Sarcoma Cell Line Screen of Oncology Drugs and Investigational Agents Identifies Patterns Associated with Gene and microRNA Expression.
The diversity in sarcoma phenotype and genotype make treatment of this family of diseases exceptionally challenging. Sixty-three human adult and pediatric sarcoma lines were screened with 100 FDA-approved oncology agents and 345 investigational agents. The investigational agents' library enabled comparison of several compounds targeting the same molecular entity allowing comparison of target specificity and heterogeneity of cell line response. Gene expression was derived from exon array data and microRNA expression was derived from direct digital detection assays. The compounds were screened against each cell line at nine concentrations in triplicate with an exposure time of 96 hours using Alamar blue as the endpoint. Results are presented for inhibitors of the following targets: aurora kinase, IGF-1R, MEK, BET bromodomain, and PARP1. Chemical structures, IC50 heat maps, concentration response curves, gene expression, and miR expression heat maps are presented for selected examples. In addition, two cases of exceptional responders are presented. The drug and compound response, gene expression, and microRNA expression data are publicly available at http://sarcoma.cancer.gov. These data provide a unique resource to the cancer research community.
Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland. teicherba@mail.nih.gov.
Beverly A
BA
Teicher
Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland.
Eric
E
Polley
Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland.
Mark
M
Kunkel
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
David
D
Evans
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Thomas
T
Silvers
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Rene
R
Delosh
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Julie
J
Laudeman
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Chad
C
Ogle
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Russell
R
Reinhart
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Michael
M
Selby
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
John
J
Connelly
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Erik
E
Harris
Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Anne
A
Monks
Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland.
Joel
J
Morris
D000328:Adult; D064127:Aurora Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D015507:Drugs, Investigational / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D015507:Drugs, Investigational; D035683:MicroRNAs; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D047428:Protein Kinase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017526:Receptor, IGF Type 1; D064127:Aurora Kinases; D020930:MAP Kinase Kinase Kinases