Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening

PLoS One. 2021 Mar 10;16(3):e0248140. doi: 10.1371/journal.pone.0248140. eCollection 2021.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Antineoplastic Agents / analysis
  • Antineoplastic Agents / chemistry
  • Biomarkers, Pharmacological
  • Boron Compounds / pharmacology
  • Cell Line, Tumor
  • Diterpenes / pharmacology
  • Drug Evaluation, Preclinical / methods*
  • Epoxy Compounds / pharmacology
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • High-Throughput Screening Assays / methods*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Imidazoles / pharmacology
  • Liposarcoma / drug therapy*
  • Naphthoquinones / pharmacology
  • Phenanthrenes / pharmacology
  • Piperidines / pharmacology
  • Pyridazines / pharmacology
  • Quinolines / pharmacology
  • Small Molecule Libraries / pharmacology
  • Sulfonamides / pharmacology

Substances

  • Acrylamides
  • Antineoplastic Agents
  • Biomarkers, Pharmacological
  • Boron Compounds
  • Diterpenes
  • Epoxy Compounds
  • Hydroxamic Acids
  • Imidazoles
  • MLN2238
  • N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
  • Naphthoquinones
  • Phenanthrenes
  • Piperidines
  • Pyridazines
  • Quinolines
  • Small Molecule Libraries
  • Sulfonamides
  • YM 155
  • quisinostat
  • triptolide
  • omipalisib
  • Glycine

Grant support

This work was supported by grants from the Norwegian Cancer Society to OM/IG (4489653) and JME (182524, 4487303 and 208012), and from the Norwegian Research Council to OM/RH 221580) and JME (294916). This work was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme (262652). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.