A5086780533- Cancer Genomics and Diagnostics
- Cancer therapeutics and mechanisms
- Lung Cancer Treatments and Mutations
- Medical Imaging Techniques and Applications
- Protein Degradation and Inhibitors
- DNA Repair Mechanisms
- Chemical Reactions and Isotopes
- PARP inhibition in cancer therapy
- Computational Drug Discovery Methods
- Lung Cancer Research Studies
- HER2/EGFR in Cancer Research
- Cardiac Imaging and Diagnostics
- Radiomics and Machine Learning in Medical Imaging
- Mathematical Biology Tumor Growth
- Melanoma and MAPK Pathways
- Histone Deacetylase Inhibitors Research
- Radiopharmaceutical Chemistry and Applications
- Colorectal Cancer Treatments and Studies
- Epigenetics and DNA Methylation
- Cancer Research and Treatments
- RNA modifications and cancer
- Cancer Cells and Metastasis
- Microtubule and mitosis dynamics
- Cancer, Hypoxia, and Metabolism
- Cancer Treatment and Pharmacology
National Cancer Institute
2015-2025
National Institutes of Health
2013-2025
Center for Cancer Research
2013-2023
Leidos (United States)
2016
Frederick National Laboratory for Cancer Research
2016
Kyoto University
2013-2014
NeuroDevelopment Center
2014
ORCID
2014
Target (United States)
2013
SRA International (United States)
2012
Abstract High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, pharmacology. However, the information usually resides unwieldy databases, limiting ready data analysis integration. One resource that offers substantial potential for improvement this regard is NCI-60 cell line database compiled by U.S. National Cancer Institute, which has been extensively characterized across numerous genomic pharmacologic response platforms. In...
Anti-PARP drugs were initially developed as catalytic inhibitors to block the repair of DNA single-strand breaks. We recently reported that several PARP have an additional cytotoxic mechanism by trapping PARP-DNA complexes, and both olaparib niraparib act poisons at pharmacologic concentrations. Therefore, we proposed should be evaluated based on inhibition trapping. Here, novel inhibitor, BMN 673, compared its effects PARP1 PARP2 with two other clinical inhibitors, rucaparib, using...
A well-characterized library of experimental kinase inhibitors provides leads for targeting the untargeted kinome. Despite success protein as approved therapeutics, drug discovery has focused on a small subset targets. Here we provide thorough characterization Published Kinase Inhibitor Set (PKIS), set 367 small-molecule ATP-competitive that was recently made freely available with aim expanding research in this field and an experiment open-source target validation. We screen activity assays...
We recently showed that poly(ADP-ribose) polymerase (PARP) inhibitors exert their cytotoxicity primarily by trapping PARP-DNA complexes in addition to NAD<sup>+</sup>-competitive catalytic inhibitory mechanism. PARP is drug-specific, with olaparib exhibiting a greater ability than veliparib, whereas both compounds are potent inhibitors. Here, we evaluated the combination of or veliparib therapeutically relevant DNA-targeted drugs, including topoisomerase I inhibitor camptothecin, alkylating...
Abstract Camptothecin and its derivatives, topotecan irinotecan, are specific topoisomerase I (Top1) inhibitors potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop drug combinations, we conducted synthetic lethal siRNA screen using library that targets nearly 7,000 human genes. Depletion of ATR, main transducer replication stress, came as...
Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it challenging treat. Methods: Sixty-three human SCLC lines three NSCLC were screened for response 103 US Food Drug Administration–approved oncology agents 423 investigational agents. The library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. in triplicate nine...
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is a key contributor to cancer, making PI3K inhibitors promising approach for targeted therapy. The selectivity available varies across different isoforms. Alpelisib and inavolisib are selective α-isoform, while duvelisib targets δ- γ-isoforms, copanlisib pan-PI3K inhibitor, active against all This study investigated activity these four in combination with other agents using multi-cell type tumor spheroids composed 60%...
Abstract The diversity in sarcoma phenotype and genotype make treatment of this family diseases exceptionally challenging. Sixty-three human adult pediatric lines were screened with 100 FDA-approved oncology agents 345 investigational agents. agents' library enabled comparison several compounds targeting the same molecular entity allowing target specificity heterogeneity cell line response. Gene expression was derived from exon array data microRNA direct digital detection assays. against...
Abstract The NCI-60 human tumor cell line panel has proved to be a useful tool for the global cancer research community in search novel chemotherapeutics. publicly available characterization and compound screening data from assay have significantly contributed understanding of cellular mechanisms targeted by new oncology agents. Signature sensitivity/resistance patterns generated given chemotherapeutic agent against long served as fingerprint presentations that encompass target information...
Abstract The NCI60 human tumor cell line screen has been in operation as a service to the cancer research community for more than 30 years. operated with 96-well plates, 2-day exposure period test agents, and following fixation, visible absorbance endpoint by protein-staining dye sulforhodamine B. In this study, we describe next phase of important tool, HTS384 screen. Although lines remain same, updated is performed 384-well 3-day luminescent measure viability based upon cellular ATP...
Small cell lung cancer (SCLC) is an extremely aggressive that frequently recurs. Twenty-three human SCLC lines were selected representing varied Myc status. Gene expression of cancer, stem-like, hedgehog pathway, and notch pathway genes determined by RT(2)-PCR array Exon 1.0 ST array. Etoposide topotecan concentration response was examined. The IC50's for etoposide ranged over nearly 3 logs upon 96 hrs exposure to the drugs. status, TOP2A, TOP2B TOP1 mRNA or topoisomerase 1 2 protein did not...
Exome sequencing provides unprecedented insights into cancer biology and pharmacological response. Here we assess these two parameters for the NCI-60, which is among richest genomic publicly available cell line databases. Homozygous genetic variants that putatively affect protein function were identified in 1,199 genes (approximately 6% of all genes). Variants are either enriched or depleted compared to non-cancerous genomes, thus may be influential progression differential drug response...
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates genes of drug transporters and metabolic enzymes to detoxify small molecule xenobiotics. It has complex role in cancer biology, influencing both the progression suppression tumors by modulating malignant properties tumor cells anti-tumor immunity, depending on specific type developmental stage. This led discovery development selective AhR modulators, including BAY 2416964 which currently clinical...
Multicellular spheroids comprised of malignant cells, endothelial and mesenchymal stem cells served as an in vitro model human solid tumors to investigate the potentiation DNA-damaging drugs by pharmacologic modulation DNA repair pathways. The drugs, topotecan, trabectedin, temozolomide were combined with varied inhibitors damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR Rad3-related protein; berzosertib elimusertib), DNA-PK...
Abstract The SCLC combination screen examined a 9‐point concentration response of 180 third agents, alone and in with etoposide/carboplatin. predominant effect adding agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently lines sensitive In little or no etoposide/carboplatin, greater killing over the entire spectrum but never all lines. Exposing tubulin‐targeted agents (paclitaxel vinorelbine) simultaneously resulted primarily less cell killing. As...
<p>Analytical Data</p>
Abstract In this article, 5-aza-4′-thio-2′-β-fluoro-2′-deoxycytidine (F-aza-T-dCyd, NSC801845), a novel cytidine analog, is first disclosed and compared with T-dCyd, F-T-dCyd, aza-T-dCyd in cell culture mouse xenograft studies HCT-116 human colon carcinoma, OVCAR3 ovarian NCI-H23 NSCLC HL-60 leukemia, the PDX BL0382 bladder carcinoma. three of five lines (HCT-116, HL-60, BL-0382), F-aza-T-dCyd was more efficacious than aza-T-dCyd. Comparable activity observed for these two agents against...
2603 Background: B demonstrated antitumor and radiosensitizing activity in preclinical solid tumor models. Methods: A phase I trial was designed to assess escalating doses of 0.6, 0.9 or 1.2 mg/m2 IV twice weekly concurrent with re-RT 2Gy/5 days/wk 60-70 Gy. Evaluations included standard measures for adverse events (CTC v3.0), response (RECIST), progression-free survival (PFS) overall (OS). Baroreceptor reflex testing initiated a subset patients the potential cause observed orthostatic...
16526 Background: The over expression of EGFR in HNSCC stimulates tumor cell proliferation, inhibits apoptosis, and increases resistance to chemotherapy radiation. We examined the toxicity maximum tolerated dose (MTD), downstream signaling cellular effects biopsies locally advanced patients (Pts.) treated with GEF+PAC RT. Methods: Pilot phase I escalation study initiated at GEF 250 mg/d + PAC 45 mg/m 2 weekly x 6 concurrent RT 72 Gy. Eligibility: Stage III-IVB HNSCC, age=18 years, no prior...
The lack of effective methods to perform direct β-selective glycosylation reactions with 2-deoxy-1,4-dithio-D-erythro-pentofuranosides has long been a significant stumbling block for the multi-gram synthesis 4'-thio-2'-deoxy nucleosides. In addition, previously reported preparation appropriately substituted have proven problematic large scale synthesis. To address these issues, herein we describe modification and optimization allow convenient benzyl...
Abstract Small cell lung cancer (SCLC) is an extremely aggressive that frequently recurs after conventional cytotoxic chemotherapy. SCLC a neuroendocrine malignancy for which there no effective treatment affects &gt;200,000 people world-wide every year with very high mortality rate (&lt;5% of patients survive five years). cells are, indeed, small limited cytoplasm surrounding the nuclei. The tend to grow as floating clusters or spheroids are often difficult disaggregate. Twenty-four...
Abstract We have acquired &gt;400 investigational oncology agents, comprised primarily of targeted small molecules currently in clinical and/or preclinical anticancer studies. As treatment moves toward personalized therapeutic the NCI-60 human tumor cell line panel is an ideal community-wide tool to further understanding disease targets new agents. The includes lines from nine types, and extremely well characterized at molecular level, with both in-house crowd-sourced characterization,...