Department of Tumor Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Department of Molecular Cell Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
PLoS One. 2021 Mar 10;16(3):e0248140. doi: 10.1371/journal.pone.0248140. eCollection 2021.
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.
肉瘤是一组异质性的间叶性孤儿癌，除了传统的化疗方案外，还需要新的治疗选择。到目前为止，肿瘤突变分析并没有带来显著的治疗进展，我们试图通过对一个包含 353 种抗癌化合物的文库进行直接药物测试来绕过这一限制，这些化合物要么已经获得 FDA 批准，要么正在临床试验中，要么处于临床前开发的后期阶段，我们在 13 种脂肪肉瘤细胞系中进行了测试。我们鉴定并验证了六种药物，这些药物针对不同的机制，在细胞系中具有良好的效率：MLN2238——一种蛋白酶体抑制剂，GSK2126458——一种 PI3K/mTOR 抑制剂，JNJ-26481585——一种组蛋白去乙酰化酶抑制剂，雷公藤红素——一种多靶点药物，YM155——一种存活素抑制剂，以及 APO866（FK866）——一种烟酰胺磷酸核糖基转移酶抑制剂。这些药物的 GR50 值大多在纳摩尔范围内，在许多情况下低于 10 nM。这些药物在停药后具有持久的效果，对正常细胞的毒性有限，对肿瘤外植体也有很好的疗效。最后，我们确定了它们疗效的潜在基因组生物标志物。这些药物已经获得批准或正在临床试验中，是治疗脂肪肉瘤的有前途的候选药物。
