Identification and characterization of an irreversible inhibitor of CDK2

Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)- 9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds

N plus 2 Supersonic Concept Development and Systems Integration

Supersonic airplanes for two generations into the future (N+2, 2020-2025 EIS) were designed: the 100 passenger 765-072B, and the 30 passenger 765-076E. Both achieve a trans-Atlantic range of about 4000nm. The larger 765-072B meets fuel burn and emissions goals forecast for the 2025 time-frame, and the smaller 765-076E improves the boom and confidence in utilization that accompanies lower seat count. The boom level of both airplanes was reduced until balanced with performance. The final configuration product is two "realistic", non-proprietary future airplane designs, described in sufficient detail for subsequent multi-disciplinary design and optimization, with emphasis on the smaller 765-076E because of its lower boom characteristics. In addition IGES CAD files of the OML lofts of the two example configurations, a non-proprietary parametric engine model, and a first-cycle Finite Element Model are also provided for use in future multi-disciplinary analysis, optimization, and technology evaluation studies

Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach

Structure-guided expansion of a fragment hit for the ATAD2 bromodomain enabled improvement in ATAD2 inhibition and selectivity over BRD4.</p

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

<p>Abstract</p> <p>Background</p> <p>YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.</p> <p>Methods</p> <p>This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.</p> <p>Results</p> <p>Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.</p> <p>Conclusions</p> <p>The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations.</p> <p>Trial registration</p> <p>ClinicalTrials.gov unique identifier: NCT00633490</p

Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

ESyM: An Electronic Health Record-Integrated Patient-Reported Outcomes-Based Cancer Symptom Management Program Used by Six Diverse Health Systems

PURPOSE: Collecting patient-reported outcomes (PROs) can improve symptom control and quality of life, enhance doctor-patient communication, and reduce acute care needs for patients with cancer. Digital solutions facilitate PRO collection, but without robust electronic health record (EHR) integration, effective deployment can be hampered by low patient and clinician engagement and high development and deployment costs. The important components of digital PRO platforms have been defined, but procedures for implementing integrated solutions are not readily available. METHODS: As part of the NCI's IMPACT consortium, six health care systems partnered with Epic to develop an EHRintegrated, PRO-based electronic symptom management program (eSyM) to optimize postoperative recovery and well-being during chemotherapy. The agile development process incorporated user-centered design principles that required engagement from patients, clinicians, and health care systems. Whenever possible, the systemused validated content from the public domain and took advantage of existing EHR capabilities to automate processes. RESULTS: eSyM includes symptom surveys on the basis of the PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE) plus two global wellness questions; reminders and symptom self-management tip sheets for patients; alerts and symptom reports for clinicians; and population management dashboards. EHR dependencies include a secure Health Insurance Portability and Accountability Act-compliant patient portal; diagnosis, procedure and chemotherapy treatment plan data; registries that identify and track target populations; and the ability to create reminders, alerts, reports, dashboards, and charting shortcuts. CONCLUSION: eSyM incorporates validated content and leverages existing EHR capabilities. Build challenges include the innate technical limitations of the EHR, the constrained availability of site technical resources, and sites' heterogenous EHR configurations and policies. Integration of PRO-based symptom management programs into the EHR could help overcome adoption barriers, consolidate clinical workflows, and foster scalability and sustainability. We intend to make eSyM available to all Epic users

RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.

Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq. Key to this strategy is a species-specific mapping approach that removes the need for manipulation of the RNA population, customised sequencing protocols, or prior knowledge of the species component ratio. The method demonstrates comparable performance to species-specific RT-qPCR and a standard microarray platform, and allowed us to quantify gene expression changes in both the tumour and host tissue following treatment with cediranib, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, including the reduction of multiple murine transcripts associated with endothelium or vessels, and an increase in genes associated with the inflammatory response in response to cediranib. In the human compartment, we observed a robust induction of hypoxia genes and a reduction in cell cycle associated transcripts. In conclusion, the study establishes that RNA-Seq can be applied to pre-clinical models to gain deeper understanding of model characteristics and compound mechanism of action, and to identify both tumour and host biomarkers

Targeted antitumour therapy – future perspectives

The advent of targeted therapy presents an unprecedented opportunity for advances in the treatment of cancer. A key challenge will be to translate the undoubted promise of targeted agents into tangible clinical benefits. Achieving this goal is likely to be dependent upon a number of factors. These include continued research to improve our understanding of the heterogeneity and complexity of the tumour microenvironment; refinement of clinical trial design to incorporate nontraditional end points such as the optimum biological dose and health-related quality of life; and the use of technological advancements in proteomics, genomics and biomarker development to better predict tumour types and patient subsets that may be particularly responsive to treatment, as well as enable a more accurate assessment of drug effect at the molecular level. In summary, the future success of targeted agents will require an integrated multidisciplinary approach involving all stakeholders

Capturing complex tumour biology in vitro: Histological and molecular characterisation of precision cut slices

Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1α. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means