Vascular endothelial growth factor A as predictive marker for mTOR inhibition in relapsing high-grade serous ovarian cancer.
Vascular endothelial growth factor A as predictive marker for mTOR inhibition in relapsing high-grade serous ovarian cancer.
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DOI：
10.1186/s12918-016-0278-z
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发表时间：
2016-04-18
影响因子：
--
通讯作者：
Perco P
中科院分区：
文献类型：
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作者：
Andorfer P;Heuwieser A;Heinzel A;Lukas A;Mayer B;Perco P
高级别浆液性卵巢癌（HGSOC）对包括顺铂和紫杉醇在内的一线药物治疗产生耐药性是一个重大挑战。为了延长卵巢癌患者的无进展生存期，需要鉴定突破耐药性的候选药物，理想地与允许精确使用的预测性生物标志物组合。进一步结合药物作用机制对肿瘤组织中驱动耐药性的分子过程进行建模，为鉴定候选药物和相关的预测性生物标志物提供了策略。转录组学概况和生物医学文献挖掘结果的整合提供了1242种与卵巢癌耐药性相关的蛋白质。将这一组整合到蛋白质相互作用网络上，然后进行图形分割，得到在24个分子过程中嵌入409个蛋白质的耐药HGSOC的分子过程模型表示。利用独立的转录组学谱和无进展生存期的随访数据，可以推导出基于分子生物标志物的分类器，用于预测一线治疗下的复发。在包封TGF-β、mTOR、Jak-STAT和神经营养因子信号传导的分子过程中鉴定特定相关的生物标志物。顺铂和紫杉醇的作用机制分子模型表示嵌入了非常相同的信号传导组分，并且特别是受mTOR途径激活状态影响的蛋白质变得明显，包括VEGFA。分析mTOR抑制剂西罗莫司的作用干扰机制显示了对顺铂和紫杉醇施加的耐药性特征的特异性影响，进一步证明了与紫杉醇作用机制的合成致死相互作用涉及细胞周期蛋白D1。通过VEGFA对耐药性高级别浆液性卵巢癌进行分层，并在途径激活的情况下用mTOR抑制剂进行特异性治疗，可以增加克服一线治疗耐药性的精度。
Development of resistance against first line drug therapy including cisplatin and paclitaxel in high-grade serous ovarian cancer (HGSOC) presents a major challenge. Identifying drug candidates breaking resistance, ideally combined with predictive biomarkers allowing precision use are needed for prolonging progression free survival of ovarian cancer patients. Modeling of molecular processes driving drug resistance in tumor tissue further combined with mechanism of action of drugs provides a strategy for identification of candidate drugs and associated predictive biomarkers. Consolidation of transcriptomics profiles and biomedical literature mining results provides 1242 proteins linked with ovarian cancer drug resistance. Integrating this set on a protein interaction network followed by graph segmentation results in a molecular process model representation of drug resistant HGSOC embedding 409 proteins in 24 molecular processes. Utilizing independent transcriptomics profiles with follow-up data on progression free survival allows deriving molecular biomarker-based classifiers for predicting recurrence under first line therapy. Biomarkers of specific relevance are identified in a molecular process encapsulating TGF-beta, mTOR, Jak-STAT and Neurotrophin signaling. Mechanism of action molecular model representations of cisplatin and paclitaxel embed the very same signaling components, and specifically proteins afflicted with the activation status of the mTOR pathway become evident, including VEGFA. Analyzing mechanism of action interference of the mTOR inhibitor sirolimus shows specific impact on the drug resistance signature imposed by cisplatin and paclitaxel, further holding evidence for a synthetic lethal interaction to paclitaxel mechanism of action involving cyclin D1. Stratifying drug resistant high grade serous ovarian cancer via VEGFA, and specifically treating with mTOR inhibitors in case of activation of the pathway may allow adding precision for overcoming resistance to first line therapy.