A simplified method for monitoring the incorporation of radiolabeled acetate into lipids in a cellular system is described. The assay eliminates the commonly employed labor-intensive organic extraction step by plating the cells in 96-well tissue culture-treated ScintiPlates() that enable direct measurement of radiolabeled cell membrane-embedded lipids. Since the scintillant is entrenched in the plates, radioactivity in close proximity to the scintillant is measured without the need for liquid scintillation cocktail. The utility of this method for evaluating inhibitors of the de novo fatty acid synthetic pathway is demonstrated here with fatty acid synthase (FASN). Due to the upregulation of FASN activity in many tumor types, development of inhibitors to block the FASN activity in cells shows promise as an attractive and tractable approach for therapeutic intervention.

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Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus causally associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of postchemotherapy triple-negative breast cancers (TNBCs) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase 2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC withoutJAK2amplification. Detection ofJAK2/9p24 amplifications was more common in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes. Similar rates ofJAK2amplification were confirmed in patient-derived TNBC xenografts. In patients for whom longitudinal specimens were available,JAK2amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem cell-like cell population. In TNBC cell lines withJAK2copy gains or amplification, specific inhibition of JAK2 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-signal transducer and activator of transcription 3 (STAT3) signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore,JAK2amplification is a potential biomarker for JAK2 dependence, which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors.
Copyright © 2016, American Association for the Advancement of Science.

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Chronic obstructive pulmonary disease (COPD) is associated with exercise limitation and physical inactivity, which are believed to have significant long-term negative health consequences for patients. While a number of COPD treatments and exercise training programmes increase exercise capacity, there is limited evidence for their effects on physical activity levels, with no clear association between exercise capacity and physical activity in clinical trials. Physical activity depends on a number of behaviour, environmental and physiological factors. We describe the design of the PHYSACTO trial, which is investigating the effects of bronchodilators, either alone or with exercise training, in combination with a standardised behaviour-change self-management programme, on exercise capacity and physical activity in patients with COPD. It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training.
Patients are being recruited from 34 sites in Australia, New Zealand, the USA, Canada and Europe. Patients receiving a multicomponent intervention designed to support behaviour change related to physical activity are randomised to four treatment arms: placebo, tiotropium, tiotropium+olodaterol, and tiotropium+olodaterol+exercise training. The primary outcome is improvement in exercise capacity after 8 weeks, measured by endurance time during a shuttle walk test. The secondary outcome is improvement in physical activity, including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory-Short Form and the novel hybrid PROactive instrument. Additionally, the influence of moderating variables (ie, factors influencing a patient’s choice to be physically active) on increases in physical activity is also explored.
The study has been approved by the relevant Institutional Review Boards, Independent Ethics Committee and Competent Authority according to national and international regulations. The findings of the trial will be disseminated through relevant peer-reviewed journals and international conference presentations.
NCT02085161.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to View Source

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THIOMAB drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs.
Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice.
An integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells.
Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.

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On April 15, 2016 Incyte Corporation (Nasdaq: INCY) reported that it will highlight the productivity of its drug discovery and development organization and aspects of its development portfolio at an investor event on Sunday, April 17, 2016 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana (Press release, Incyte, APR 15, 2016, View Source;p=RssLanding&cat=news&id=2157635 [SID:1234510922]).

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The event will include a discussion of Incyte’s second-generation PI3Kδ inhibitor, INCB50465; the Company’s immuno-oncology portfolio, including its anti-GITR antibody, INCAGN1876, anti-OX40 antibody, INCAGN1949, and emerging data with its small molecule BRD inhibitor, INCB54329; as well as its targeted epigenetic therapies, including a novel LSD1 inhibitor entering Phase 1 development, INCB59872 .

"Incyte operates with the conviction that investment in basic research can translate into innovative therapies that can address important unmet medical needs. To that end, we are pleased to be able to highlight such a broad collection of abstracts from our emerging development portfolio at this year’s AACR (Free AACR Whitepaper) Annual Meeting," stated Reid Huber, Ph.D., Incyte’s Chief Scientific Officer. "The research team’s productivity is a result of the quality of our scientific organization and the efficiency of our R&D model."

As part of its succession plan, Incyte also announced that after almost 13 years at the Company, Dr. Richard Levy, Chief Drug Development Officer, is retiring effective April 30, 2016. Dr. Steven Stein, Incyte’s Chief Medical Officer, will now assume all of Dr. Levy’s responsibilities. Dr. Levy was instrumental in building the broad and diverse portfolio Incyte has today, and developing Jakafi (ruxolitinib), the Company’s proprietary JAK 1/JAK 2 inhibitor