Molecular Pharmacology Group, Institute of Pharmaceutical Sciences of Western Switzerland, 1 Rue Michel-Servet, 1211, Geneva 4, Switzerland.
Translational Research Center in Oncohaematology, 1 Rue Michel-Servet, 1211, Geneva 4, Switzerland.
Br J Cancer. 2020 Aug;123(4):556-567. doi: 10.1038/s41416-020-0890-y. Epub 2020 May 22.
Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance.
We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (-ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC).
Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3-kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic co-culture models revealed significant inhibition of the spheroid growth (up to 95%).
We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development.
药物联合使用可以提高癌症治疗的疗效，降低副作用的发生和获得性耐药的发生。
我们使用经过验证的治疗指导多药物优化（TGMO）方法从数学角度解决了这一挑战。在一组遗传上不同的人肾细胞癌（RCC）细胞系中，无论是慢性用舒尼替尼（-ST）治疗还是舒尼替尼初治，我们都确定了细胞系特异性的低剂量优化药物组合（ODC）。
建立了针对三种舒尼替尼初治和三种舒尼替尼预处理细胞的六种细胞类型特异性的低剂量药物组合。这些 ODC 有效地抑制了 RCC 细胞的代谢活性，而对非癌细胞无效。基于单次筛选测试和三次搜索，从十种药物开始，我们确定了含有四种药物的高效药物混合物。所有 ODC 均包含 AZD4547（FGFR 信号通路抑制剂）和 pictilisib（全磷酸肌醇 3-激酶抑制剂），但第三和第四种药物不同。ODC 治疗显著降低了细胞代谢活性（高达 70%）并诱导细胞凋亡，与舒尼替尼预处理无关。ODC 的疗效优于 RCC 的标准治疗药物舒尼替尼。此外，短期饥饿增强了 ODC 的活性。二维结果的转化为三维异质共培养模型显示出对球体生长的显著抑制（高达 95%）。
我们证明了一种有前途的低剂量药物组合开发方法，可以获得对初治和耐药肿瘤有效的药物组合。然而，我们强调需要进一步的机制研究和临床前开发。
