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| 10002 | Tox21 Cross-Partner Projects | To accommodate the expanded strategic direction and focus of the Tox21 collaboration, a central functional group called the cross-partner project was created in 2018. Cross-partner projects are defined research activities that fall into one of five areas of focus: Develop alternative test systems that are predictive of human toxicity and dose response. Address key technical limitations of current in vitro test systems. Curate and characterize legacy in vivo toxicity studies. Establish scientific confidence in in vitro test systems and integrated assay batteries. Refine and deploy in vitro methods for characterizing pharmacokinetics and in vitro dispositions. Cross-partner projects must have support from two or more Tox21 partners. Each project has a three-year term and is reviewed annually by Tox21 leadership, enabling a more formal research planning and execution process. Current Cross-Partner Projects Development of a High-Throughput Assay to Identify 5-α Reductase Inhibitors for Orthogonal Evaluation in an Androgen-Dependent Human 3-D Prostate Microtissue Cell Line Selection for High-Throughput Transcriptomics (HTT) Profiling Environmental, Drug and Food-Related Chemicals that Inhibit Acetylcholinesterase Activity In Vitro Chemical Disposition High-Throughput Transcriptomic Analysis Predictive Modeling of Developmental Toxicity with Human Pluripotent Stem Cells Toxicodynamic Variability in Developmental Neurotoxicity Performance-Based Validation of Alternative Test Systems and Models 1. Development of a High-Throughput Assay to Identify 5-α Reductase Inhibitors for Orthogonal Evaluation in an Androgen-Dependent Human 3-D Prostate Microtissue Leads: Chad Deisenroth, Josh Harrill, Menghang Xia Goal: Develop additional human-based, cellular test systems to more completely model androgen pathway activity. Issue: Environmental factors that alter the metabolism or bioactivity of androgen, a male sex hormone, can harm human reproductive and sexual development. Current guidelines rely on animal testing to evaluate the potential for certain chemicals to disrupt normal androgenic functions. Efforts to evaluate androgen-active chemicals using predictive computational models with in vitro data are limited; unlike animal models, computational models have insufficient coverage of key metabolic outcomes and observable characteristics resulting from gene-environment interactions. Project Focus: Develop a high-throughput assay to evaluate the effects of blocking the activity of enzyme 5α-reductase and develop a 3-D human prostate microtissue assay that may enable better assessments of androgen-active chemicals. Together, the assays can provide greater depth for predicting the negative effects of androgen-disrupting compounds. 2. Cell Line Selection for High-Throughput Transcriptomics (HTT) Leads: Nisha Sipes, Josh Harrill, Woody Setzer Goal: Develop a strategy for selecting maximally diverse cell types/lines to maximally cover biological targets and pathways for high-throughput chemical screening using gene expression (i.e., transcriptomics). Issue: HTT is an efficient means of screening chemicals for bioactivity across a broad range of potential molecular targets. However, no single laboratory (in vitro) model will express all molecular targets or accurately model the diversity of chemical disturbances observed in different cell types of the human body. As in vitro models derived from diverse tissues and sources have different gene/protein expression patterns, they may respond differently to chemical exposures. A HTT screening panel using diverse cell lines would provide a more comprehensive understanding of chemical bioactivity than studies in any single cell type. Project Focus: Use computational modeling of existing transcriptomics data to select a set of “diverse” cell lines, measure transcriptomic responses of “diverse” cells following exposure to a panel of chemicals, determine the degree to which “diverse” cell lines respond differently to chemicals, and analyze the responses among pooled cell lysates. 3. Profiling Environmental, Drug and Food-Related Chemicals that Inhibit Acetylcholinesterase Activity Leads: Menghang Xia, Michael Santillo Goal: Develop a high-throughput in vitro test system to identify and characterize new compounds that block the activity of acetylcholinesterase. Issue: Acetylcholinesterase (AchE) inhibitors are compounds related to foods, drugs and the environment that can be toxic to humans. Project Focus: To advance existing methods, metabolism will be incorporated into the in vitro screening system, which, in addition to in-depth mechanistic studies, may improve the ability to detect emerging chemical hazards. 4. In Vitro Chemical Disposition Leads: Katie Paul Friedman, Mike Devito Goal: Understand the impact of chemical disposition within in vitro test systems across a broad range of chemical categories and develop a computational model to predict differences between the “nominal” concentration of a chemical compared with “true” concentration in the media and cells. Issue: In a cell-based laboratory test (in vitro assay), the actual concentration of a chemical inside cells is likely different from the nominal concentration applied to the medium in the well of a microtiter assay plate. Mathematical models exist for predicting in vitro disposition, but very few chemicals have been evaluated for in vitro disposition. Across the Tox21 chemical library, chemical partitioning could affect the accuracy of predictions made from laboratory (in vitro) data about living (in vivo) systems, but the number of chemicals affected and to what degree are unknown. Project Focus: This cross-partner project includes measurement of in vitro disposition of approximately 200 chemicals, with the goal of developing model predictions for the rest of the Tox21 chemical library. 5. High-Throughput Transcriptomic Analysis Leads: Steve Ferguson, Josh Harrill, Menghang Xia Goal: Develop a common chemical reference dataset for interpretation of high-throughput transcriptomic screening data. Issue: Gene expression profiling has proven to be an invaluable tool to explore mechanisms of chemical interactions with biological systems (e.g., pharmacology, toxicology). However, these tools have historically lacked sufficient throughput to study a broad range of chemicals, or characterize concentration-response profiles necessary to identify perturbed biological-response pathways. Project Focus: Build a robust transcriptomic data set with hundreds of chemicals (largely data-rich reference chemicals with established linkages to biological response-pathways). Transcriptomic signatures are being developed to identify molecular targets and pathways which are perturbed by chemical treatment, as well as the progression of target and pathway perturbations as a function of chemical concentration. 6. Predictive Modeling of Developmental Toxicity with Human Pluripotent Stem Cells Leads: Thomas Knudsen, Nicole Kleinstreuer, Annie Lumen Goal: Evaluate a human-based, induced pluripotent stem cell (iPSC) test system to predict developmental toxicity. Issue: Traditionally, information from studies using laboratory animals has been used to predict the impact of chemical exposure on the human fetus. However, these studies are slow, costly and unrealistic for assessing tens of thousands of environmental chemicals in commerce, and this approach may not provide adequate coverage of human biology. Project Focus: Evaluate an assay (test) based on reducing cellular ornithine's release relative to cystine uptake by iPSCs. Coupled with computational predictive modeling, the in vitro test system findings can be extrapolated to living systems (in vivo) and dose-activity measures translated to the whole-body level. This approach enables exposure-based risk characterization for chemicals considered high priority for developmental toxicity. This cross-program project will work towards the characterization, validation, and implementation of this platform by modeling the predictive and health-protective potential of the assay with regards to fundamental principles of abnormal development in the womb. 7. Toxicodynamic Variability in Developmental Neurotoxicity Leads: Mamta Behl, Alison Harrill Goal: Incorporate genetic variation into cell-based test systems to better understand potential population differences in response to chemicals that may cause toxic neurological effects. Issue: Genetic differences between people can have a profound effect on whether an individual is susceptible to negative health outcomes caused by a given chemical. Project Focus: Use neural progenitor cells derived from a highly diverse rodent population, called the Diversity Outbred, to determine variability in toxicity outcomes after exposure to known or suspected neurotoxic chemicals. The data collected has the potential to inform human health risk assessments for chemical exposures, replacing default inter-individual uncertainty factors. 8. Performance-Based Validation of Alternative Test Systems and Models Leads: Keith Houck, Richard Judson, Nicole Kleinstreuer Goal: Develop an evaluation framework for the development of performance standards which can be used to establish confidence in alternative test systems and models. Issue: Validation is needed to increase the usefulness of ToxCast and Tox21 high-throughput screening data in regulatory applications. Project Focus: Develop curated sets of active and inactive reference chemicals as well as known assay interference chemicals. In addition to developing a process for identifying reference chemicals, defining a process for describing the essential test method components, evaluating the assay data for accuracy and reliability, and declaring the assay “validated” is necessary. Finally, both the development of reference chemical sets and a validation process must be streamlined and fast enough to manage the tens to hundreds of assays that can help inform regulatory decisions. | To accommodate the expanded strategic direction of the Tox21 collaboration, cross-partner projects were developed to address one of five areas of focus. | /sites/default/files/tox21_1260x630.jpg | Tox21 Cross-Partner Projects | To accommodate the expanded strategic direction of the Tox21 collaboration, cross-partner projects were developed to address one of five areas of focus. | /sites/default/files/tox21_1260x630.jpg | Tox21 Cross-Partner Projects | ||
| 9971 | Tox21 Collaborators Release New Strategic Plan for Chemical Testing | Using NCATS’ state-of-the-art robotic screening system, Tox21 scientists have produced more than 120 million data points on approximately 8,500 chemicals since 2008. (NCATS)March 29, 2018Ten years ago, a group of federal partners formed a unique collaboration — Toxicology in the 21st Century (Tox21) — to develop faster, more efficient approaches to predict how exposure to chemicals may affect human health. On March 8, 2018, Tox21 program partners from NCATS, the National Toxicology Program at the National Institute of Environmental Health Sciences, the Environmental Protection Agency, and the Food and Drug Administration published a new strategic and operational plan to broaden the scope of their research activities to address new challenges.Traditional preclinical approaches to testing drugs, environmental chemicals and other substances involve animal models or other living organisms. These methods are slow, costly and often unable to predict toxic health effects observed in clinical trials. In contrast, in vitro approaches involve testing substances outside living systems, making it possible to increase the volume and speed of testing through automated, “high-throughput” screening.Using NCATS’ state-of-the-art robotic screening system, Tox21 scientists have produced more than 120 million data points on approximately 8,500 chemicals since 2008. These data help researchers understand the potential effects of exposure to a substance based on how it interacts with biological molecules during screening.All Tox21 data are publicly released for broad use in research and regulatory decisions, and screening results have been published in over 200 articles in more than 55 scientific journals. Many of the tested chemicals had no prior information available about potential toxic effects.Challenges remain in improving the reliability, efficiency and predictive capability of toxicity testing using in vitro high-throughput screening. To address these obstacles, the Tox21 collaborators have published a plan in the journal ALTEX to expand the scope of their research, including five new areas of focus:Develop alternative test systems that can predict human response to chemicals and capture more potential toxic effects, including variability among different groups of peopleAddress key technical limitations of current in vitro test systems, including technological and biological barriers and obstacles to translating resultsCollect, organize and analyze available data from toxicity studies in living systems, which can help inform analysis of in vitro testing resultsStrengthen scientific confidence in the data produced by in vitro test systems, including developing an evaluation framework for performance standardsDevelop new in vitro methods and models for predicting how substances will move through and be processed by the human body, thus improving estimates of impact and effectivenessTox21 collaborators are launching new cross-partner research projects to address these five focus areas. The three-year projects each have support from a minimum of two Tox21 partners and will be reviewed annually by Tox21 leadership. Learn more about the projects.“Tox21 is truly a collaborative initiative, with each partner bringing unique expertise and resources that are crucial to advancing toxicity testing methods,” said Anton Simeonov, Ph.D., NCATS scientific director. “The new strategic plan and expanded research areas will ensure Tox21 efforts continue to benefit the entire toxicology community and help protect individuals from potential harmful effects of exposure to chemicals.” | Leaders of the Toxicology in the 21st Century (Tox21) program have published a new strategic and operational plan to address new research challenges. | /sites/default/files/tox21_1260x630.jpg | Tox21 Collaborators Release New Strategic Plan for Chemical Testing | Leaders of the Toxicology in the 21st Century (Tox21) program have published a new strategic and operational plan to address new research challenges. | /sites/default/files/tox21_1260x630.jpg | Tox21 Collaborators Release New Strategic Plan for Chemical Testing | ||
| 9961 | Common Metrics Initiative | The Common Metrics Initiative was designed to assess and optimize the CTSA Program’s overall impact on the nation’s health. Establishing a set of standard evaluation measures across CTSA Program institutions helps focus program activities, streamline data collection and demonstrate measurable progress toward program goals, including improvements in research translation and workforce development.We work collaboratively with researchers, administrators, program evaluators and a diverse range of staff from various CTSA Program institutions to develop, demonstrate and disseminate new common metrics. Three metrics were established across the institutions:• Careers in clinical and translational research• Institutional review board duration• Pilot funding and publicationsInvestigators at the CTSA Program’s Center for Leading Innovation and Collaboration (CLIC) at the University of Rochester lead the Coordinating Center, which was supporting the Common Metrics Initiative. | The Common Metrics Initiative is designed to assess and optimize the CTSA Program’s overall impact on the nation’s health. | Common Metrics Initiative | The Common Metrics Initiative is designed to assess and optimize the CTSA Program’s overall impact on the nation’s health. | Common Metrics Initiative | ||||
| 9874 | 2018 Therapeutic/Indication Pairing Projects | In spring and fall 2018, NCATS issued four Therapeutic/Indication Pairing Projects awards. The funded preclinical projects are serving as “use cases” to demonstrate the utility of an independent crowdsourcing effort or a computational algorithm to predict new therapeutic uses of an existing drug or biologic. View the projects below: Impact of SAR152954 on Prenatal Alcohol Exposure-Induced Neurobehavioral Deficits Repurposing Misoprostol to Prevent Recurrence of Clostridium Difficile Infection Preclinical Characterization of Saracatinib for Cystic Fibrosis Therapy Repositioning AZD0530 for Surgical Treatment of Fibrodysplasia Ossificans Progressiva Impact of SAR152954 on Prenatal Alcohol Exposure-Induced Neurobehavioral Deficits University of New Mexico Health Sciences Center Principal Investigators: Daniel Savage, Ph.D. Grant Number: 5-UH2TR002082-02 At least 2% to 4% of children born in the United Staters each year are at risk for having prenatal alcohol-associated brain damage that can cause cognitive disabilities which, in turn, can lead to numerous secondary consequences including failure in school, trouble with the law, confinement, and dependent living, along with an increased risk for behavioral health problems. Currently, there are no evidence-based clinically useful pharmacotherapeutic interventions for these deficits. The long-term objective of our research program is to understand the neurobiologic bases of prenatal alcohol-induced learning deficits and, subsequently, to identify therapeutic agents whose mechanisms of action would be predicted to have clinical utility in treating the cognitive disabilities associated with Fetal Alcohol Spectrum Disorder (FASD). This research project will examine the effectiveness of a novel class of drugs for ameliorating neurophysiologic and learning deficits in a well-established animal model of FASD. Learn more about this project in the NIH RePORTER. Repurposing Misoprostol to Prevent Recurrence of Clostridium Difficile Infection Vanderbilt University Medical Center, Washington University School of Medicine and University of North Carolina at Chapel Hill Principal Investigators: David M. Aronoff, M.D. (Vanderbilt), Erik R. Dubberke, M.D. (WUSTL), and Sarah McGill, M.D. (UNC) Grant Number: 1-U01TR002398-01 The bacterium Clostridium difficile is a major cause of antibiotic-associated diarrhea and a leading infectious disease in U.S. hospitals. The infection can recur multiple times despite initially adequate treatment. This project builds on the results of studies that demonstrated a possible new therapeutic use for misoprostol, a drug approved by the Food and Drug Administration to treat certain types of ulcers, in preventing or treating C. difficile colitis. This team will conduct a clinical trial to test the hypothesis that patients with a primary episode of C. difficile infection who are treated with misoprostol in addition to standard therapy will have a reduced rate of C. difficile infection recurrence compared to patients receiving standard care only. Learn more about this project in the NIH RePORTER. Preclinical Characterization of Saracatinib for Cystic Fibrosis Therapy Cincinnati Children’s Hospital Medical Center Principal Investigator: Anil Jegga, D.V.M., M.Res., John Paul Clancy, M.D., Anjaparavanda P. Naren, Ph.D. Grant Number: 1-UG3TR002612-01 The pursuit of additional therapeutics for cystic fibrosis (CF) is needed due to several limitations of currently FDA-approved therapies. Our data suggest that src kinase inhibitors have a significant therapeutic benefit in CF primarily by impacting multiple CF pathophysiological processes. Saracatinib or AZD0530, a src kinase inhibitor from AstraZeneca, is well tolerated in humans on chronic administration. We therefore propose to test this asset as a novel CF disease-modifying therapy. Learn more about this project in the NIH RePORTER. Repositioning AZD0530 for Surgical Treatment of Fibrodysplasia Ossificans Progressiva Brigham and Women’s Hospital Principal Investigator: Paul B. Yu, M.D., Ph.D. Grant Number: 1-UG3TR002617-01 Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic condition that results in the replacement of soft tissues with bone, causing profound immobility, impaired quality of life and reduced life expectancy. Attempts to remove abnormal bone in FOP to improve mobility are almost always met with the return of bone formation and often the worsening of immobility. Based on promising animal model results, this proposal tests whether an existing experimental drug, AZD0530, that has already been tested for safety in hundreds of human patients could be effective and safe in suppressing bone formation following surgical removal of bone in patients with FOP. Learn more about this project in the NIH RePORTER. | /sites/default/files/socialcard.jpg | Bench-to-Clinic 2018 Project | /sites/default/files/socialcard.jpg | Bench-to-Clinic 2018 Project | ||||
| 9873 | 2018 New Therapeutic Uses for Experimental Assets | In April 2018, NCATS issued funding for three cooperative agreements designed to match academic research groups with selected compounds from industry as part of the New Therapeutic Uses program. The goal is to use molecules that already have undergone significant research and development by the pharmaceutical industry to more quickly advance new treatments for patients. AZD9668: A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency, a Genetically Linked Orphan Disease AZD9668 and Neutrophil Elastase Inhibition to Prevent Graft-versus-Host Disease Use of the Src Family Kinase Inhibitor Saracatinib in the Treatment of Pulmonary Fibrosis AZD9668: A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency, a Genetically Linked Orphan Disease University of Alabama at Birmingham Principal Investigators: Mark T. Dransfield, M.D., and Gary R. Cutter, Ph.D. Grant Number: 1-UG3-TR-002450-01 Alpha-1 antitrypsin deficiency (AATD) is the most common genetic cause of chronic obstructive pulmonary disease and emphysema. The disorder affects between 70,000 and 100,000 individuals in the United States. Individuals with AATD have extremely low plasma and lung levels of AAT, a protein that helps lung tissue remain elastic and flexible. Current treatment for AATD is invasive, expensive and does not permanently slow the development of lung damage. This project team will study the safety, tolerability and effectiveness of AZD9668 as an improved noninvasive treatment for patients with AATD. Learn more about this project in the NIH RePORTER AZD9668 and Neutrophil Elastase Inhibition to Prevent Graft-versus-Host Disease Duke University and NIH’s National Cancer Institute Principal Investigators: Nelson J. Chao, M.D., M.B.A. (Duke), and Steven Z. Pavletic, M.D. (NCI) Grant Number: 1-UG3TR002448-01 Graft-versus-host disease (GVHD) is the major cause of treatment-related death for patients who undergo stem cell transplants. The enzyme neutrophil elastase, which makes cells less elastic and flexible, may be a key trigger of GVHD. This project team will test a new strategy to prevent GVHD using AZD9668, which blocks neutrophil elastase, in a series of milestone-driven preclinical and clinical trials. Use of the Src Family Kinase Inhibitor Saracatinib in the Treatment of Pulmonary Fibrosis National Jewish Health, Icahn School of Medicine at Mount Sinai and Yale University Principal Investigators: Gregory P. Downey, M.D. (NJH), Joel Thomas Dudley, Ph.D. (Mt. Sinai), and Naftali Kaminski, M.D. (Yale) Grant Number: 1-UG3TR002445-01 Scarring of the lung, called pulmonary fibrosis, is a chronic, progressive and usually deadly disorder. Although two drugs were recently approved for the treatment of pulmonary fibrosis, neither cures the disease, and nearly 40 percent of patients stop taking their medication within one year because of side effects. This project will study the use of saracatinib, a drug originally developed to treat certain types of cancers, in the treatment of pulmonary fibrosis in both preclinical models and a clinical trial. Learn more about this project in the NIH RePORTER | 2018 NIH–Industry Partnerships Projects | 2018 NIH–Industry Partnerships Projects | ||||||
| 9856 | Identification of a Synergistic Combination Between PARP Inhibitors and NAMPT Inhibitors in Ewing Sarcoma | Ewing sarcoma is an aggressive cancer of the bones and soft tissues that affects mostly children and teenagers. The long-term survival rate of patients with recurrent or metastatic disease is less than 20 percent. Despite intensive efforts to understand the molecular mechanisms underlying such disease, few therapeutic avenues are currently available. Scientific Synopsis The goal of this project is to identify potential targeted therapeutic combinations that could overcome resistance and lead to a durable response. NCATS’ strategy was to screen drugs displaying activity as single agents in a combinatorial format versus a panel of Ewing sarcoma cell lines to identify drug combinations displaying activities higher than those of their respective single agents at similar concentrations. The results indicate that poly (ADP-ribose) polymerase (PARP) inhibitors synergized with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This result was explained by the observation that the NAMPT enzyme is the rate-limiting enzyme involved in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, a necessary substrate of PARP. Combination of the PARP inhibitor niraparib with the NAMPT inhibitor GNE-618 in vivo resulted in tumor regression, delayed disease progression and increased overall survival. These studies highlight these drugs’ potential as a possible therapeutic option in treating patients with Ewing sarcoma. Lead Collaborators Craig J. Thomas, Ph.D., NCATS, NIH Lee J. Helman, M.D., National Cancer Institute, NIH Christine M. Heske, M.D., National Cancer Institute, NIH Publication Heske CM, Davis MI, Baumgart JT, Wilson K, Gormally MV, Chen L, et al. Matrix screen identifies synergistic combination of PARP inhibitors and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in Ewing sarcoma. Clin Cancer Res. 2017;23;7301-11. Public Health Impact This study highlights the potential of the matrix combination screening platform to discover novel drug combinations toward the treatment of Ewing sarcoma. Mechanistic hindsight provided from such studies may lead to the development of a more effective chemotherapeutic regimen. | PARP Inhibitors and NAMPT Inhibitors in Ewing Sarcoma | PARP Inhibitors and NAMPT Inhibitors in Ewing Sarcoma | ||||||
| 9837 | mQC: A Quality Control Metric for High-Throughput Combination Screening | Quality control (QC) metrics are critical in high-throughput screening (HTS) platforms to ensure reliability and confidence in assay data and downstream analyses. Most HTS QC metrics are designed for plate-level or single well-level analysis. With the advent of high-throughput combination screening, there is a need for QC metrics that quantify the quality of combination response matrices. Scientific Synopsis NCATS introduces mQC, a predictive, interpretable, matrix-level QC metric, based on a mix of data-derived and heuristic features. mQC accurately reproduces the expert assessment of combination response quality and correctly identifies unreliable response matrices that can lead to erroneous or misleading characterization of synergy. When combined with a plate-level QC metric, mQC provides a more appropriate determination of the quality of a drug combination screen. The analyses indicate that mQC is a reliable QC filter that can be used to identify problematic drug combination matrices and prevent further analysis on erroneously active combinations, as well as for troubleshooting failed screens. The R source code of mQC is available at http://matrix.ncats.nih.gov/mQC. Publications Chen L, Wilson K, Goldlust I, Mott BT, Eastman R, Davis MI, Zhang X, McKnight C, Klumpp-Thomas C, Shinn P, Simmons J, Gormally M, Michael S, Thomas CJ, Ferrer M, Guha R. mQC: A heuristic quality-control metric for high-throughput drug combination screening. Sci Rep. 2016;6:37741. Public Health Impact The mQC quality control metric ensures that good quality combination screening results are analyzed and followed up. As a result, efforts and resources spent on unreliable or misleading combination responses are minimized. Projects that employ the mQC method should have more reliable outcomes that can be reproduced and form the basis for further development. | mQC: A Quality Control Metric | mQC: A Quality Control Metric | ||||||
| 9835 | Development of Novel Chemical Genomic Platforms for Pathogenic Protozoa | Scientific Synopsis Pathogenic protozoa remain a global burden with an enormous health, social and economic impact. The burden is exacerbated by the lack of licensed vaccines, although developmental efforts are ongoing. Where chemotherapeutics are available, their usefulness is threatened by the emergence and spread of drug-resistant parasites. The requirement for new chemotherapeutic agents necessitates global development efforts. To facilitate these efforts, NCATS endeavors to develop and validate innovative strategies for the discovery of new antiparasitic agents and gain insight into mechanism of action. For example, NCATS leveraged its high-throughput matrix screening capabilities to assay approximately 14,000 drug combinations against three distinct Plasmodium falciparum strains. NCATS scientists identified novel drug classes, including calcium homeostasis modulators and inhibitors of phosphatidylinositide 3-kinases, that demonstrated significant synergy with currently approved antimalarial drugs. In collaboration with Dr. Roberto Moraes Barros Ph.D. and Thomas Wellems, M.D., Ph.D., at NIH’s National Institute of Allergy and Infectious Diseases, NCATS is developing a comparative screening platform to assay compound activity against multiple species of Plasmodium infecting humans. Lead Collaborators Craig J. Thomas, Ph.D., NCATS, NIH Richard T. Eastman, Ph.D., NCATS, NIH Publications Eastman RT, Khine P, Huang R, Thomas CJ, Su XZ. PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers. Sci Rep. 2016 May 5;6:25379. doi: 10.1038/srep25379. Mott BT, Eastman RT, Guha R, Sherlach KS, Siriwardana A, Shinn P, McKnight C, Michael S, Lacerda-Queiroz N, Patel PR, Khine P, Sun H, Kasbekar M, Aghdam N, Fontaine SD, Liu D, Mierzwa T, Mathews-Griner LA, Ferrer M, Renslo AR, Inglese J, Yuan J, Roepe PD, Su XZ, Thomas CJ. High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations. Sci Rep. 2015 Sep 25;5:13891. doi: 10.1038/srep13891. Public Health Impact Development of novel chemical genomic platforms for the development of drugs for the treatment of pathogenic protozoa, and assay development to elucidate compound mechanism of action. These developments will be leveraged to support ongoing global efforts to reduce the impact that pathogenic protozoa have on infected individuals and to reduce economic, social and health burdens resulting from these infectious agents. | Development of Novel Chemical Genomic Platforms for Pathogenic Protozo | Development of Novel Chemical Genomic Platforms for Pathogenic Protozo | ||||||
| 9830 | High-Throughput Drug Screening Identifies Novel Therapeutic Options for BPDCN | Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from neoplastic transformation of plasmacytoid dendritic cells (pDCs). Although an initial response to chemotherapy is common, BPDCN prognosis is extremely poor, and most patients relapse into a drug-resistant disease, highlighting the need for new treatment strategies. Scientific Synopsis To identify novel therapeutic options for BPDCN, researchers in the Chemical Technology group at NCATS performed a high-throughput single agent drug screening in two different BPDCN cell lines. By focusing only on drugs that were active in both models, NCATS researchers discovered that several bromodomain and extra-terminal domain inhibitors (BETis) were highly toxic to BPDCN. Mechanistically, BETi-induced apoptosis in BPDCN takes place via the disruption of a BPDCN-specific transcriptional network controlled by pDC-restricted master transcriptional regulator TCF4. To expand these findings in vivo, NCATS researchers established BPDCN xenografts by subcutaneous injection of BPDCN cell lines into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Treatment with the BETi CPI 203 was effective as a single agent in reducing tumor growth in both BPDCN xenograft models, supporting the clinical evaluation of BETis in this recalcitrant malignancy. The results of this study were published in Cancer Cell in November 2016. (A) Results of the HTS screening: Log10 molar IC50 plots comparing Cal-1 and Gen2.2 BPDCN cell lines. Of the 1,910 compounds screened, 314 showed activity in both BPDCN lines, after excluding inactive and poorly fitting compounds. BETis are highlighted in red. (B) Toxicity of BRD4 and TCF4 shRNAs in BPDCN cell lines. Shown is the fraction of live, shRNA-expressing (GFP+) cells over time after shRNA induction, compared with the day-0 uninduced value. (C) BPDCN cells were treated with either DMSO or the indicated amount of BETi JQ1. Cell viability was assessed by MTS assay at day 3 after treatment. (D) BPDCN cells were treated with either DMSO or the indicated amount of JQ1. The percentage of apoptotic cells (active caspase-3+, cleaved Parp1+) is shown at day 1 and day 2 after treatment. (E) BPDCN xenograft models were established by subcutaneous injection of Cal-1 and Gen2.2 cells in NOD/SCID mice and treated with either vehicle or the BETi CPI 203 (5 mg/kg) for the indicated time points. Tumor growth was measured as a function of tumor volume. (F) Relative mRNA levels of TCF4 and three of its targets in Cal-1 xenografts from mice treated for 5 days with CPI 203 or vehicle control. (Reprinted with permission from Ceribelli, M., et al. A Druggable TCF4 and BRD4 dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Cell, 30(5), 764–778. Copyright 2016 Cancer Cell.) Lead Collaborators Louis, M. Staudt, MD, PhD, NCI, NIH Craig J. Thomas, PhD, NCATS, NIH Boris Reizis, PhD, Columbia University Medical Center Michele Ceribelli, PhD, NCATS NIH Publications Ceribelli, M., Hou, Z. E., Kelly, P. N., Huang, D. W., Wright, G., Ganapathi, K., Evbuomwan, M.O., Pittaluga,S., Shaffer,A.L., Marcucci,G., Forman, S.J., Xiao, W., Guha, R., Zhang,X., Ferrer, M., Chaperot, L., Plumas, J., Jaffe, E.S., Thomas, C.J., Reizis, B., Staudt, L. M. (2016). A Druggable TCF4 and BRD4 dependent Transcriptional Network Sustains Malignancy in Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Cell, 30(5), 764–778. http://doi.org/10.1016/j.ccell.2016.10.002 Public Health Impact Bromodomain and extra-terminal domain inhibitors may represent a new class of agents used to treat blastic plasmacytoid dendritic cell neoplasms that are resistant to current chemotherapy. Outcomes This study provides a mechanistic rational for the clinical evaluation of bromodomain and extra-terminal domain inhibitors as a novel strategy to treat blastic plasmacytoid dendritic cell neoplasm. | Novel Therapeutic Options for BPDCN | Novel Therapeutic Options for BPDCN | ||||||
| 9829 | Matrix Screening Program Goals | Through matrix combination screening, NCATS aims to identify new drug combinations and to prioritize highly effective drug combinations for translation into clinical trials and novel therapeutic regimens for patients. Specific objectives include: Repositioning of approved and investigational drugs in the context of combination regimens for cancer treatment; Comparing the drug-combination landscape of 30 cancer cell line models (>8,000 combination per cell line) to generate predictive models of drug-drug interactions; and Integrating the small-molecule vulnerabilities uncovered via the matrix screening platform with genetic dependencies identified by RNA interference or CRISPR screening to identify the molecular determinants of specific drug-response “signatures;” and Integrating biologics (antibodies, recombinant proteins, etc.) into the matrix screening platform. | Matrix Screening Program Goals | Matrix Screening Program Goals |
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