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

• DOI: 10.1371/journal.pone.0248140
• Publication Date: 2021-03-10T18:41:21Z
• Authors: Iwona Grad; Robert Hanes; Pilar Ayuda-Durán; Marieke Lydia Kui...; Jorrit M. Enserink; Leonardo A. Meza-...; Ola Myklebost
• Keywords: PARP inhibitor; Histone deacetylase inhibitor

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