemical (IHC) analysis, fluorescence in situ hybridization (FISH), and hotspot mutation analyses were performed in 1345 patients with advanced cancer, including 805 patients with metastatic lung adenocarcinoma.

Intermediate microRNA expression profile in Graves' disease falls between that of normal thyroid tissue and papillary thyroid carcinoma.

Aims: Many studies have previously reported a higher prevalence of papillary thyroid carcinomas (PTC) in patients with Graves' disease (GD). MicroRNAs (miRNAs) are small, non-coding RNAs that are upregulated in PTC compared with benign thyroid tissue. The objective of the study was to examine the miRNA expression of selected miRNAs that are known to be upregulated in PTC in patients with GD.

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients.

Objective: Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.

Sorafenib inhibits intracellular signaling pathways and induces cell cycle arrest and cell death in thyroid carcinoma cells irrespective of histological origin or BRAF mutational status.

Background: Patients with dedifferentiated or anaplastic thyroid carcinomas currently lack appropriate treatment options. Kinase inhibitors are among the most promising new agents as alternative strategies. The BRAF- and multi-kinase inhibitor, sorafenib, has already shown antitumor effects in thyroid carcinoma patients in a phase III clinical trial.

HER2 expression and markers of phosphoinositide-3-kinase pathway activation define a favorable subgroup of metastatic pulmonary adenocarcinomas.

Objectives: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined.

Gene Expression Analysis of the 26S Proteasome Subunit PSMB4 Reveals Significant Upregulation, Different Expression and Association with Proliferation in Human Pulmonary Neuroendocrine Tumours.

Background: Proteasomal subunit PSMB4 was suggested to be a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. In pulmonary adenocarcinoma, a high expression of these genes was found to be associated with poor differentiation and survival. This study investigates the gene expression levels of 26S proteasome subunits in human pulmonary neuroendocrine tumours including typical (TC) and atypical (AC) carcinoid tumours as well as small cell (SCLC) and large cell (LCNEC) neuroendocrine carcinomas.

Isothermal multiple displacement amplification: a methodical approach enhancing molecular routine diagnostics of microcarcinomas and small biopsies.

Background And Methods: Isothermal multiple displacement amplification (IMDA) can be a powerful tool in molecular routine diagnostics for homogeneous and sequence-independent whole-genome amplification of notably small tumor samples, eg, microcarcinomas and biopsies containing a small amount of tumor. Currently, this method is not well established in pathology laboratories. We designed a study to confirm the feasibility and convenience of this method for routine diagnostics with formalin-fixed, paraffin-embedded samples prepared by laser-capture microdissection.

Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study.

MicroRNAs (miRNAs) are a class of small (∼22 nucleotides), non-coding, highly conserved single-stranded RNAs with posttranscriptional regulatory features, including the regulation of cell proliferation, differentiation, survival, and apoptosis. They are deregulated in a broad variety of tumors showing characteristic expression patterns and can, thus, be used as a diagnostic tool. In contrast to non-small cell carcinoma of the lung neuroendocrine lung tumors, encompassing typical and atypical carcinoids, small cell lung cancer and large cell neuroendocrine lung cancer, no data about deregulation of tumor entity-specific miRNAs are available to date.

Valproic acid downregulates NF-κB p50 activity and IRAK-1 in a progressive thyroid carcinoma cell line.

Histone deacetylase inhibitor (HDACI) valproic acid (VPA) is a promising drug, currently in clinical phase 2, for the therapy of advanced/poorly differentiated thyroid cancer. The nuclear factor-κB (NF-κB) pathway is constitutively activated in most tumors, including thyroid carcinomas; this often contributes to aggressive tumor growth and therapeutic resistance. We hypothesized that VPA could be useful to decrease NF-κB activity in human thyroid cancer cells.

Development of a highly sensitive and specific method for detection of circulating tumor cells harboring somatic mutations in non-small-cell lung cancer patients.

Background: Oncogenic mutations are powerful predictive biomarkers for molecularly targeted cancer therapies. For mutation detection patients have to undergo invasive tumor biopsies. Alternatively, archival samples are used which may no longer reflect the actual tumor status.

BAP1 germline mutation in two first grade family members with uveal melanoma.

Background: Uveal melanoma (UM) is the most common primary cancer of the eye in adults. About half of the patients are at risk of developing metastatic disease resulting in a poor clinical prognosis. Metastatic progression is strongly associated with loss of one chromosome 3 in the tumour (monosomy 3).