piperidines and quisinostat

Sarcomas are a heterogeneous group of mesenchymal orphan cancers and new treatment alternatives beyond traditional chemotherapeutic regimes are much needed. So far, tumor mutation analysis has not led to significant treatment advances, and we have attempted to bypass this limitation by performing direct drug testing of a library of 353 anti-cancer compounds that are either FDA-approved, in clinical trial, or in advanced stages of preclinical development on a panel of 13 liposarcoma cell lines. We identified and validated six drugs, targeting different mechanisms and with good efficiency across the cell lines: MLN2238 -a proteasome inhibitor, GSK2126458 -a PI3K/mTOR inhibitor, JNJ-26481585 -a histone deacetylase inhibitor, triptolide-a multi-target drug, YM155 -a survivin inhibitor, and APO866 (FK866)-a nicotinamide phosphoribosyl transferase inhibitor. GR50s for those drugs were mostly in the nanomolar range, and in many cases below 10 nM. These drugs had long-lasting effect upon drug withdrawal, limited toxicity to normal cells and good efficacy also against tumor explants. Finally, we identified potential genomic biomarkers of their efficacy. Being approved or in clinical trials, these drugs are promising candidates for liposarcoma treatment.

Topics: Acrylamides; Antineoplastic Agents; Biomarkers, Pharmacological; Boron Compounds; Cell Line, Tumor; Diterpenes; Drug Evaluation, Preclinical; Epoxy Compounds; Glycine; High-Throughput Screening Assays; Humans; Hydroxamic Acids; Imidazoles; Liposarcoma; Naphthoquinones; Phenanthrenes; Piperidines; Pyridazines; Quinolines; Small Molecule Libraries; Sulfonamides

Mutations in the

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lung Neoplasms; MicroRNAs; Mutation; Piperidines; Protein Kinase Inhibitors