Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef() ) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma NSCLC after first-line chemotherapy, and as monotherapy (Ofev() ) in the USA and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single- and multiple-doses and intravenous (i.v.) administration were assessed using three datasets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of four studies that enrolled a total of 113 healthy volunteers; (3) a pooled data analysis of four studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean: 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of i.v. nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after i.v. administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to i.v. dosing (4-hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice-daily dosing. Nintedanib’s PK was time-independent; accumulation after repeated administration was negligible. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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Mitochondrial dysfunction is a hallmark of aging, and underlies the development of many diseases. Cells maintain mitochondrial homeostasis through a number of pathways that remodel the mitochondrial proteome or alter mitochondrial content during times of stress or metabolic adaptation. Here, using yeast as a model system, we identify a new mitochondrial degradation system that remodels the mitochondrial proteome of aged cells. Unlike many common mitochondrial degradation pathways, this system selectively removes a subset of membrane proteins from the mitochondrial inner and outer membranes, while leaving the remainder of the organelle intact. Selective removal of preexisting proteins is achieved by sorting into a mitochondrial-derived compartment, or MDC, followed by release through mitochondrial fission and elimination by autophagy. Formation of MDCs requires the import receptors Tom70/71, and failure to form these structures exacerbates preexisting mitochondrial dysfunction, suggesting that the MDC pathway provides protection to mitochondria in times of stress.

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Cytokines serve as a major mechanism of communication between immune cells and are the functional molecules at the end of immune pathways. Abnormalities in cytokines are involved in a wide variety of diseases, including chronic inflammation, autoimmune diseases, and cancer. Cytokines are not only direct targets of therapeutics but also important biomarkers for assessing drug efficacy and safety. Traditionally, enzyme-linked immunosorbent assays (ELISA) were most popular for identifying and quantifying cytokines. However, ELISA is expensive, labor intensive, and low throughput. Here, we report the development of a miniaturized Luminex (Austin, TX) assay platform to establish a panel of high-throughput, multiplexed assays for measuring cytokines in human whole blood. The miniaturized 384-well Luminex assay uses <25% of the assay reagents compared with the 96-well assay. The development and validation of the 384-well Luminex cytokine assays enabled high-throughput screening of compounds in primary cells using cytokines as physiologically relevant readouts. Furthermore, this miniaturized multiplexed technology platform allows for high-throughput biomarker profiling of biofluids from animal studies and patient samples for translational research.
© 2016 Society for Laboratory Automation and Screening.

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Large-scale multiplexed identification of somatic alterations in cancer has become feasible with next generation sequencing (NGS). However, calibration of NGS somatic analysis tools has been hampered by a lack of tumor/normal reference standards. We thus performed paired PCR-free whole genome sequencing of a matched metastatic melanoma cell line (COLO829) and normal across three lineages and across separate institutions, with independent library preparations, sequencing, and analysis. We generated mean mapped coverages of 99X for COLO829 and 103X for the paired normal across three institutions. Results were combined with previously generated data allowing for comparison to a fourth lineage on earlier NGS technology. Aggregate variant detection led to the identification of consensus variants, including key events that represent hallmark mutation types including amplified BRAF V600E, a CDK2NA small deletion, a 12 kb PTEN deletion, and a dinucleotide TERT promoter substitution. Overall, common events include >35,000 point mutations, 446 small insertion/deletions, and >6,000 genes affected by copy number changes. We present this reference to the community as an initial standard for enabling quantitative evaluation of somatic mutation pipelines across institutions.

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On April 21, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported that researchers from the Icahn School of Medicine at Mount Sinai, led by Professor E. Premkumar Reddy, scientific founder of Onconova, have published a study describing the novel RAS-targeted mechanism of action for rigosertib in the journal Cell (Press release, Onconova, APR 21, 2016, View Source [SID:1234511258]). The paper, titled "A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling," can be accessed in the current online edition of Cell.

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RAS represents one of the most sought-after targets in cancer. Thus far the development of drugs to block RAS has been difficult, leading many to label RAS the undruggable oncogene.

"This discovery is the culmination of my laboratory’s work with RAS genes over the last three decades," said Dr. E. Premkumar Reddy, lead author of the paper and Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai. "RAS genes have been a challenging target for molecular oncologists and drug developers. However, the allosteric mechanism by which rigosertib blocks activation of signaling proteins downstream of RAS may represent a new paradigm for attacking this oncogene."

The research published in Cell and carried out by a multidisciplinary team from Mount Sinai, The Scripps Cancer Research Institute, Albert Einstein College of Medicine, and the New York Structural Biology Center, demonstrated that rigosertib blocks RAS signaling by directly binding to various RAS effector proteins, including RAF and PI3-kinase. These mechanistic findings support the development of rigosertib in malignancies with over-activate RAS signaling, such as higher-risk myelodysplastic syndromes (HR-MDS). Onconova is actively enrolling patients in the global INSPIRE trial, a randomized Phase 3 study to assess the efficacy and safety of single-agent intravenous rigosertib in HR-MDS.

About Rigosertib

Rigosertib is a small molecule inhibitor of cellular signaling and acts as a Ras mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the Ras-binding domain (RBD) found in many Ras effector proteins, including the Raf kinases and PI3K. The initial therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.

About RAS

Point mutations in RAS genes (HRAS, KRAS and NRAS) are frequently observed in many of the most common and lethal tumors, including cancers of the pancreas, lung, colon, skin, bladder and bone marrow. RAS genes encode important intracellular proteins that when mutated activate pathways involved in cancer cell proliferation, survival and metastasis. Although molecular oncologists have made significant headway in understanding RAS mutations and their impact on cellular signaling, less progress has been made towards developing RAS-targeted drugs. Thus, there is an urgent need for new therapeutic modalities that address this important oncogene.