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Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening
Iwona Grad1, Robert Hanes1,2,3, Pilar Ayuda-Durán3
1Department of Tumor Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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.
Insights
Researchers screened 353 anti-cancer drugs against liposarcoma cell lines, identifying six effective drugs including proteasome and PI3K/mTOR inhibitors. These compounds show promise for liposarcoma treatment with potential biomarkers identified.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Sarcomas, particularly liposarcomas, are rare mesenchymal cancers lacking effective treatment options.
- Traditional mutation analysis has yielded limited therapeutic advances for sarcomas.
- Novel therapeutic strategies are urgently needed for liposarcoma treatment.
Purpose of the Study:
- To identify effective anti-cancer drugs for liposarcoma treatment through direct drug screening.
- To bypass limitations of tumor mutation analysis by testing drug efficacy directly on cell lines.
- To discover potential genomic biomarkers associated with drug response in liposarcoma.
Main Methods:
- A library of 353 anti-cancer compounds was screened against 13 liposarcoma cell lines.
- Drug efficacy was assessed by determining half-maximal growth inhibitory concentrations (GR50).
- Genomic biomarkers correlating with drug efficacy were identified.
Main Results:
- Six drugs demonstrated high efficacy across liposarcoma cell lines, with GR50 values often in the nanomolar range.
- Effective drugs included MLN2238 (proteasome inhibitor), GSK2126458 (PI3K/mTOR inhibitor), JNJ-26481585 (HDAC inhibitor), triptolide, YM155 (survivin inhibitor), and APO866 (NAMPT inhibitor).
- These drugs exhibited long-lasting effects, low toxicity to normal cells, and efficacy in tumor explants.
Conclusions:
- Several FDA-approved or clinical-stage drugs show significant potential for liposarcoma treatment.
- The identified drugs target diverse mechanisms and are effective across multiple liposarcoma cell lines.
- Potential genomic biomarkers may guide personalized liposarcoma therapy selection.
