Charles River Discovery Research Services
Charles River Discovery Research Services
News Article | May 16, 2017
WILMINGTON, Mass.--(BUSINESS WIRE)--Charles River Laboratories International, Inc. (NYSE: CRL) recently announced updates to its expanding oncology discovery business, including significant additions to its online Tumor Model Compendium. The Compendium provides oncology researchers with a resource to identify and locate targeted, suitable patient-derived xenografts (PDXs) based on specific histology and molecular properties, and now includes additional molecular characteristics for syngeneic models. “The use of a human tumor graft in a humanized model represents the future of immuno-oncology research,” said Birgit Girshick, Corporate Senior Vice President, Global Discovery, at Charles River. “A model that more closely mirrors human immune systems allows researchers to conduct groundbreaking studies more efficiently and effectively, with the goal of developing more translational therapies. Utilizing the Tumor Model Compendium, oncology researchers can identify the exact tumor model and target for their research, getting them that much closer to that goal.” Charles River has more than 450 fully characterized proprietary PDXs in its portfolio, which represents all major tumor histotypes, and provides extensive background and characterization for oncology research. The most recent Compendium update expands the existing tumor model collection to include: Recognizing the importance of selecting the appropriate tumor model for in vivo and in vitro oncology, Charles River partnered with OcellO to further expand their capabilities with PDX models. Through their agreement, OcellO utilizes human tumor material from Charles River PDX models and applies it in their 3D cell culture drug screening platform. This high-throughput platform enables the growth of micro-tumors in a natural extracellular matrix environment and uses automated 3D imaging to analyze the effects of small molecules and antibodies on tumor development. “The extended range of tumor subtypes and high level of annotation of Charles River’s PDX Compendium enables the selection of the optimum tumor models with the most appropriate mutational profile for in vivo studies,” said Leo Price, CEO and founder of OcellO. “The use of the same PDX tumor cells in OcellO's in vitro 3D culture platform enables pre-screening of tumor models with test compounds in a highly translational high-throughput platform.” In addition to utilizing the Compendium in integrated client relationships, recent tumor model updates have also enhanced scientific presentations. At the 2017 AACR Annual Meeting, a meeting which highlights the advances in cancer science and medicine from institutions all over the world, Charles River presented three posters highlighting the enhancement of certain models for oncology drug discovery: Charles River’s extensive portfolio of oncology products and services, including studies in human xenograft, syngeneic, humanized immunotherapy research models, flow cytometry, and IVIS® imaging services, was strengthened by the acquisition of Oncotest GmbH. Now known as Charles River Discovery Research Services Germany GmbH, the company is a Freiburg, Germany-based organization with a specialization in PDX models with more than 25 years of experience. To address the increasing importance of immuno-oncology, in April 2017 Charles River announced the availability of its triple-immunodeficient mouse model, known as the NCG model. To learn more about Charles River’s oncology research capabilities, visit www.criver.com. Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit www.criver.com.
Khatoon S.,New Hill |
Chalbot S.,New Hill |
Bolognin S.,New Hill |
Puolivali J.,Charles River Discovery Research Services |
Iqbal K.,New Hill
Journal of Alzheimer's Disease | Year: 2015
Alzheimer's disease (AD) is the single major cause of dementia in middle- to old-Age individuals, and, as of yet, no disease-modifying therapeutic drug is available for its treatment. A major obstacle in the successful development of diseasemodifying therapeutic drugs has been the lack of suitable animal models of the sporadic form of AD as well as a biomarker that can be used both for therapeutic preclinical studies and for human clinical trials. Previously we showed neurogenesis and neuronal plasticity deficits and cognitive impairment and their rescue with a neurotrophic peptidergic compound, DGGLAG named P021, in aged Fisher rats. Here we show that P021 is blood-brain-barrier-permeable, and chronic oral treatment with this compound can reduce the brain level of total tau in the aged rats. Furthermore, cerebrospinal fluid (CSF) levels of both tau and Aβ/AβPP are elevated in the aged animals, and chronic treatment with P021 can reduce tau but not Aβ/AβPP to that of the levels found in young adult rats. Importantly, P021 does not induce any detectable immune reaction in rats. Collectively, these studies show the therapeutic potential of P021 as a disease-modifying compound and the suitability of the aged Fisher rats as a model of cerebral aging in which the therapeutic efficacy of a tau-reducing compound can be monitored in the CSF. © 2015 - IOS Press and the authors. All rights reserved.
Lansdell T.A.,Michigan State University |
O'Reilly S.,Michigan State University |
Woolliscroft T.,Charles River Discovery Research Services |
Azevedo L.M.,Michigan State University |
And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012
The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice. © 2012 Elsevier Ltd. All rights reserved.
Northrup R.,Helsinn Therapeutics U.S. Inc. |
Kuroda K.,Safety Research Laboratories |
Duus E.M.,Helsinn Therapeutics U.S. Inc. |
Barnes S.R.,Charles River Discovery Research Services |
And 3 more authors.
Supportive Care in Cancer | Year: 2013
Purpose: Anamorelin (ONO-7643) is an orally active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia. It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH). However, increasing GH and insulin-like growth factor-1 in cancer patients raises concerns of potentially stimulating tumor growth. Therefore, we investigated the effect of ghrelin and anamorelin on tumor growth in a murine NSCLC xenograft model. Methods: Female nude mice (15-21/group) with established A549 tumors were administered ghrelin (2 mg/kg i.p.), anamorelin (3, 10, or 30 mg/kg p.o.), or vehicle controls daily for 28 days. Tumor growth, food consumption, and body weight were monitored. Murine growth hormone (mGH) and murine insulin-like growth factor-1 (mIGF-1) were measured in plasma. Results: Tumor growth progressed throughout the study, with no significant differences between treatment groups. Daily food consumption was also relatively unchanged, while the percentage of mean body weight gain at the end of treatment was significantly increased in animals administered 10 and 30 mg/kg compared with controls (p < 0.01). Peak mGH levels were significantly higher in ghrelin- and anamorelin-treated animals than in controls, while peak mIGF-1 levels were slightly elevated but not statistically significant. All regimens were well tolerated. Conclusions: These findings demonstrate that neither anamorelin nor ghrelin promoted tumor growth in this model, despite increased levels of mGH and a trend of increased mIGF-1. Together with anamorelin's ability to increase body weight, these results support the clinical development of ghrelin receptor agonist treatments for managing NSCLC-related anorexia/cachexia. © 2013 The Author(s).
Roix J.J.,Biomedical Valley Discoveries Inc. |
Harrison S.D.,Charles River Discovery Research Services |
Rainbolt E.A.,Charles River Discovery Research Services |
Meshaw K.R.,Charles River Discovery Research Services |
And 3 more authors.
PLoS ONE | Year: 2014
Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anticancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity. © 2014 Roix et al.
Heikkinen T.,Charles River Discovery Research Services |
Lehtimaki K.,Charles River Discovery Research Services |
Vartiainen N.,Charles River Discovery Research Services |
Puolivali J.,Charles River Discovery Research Services |
And 12 more authors.
PLoS ONE | Year: 2012
Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe behavioral, cognitive, and motor deficits. Since the discovery of the huntingtin gene (HTT) mutation that causes the disease, several mouse lines have been developed using different gene constructs of Htt. Recently, a new model, the zQ175 knock-in (KI) mouse, was developed (see description by Menalled et al, ) in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. Here we confirm the behavioral phenotypes reported by Menalled et al , and extend the characterization to include brain volumetry, striatal metabolite concentration, and early neurophysiological changes. The overall reproducibility of the behavioral phenotype across the two independent laboratories demonstrates the utility of this new model. Further, important features reminiscent of human HD pathology are observed in zQ175 mice: compared to wild-type neurons, electrophysiological recordings from acute brain slices reveal that medium spiny neurons from zQ175 mice display a progressive hyperexcitability; glutamatergic transmission in the striatum is severely attenuated; decreased striatal and cortical volumes from 3 and 4 months of age in homo- and heterozygous mice, respectively, with whole brain volumes only decreased in homozygotes. MR spectroscopy reveals decreased concentrations of N-acetylaspartate and increased concentrations of glutamine, taurine and creatine + phosphocreatine in the striatum of 12-month old homozygotes, the latter also measured in 12-month-old heterozygotes. Motor, behavioral, and cognitive deficits in homozygotes occur concurrently with the structural and metabolic changes observed. In sum, the zQ175 KI model has robust behavioral, electrophysiological, and histopathological features that may be valuable in both furthering our understanding of HD-like pathophyisology and the evaluation of potential therapeutic strategies to slow the progression of disease. © 2012 Heikkinen et al.
PubMed | CHDI Management CHDI Foundation, Psychogenics, Inc., Brains On Line LLC, Neuroservice and 2 more.
Type: | Journal: PLoS currents | Year: 2014
Huntingtons disease is a neurodegenerative disorder caused by mutations in the CAG tract of huntingtin. Several studies in HD cellular and rodent systems have identified disturbances in cyclic nucleotide signaling, which might be relevant to pathogenesis and therapeutic intervention. To investigate whether selective phosphodiesterase (PDE) inhibitors can improve some aspects of disease pathogenesis in HD models, we have systematically evaluated the effects of a variety of cAMP and cGMP selective PDE inhibitors in various HD models. Here we present the lack of effect in a variety of endpoints of the PDE subtype selective inhibitor SCH-51866, a PDE1/5 inhibitor, in the R6/2 mouse model of HD, after chronic oral dosing.
PubMed | Charles River Discovery Research Services, Johns Hopkins University, Robin Medical, Inc. and Institute of Bioinformatics
Type: | Journal: Scientific reports | Year: 2015
Delays between tissue collection and tissue fixation result in ischemia and ischemia-associated changes in protein phosphorylation levels, which can misguide the examination of signaling pathway status. To identify a biomarker that serves as a reliable indicator of ischemic changes that tumor tissues undergo, we subjected harvested xenograft tumors to room temperature for 0, 2, 10 and 30minutes before freezing in liquid nitrogen. Multiplex TMT-labeling was conducted to achieve precise quantitation, followed by TiO2 phosphopeptide enrichment and high resolution mass spectrometry profiling. LC-MS/MS analyses revealed phosphorylation level changes of a number of phosphosites in the ischemic samples. The phosphorylation of one of these sites, S82 of the heat shock protein 27kDa (HSP27), was especially abundant and consistently upregulated in tissues with delays in freezing as short as 2minutes. In order to eliminate effects of ischemia, we employed a novel cryogenic biopsy device which begins freezing tissues in situ before they are excised. Using this device, we showed that the upregulation of phosphorylation of S82 on HSP27 was abrogated. We thus demonstrate that our cryogenic biopsy device can eliminate ischemia-induced phosphoproteome alterations, and measurements of S82 on HSP27 can be used as a robust marker of ischemia in tissues.
PubMed | Biomedical Valley Discoveries Inc. and Charles River Discovery Research Services
Type: Journal Article | Journal: PloS one | Year: 2014
Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity.
PubMed | CHDI Management CHDI Foundation, Psychogenics, Inc., Charles River Discovery Research Services and King's College London
Type: Journal Article | Journal: PloS one | Year: 2014
Huntingtons disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines. To further evaluate the validity of this target for the treatment of HD, we examined the effects of TG2 deletion in two genetic mouse models of HD: R6/2 CAG 240 and zQ175 knock in (KI). Contrary to previous reports, under rigorous experimental conditions we found that TG2 ablation had no effect on either motor or cognitive deficits, or on the weight loss. In addition, under optimal husbandry conditions, TG2 ablation did not extend R6/2 lifespan. Moreover, TG2 deletion did not change the huntingtin aggregate load in cortex or striatum and did not decrease the brain atrophy observed in either mouse line. Finally, no amelioration of the dysregulation of striatal and cortical gene markers was detected. We conclude that TG2 is not a valid therapeutic target for the treatment of HD.