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Assessing cardiac safety in oncology drug development.
Seltzer JH, Gintant G, Amiri-Kordestani L, Singer J, Koplowitz LP, Moslehi JJ, Barac A, Yu AF
(2019) Am Heart J 214: 125-133
MeSH Terms: Antineoplastic Agents, Antineoplastic Agents, Immunological, Biomarkers, Cardiologists, Cardiovascular Diseases, Cell Line, Tumor, Clinical Trials as Topic, Data Collection, Drug Development, Drug Screening Assays, Antitumor, Heart, Humans, Immunotherapy, Medical Oncology, Research Design, Trastuzumab
Added November 12, 2019
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16 MeSH Terms
Colorectal Cancer Cell Line Proteomes Are Representative of Primary Tumors and Predict Drug Sensitivity.
Wang J, Mouradov D, Wang X, Jorissen RN, Chambers MC, Zimmerman LJ, Vasaikar S, Love CG, Li S, Lowes K, Leuchowius KJ, Jousset H, Weinstock J, Yau C, Mariadason J, Shi Z, Ban Y, Chen X, Coffey RJC, Slebos RJC, Burgess AW, Liebler DC, Zhang B, Sieber OM
(2017) Gastroenterology 153: 1082-1095
MeSH Terms: Antineoplastic Agents, Biomarkers, Tumor, Cell Line, Tumor, Chromatography, Liquid, Colorectal Neoplasms, Databases, Protein, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Mutation, Neoplasm Proteins, Patient Selection, Polymorphism, Single Nucleotide, Precision Medicine, Proteome, Proteomics, Signal Transduction, Stromal Cells, Tandem Mass Spectrometry, Transcriptome, Tumor Microenvironment
Show Abstract · Added July 17, 2017
BACKGROUND AND AIMS - Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses.
METHODS - Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data.
RESULTS - Cell lines mirrored the proteomic aberrations of primary tumors, in particular for intrinsic programs. Tumor relationships of protein expression with DNA copy number aberrations and signatures of post-transcriptional regulation were recapitulated in cell lines. The 5 proteomic subtypes previously identified in tumors were represented among cell lines. Nonetheless, systematic differences between cell line and tumor proteomes were apparent, attributable to stroma, extrinsic signaling, and growth conditions. Contribution of tumor stroma obscured signatures of DNA mismatch repair identified in cell lines with a hypermutation phenotype. Global proteomic data showed improved utility for predicting both known drug-target relationships and overall drug sensitivity as compared with genomic or transcriptomic measurements. Inhibition of targetable proteins associated with drug responses further identified corresponding synergistic or antagonistic drug combinations. Our data provide evidence for CRC proteomic subtype-specific drug responses.
CONCLUSIONS - Proteomes of established CRC cell line are representative of primary tumors. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Functional Optical Imaging of Primary Human Tumor Organoids: Development of a Personalized Drug Screen.
Walsh AJ, Cook RS, Skala MC
(2017) J Nucl Med 58: 1367-1372
MeSH Terms: Drug Screening Assays, Antitumor, Humans, Neoplasms, Optical Imaging, Organoids, Precision Medicine
Show Abstract · Added April 15, 2019
Primary tumor organoids are a robust model of individual human cancers and present a unique platform for patient-specific drug testing. Optical imaging is uniquely suited to assess organoid function and behavior because of its subcellular resolution, penetration depth through the entire organoid, and functional endpoints. Specifically, optical metabolic imaging (OMI) is highly sensitive to drug response in organoids, and OMI in tumor organoids correlates with primary tumor drug response. Therefore, an OMI organoid drug screen could enable accurate testing of drug response for individualized cancer treatment. The objective of this perspective is to introduce OMI and tumor organoids to a general audience in order to foster the adoption of these techniques in diverse clinical and laboratory settings.
© 2017 by the Society of Nuclear Medicine and Molecular Imaging.
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MeSH Terms
Human sterol 14α-demethylase as a target for anticancer chemotherapy: towards structure-aided drug design.
Hargrove TY, Friggeri L, Wawrzak Z, Sivakumaran S, Yazlovitskaya EM, Hiebert SW, Guengerich FP, Waterman MR, Lepesheva GI
(2016) J Lipid Res 57: 1552-63
MeSH Terms: 14-alpha Demethylase Inhibitors, Antifungal Agents, Antineoplastic Agents, Antiprotozoal Agents, Catalytic Domain, Cell Line, Tumor, Cholestadienols, Crystallography, X-Ray, Drug Design, Drug Screening Assays, Antitumor, Humans, Hydrogen Bonding, Lanosterol, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Sterol 14-Demethylase
Show Abstract · Added April 6, 2017
Rapidly multiplying cancer cells synthesize greater amounts of cholesterol to build their membranes. Cholesterol-lowering drugs (statins) are currently in clinical trials for anticancer chemotherapy. However, given at higher doses, statins cause serious side effects by inhibiting the formation of other biologically important molecules derived from mevalonate. Sterol 14α-demethylase (CYP51), which acts 10 steps downstream, is potentially a more specific drug target because this portion of the pathway is fully committed to cholesterol production. However, screening a variety of commercial and experimental inhibitors of microbial CYP51 orthologs revealed that most of them (including all clinical antifungals) weakly inhibit human CYP51 activity, even if they display high apparent spectral binding affinity. Only one relatively potent compound, (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide (VFV), was identified. VFV has been further tested in cellular experiments and found to decrease proliferation of different cancer cell types. The crystal structures of human CYP51-VFV complexes (2.0 and 2.5 Å) both display a 2:1 inhibitor/enzyme stoichiometry, provide molecular insights regarding a broader substrate profile, faster catalysis, and weaker susceptibility of human CYP51 to inhibition, and outline directions for the development of more potent inhibitors.
Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.
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17 MeSH Terms
High Throughput Screening for Colorectal Cancer Specific Compounds.
Xie J, Wang C, Gore JC
(2016) Comb Chem High Throughput Screen 19: 180-8
MeSH Terms: Antineoplastic Agents, Apoptosis, Cardiac Glycosides, Cardiotonic Agents, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Glioma, High-Throughput Screening Assays, Humans, Hypolipidemic Agents, Structure-Activity Relationship
Show Abstract · Added February 6, 2016
The development of new anti-cancer therapeutic agents is necessary to improve antitumor efficacy and reduce toxicities. Here we report using a systematic anticancer drug screening approach we developed previously, to concurrently screen colon and glioma cancer cell lines for 2000 compounds with known bioactivity and 1920 compounds with unknown activity. The hits specific to each tumor cell line were then selected, and further tested with the same cells transfected with EGFP (Enhanced Green Fluorescent Protein) alone. By comparing the percentage of signal reduction from the same cells transfected with the sensor-conjugated reporter system; hits preferably causing apoptosis were identified. Among the known lead compounds, many cardiac glycosides used as cardiotonic drugs were found to effectively and specifically kill colon cancer cells, while statins (hypolipidemic agents) used as cholesterol lowering drugs were relatively more effective in killing glioma cells.
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14 MeSH Terms
High efficacy vasopermeability drug candidates identified by screening in an ex ovo chorioallantoic membrane model.
Pink D, Luhrs KA, Zhou L, Schulte W, Chase J, Frosch C, Haberl U, Nguyen V, Roy AI, Lewis JD, Zijlstra A, Parseghian MH
(2015) Sci Rep 5: 15756
MeSH Terms: Animals, Antineoplastic Agents, Capillary Permeability, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane, Drug Screening Assays, Antitumor, Humans, Mice
Show Abstract · Added April 6, 2017
The use of rodent models to evaluate efficacy during testing is accompanied by significant economic and regulatory hurdles which compound the costs of screening for promising drug candidates. Vasopermeation Enhancement Agents (VEAs) are a new class of biologics that are designed to increase the uptake of cancer therapeutics at the tumor site by modifying vascular permeability in the tumor to increase the therapeutic index of co-administered drugs. To evaluate the efficacy of a panel of VEA clinical candidates, we compared the rodent Miles assay to an equivalent assay in the ex ovo chicken embryo model. Both model systems identified the same candidate (PVL 10) as the most active promoter of vasopermeation in non-tumor tissues. An ex ovo chicken embryo system was utilized to test each candidate VEA in two human tumor models at a range of concentrations. Vasopermeation activity due to VEA was dependent on tumor type, with HEp3 tumors displaying higher levels of vasopermeation than MDA-MB-435. One candidate (PVL 10) proved optimal for HEp3 tumors and another (PVL 2) for MDA-MB-435. The use of the ex ovo chicken embryo model provides a rapid and less costly alternative to the use of rodent models for preclinical screening of drug candidates.
1 Communities
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9 MeSH Terms
Oncogenic KRAS promotes malignant brain tumors in zebrafish.
Ju B, Chen W, Orr BA, Spitsbergen JM, Jia S, Eden CJ, Henson HE, Taylor MR
(2015) Mol Cancer 14: 18
MeSH Terms: Animals, Animals, Genetically Modified, Brain, Brain Neoplasms, Cell Transformation, Neoplastic, Disease Models, Animal, Drug Screening Assays, Antitumor, Gene Expression, Humans, Immunohistochemistry, Keratin-5, Nerve Tissue Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Signal Transduction, TOR Serine-Threonine Kinases, Transgenes, Zebrafish, ras Proteins
Show Abstract · Added February 12, 2015
BACKGROUND - Zebrafish have been used as a vertebrate model to study human cancers such as melanoma, rhabdomyosarcoma, liver cancer, and leukemia as well as for high-throughput screening of small molecules of therapeutic value. However, they are just emerging as a model for human brain tumors, which are among the most devastating and difficult to treat. In this study, we evaluated zebrafish as a brain tumor model by overexpressing a human version of oncogenic KRAS (KRAS(G12V)).
METHODS - Using zebrafish cytokeratin 5 (krt5) and glial fibrillary acidic protein (gfap) gene promoters, we activated Ras signaling in the zebrafish central nervous system (CNS) through transient and stable transgenic overexpression. Immunohistochemical analyses were performed to identify activated pathways in the resulting brain tumors. The effects of the MEK inhibitor U0126 on oncogenic KRAS were evaluated.
RESULTS - We demonstrated that transient transgenic expression of KRAS(G12V) in putative neural stem and/or progenitor cells induced brain tumorigenesis. When expressed under the control of the krt5 gene promoter, KRAS(G12V) induced brain tumors in ventricular zones (VZ) at low frequency. The majority of other tumors were composed mostly of spindle and epithelioid cells, reminiscent of malignant peripheral nerve sheath tumors (MPNSTs). In contrast, when expressed under the control of the gfap gene promoter, KRAS(G12V) induced brain tumors in both VZs and brain parenchyma at higher frequency. Immunohistochemical analyses indicated prominent activation of the canonical RAS-RAF-ERK pathway, variable activation of the mTOR pathway, but no activation of the PI3K-AKT pathway. In a krt5-derived stable and inducible transgenic line, expression of oncogenic KRAS resulted in skin hyperplasia, and the MEK inhibitor U0126 effectively suppressed this pro-proliferative effects. In a gfap-derived stable and inducible line, expression of oncogenic KRAS led to significantly increased mitotic index in the spinal cord.
CONCLUSIONS - Our studies demonstrate that zebrafish could be explored to study cellular origins and molecular mechanisms of brain tumorigenesis and could also be used as a platform for studying human oncogene function and for discovering oncogenic RAS inhibitors.
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20 MeSH Terms
Repurposing the FDA-approved pinworm drug pyrvinium as a novel chemotherapeutic agent for intestinal polyposis.
Li B, Flaveny CA, Giambelli C, Fei DL, Han L, Hang BI, Bai F, Pei XH, Nose V, Burlingame O, Capobianco AJ, Orton D, Lee E, Robbins DJ
(2014) PLoS One 9: e101969
MeSH Terms: Adenomatous Polyposis Coli, Animals, Antineoplastic Agents, Cell Survival, Drug Approval, Drug Repositioning, Drug Screening Assays, Antitumor, HCT116 Cells, Humans, Mice, Inbred C57BL, Mice, Transgenic, Pyrvinium Compounds, Wnt Signaling Pathway
Show Abstract · Added November 2, 2015
Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes.
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13 MeSH Terms
Myostatin inhibits proliferation and insulin-stimulated glucose uptake in mouse liver cells.
Watts R, Ghozlan M, Hughey CC, Johnsen VL, Shearer J, Hittel DS
(2014) Biochem Cell Biol 92: 226-34
MeSH Terms: Animals, Antineoplastic Agents, Cell Proliferation, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Glucose, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Myostatin, Phosphorylation, Proto-Oncogene Proteins c-akt, RNA, Long Noncoding, Structure-Activity Relationship, Tumor Cells, Cultured
Show Abstract · Added June 7, 2014
Although myostatin functions primarily as a negative regulator of skeletal muscle growth and development, accumulating biological and epidemiological evidence indicates an important contributing role in liver disease. In this study, we demonstrate that myostatin suppresses the proliferation of mouse Hepa-1c1c7 murine-derived liver cells (50%; p < 0.001) in part by reducing the expression of the cyclins and cyclin-dependent kinases that elicit G1-S phase transition of the cell cycle (p < 0.001). Furthermore, real-time PCR-based quantification of the long noncoding RNA metastasis associated lung adenocarcinoma transcript 1 (Malat1), recently identified as a myostatin-responsive transcript in skeletal muscle, revealed a significant downregulation (25% and 50%, respectively; p < 0.05) in the livers of myostatin-treated mice and liver cells. The importance of Malat1 in liver cell proliferation was confirmed via arrested liver cell proliferation (p < 0.05) in response to partial Malat1 siRNA-mediated knockdown. Myostatin also significantly blunted insulin-stimulated glucose uptake and Akt phosphorylation in liver cells while increasing the phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS), a protein that is essential for cancer cell proliferation and insulin-stimulated glucose transport. Together, these findings reveal a plausible mechanism by which circulating myostatin contributes to the diminished regenerative capacity of the liver and diseases characterized by liver insulin resistance.
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17 MeSH Terms
Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.
May WA, Grigoryan RS, Keshelava N, Cabral DJ, Christensen LL, Jenabi J, Ji L, Triche TJ, Lawlor ER, Reynolds CP
(2013) PLoS One 8: e80060
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p16, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Humans, Sarcoma, Ewing, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Show Abstract · Added February 8, 2016
Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.
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9 MeSH Terms