Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment
Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment
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DOI：
10.1016/j.ebiom.2016.07.017
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发表时间：
2016-08-01
期刊：
影响因子：
11.1
通讯作者：
Harris, Adrian L.
中科院分区：
文献类型：
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作者：
Mehta, Shaveta;Hughes, Nick P.;Harris, Adrian L.
抗 VEGF 抗体贝伐单抗可延长多种癌症类型的无进展生存期，但获得性耐药很常见。临床前已观察到适应情况，但尚无人类研究显示涉及的时间和基因，从而能够制定新的临床范例。在一项对 35 名导管乳腺癌患者进行新辅助化疗前 2 周的机会窗口研究中，我们通过动态对比增强磁共振 [DCEMRI]、转录组学和病理学监测贝伐单抗反应。初始治疗反应显示 DCE-MRI 中位 K-trans 总体显着下降，血管生成因子如 ESM1 和 FLT1 以及增殖。然而，它也揭示了巨大的异质性，从血管密度的下调和中心坏死到新脉管系统的持续生长。至关重要的是，导致耐药的显着上调途径包括糖酵解和 pH 适应、PI3K-Akt 和免疫检查点信号传导（这些途径存在抑制剂），为研究此类组合提供了强有力的理由。这些发现支持抗血管生成试验应纳入高 K-trans 患者的初始富集，以及一系列有针对性的治疗方案，以满足潜在的早期耐药途径。正在进行使用分子标记作为靶向药物的多臂适应性试验，但我们的结果表明，在使用影响肿瘤微环境的药物时，需要通过更早的适应来进一步修改。 (C) 2016 年作者。由 Elsevier B.V. 出版
Anti-VEGF antibody bevacizumab has prolonged progression-free survival in several cancer types, however acquired resistance is common. Adaption has been observed pre-clinically, but no human study has shown timing and genes involved, enabling formulation of new clinical paradigms.In a window-of-opportunity study in 35 ductal breast cancer patients for 2 weeks prior to neoadjuvant chemotherapy, we monitored bevacizumab response by Dynamic Contrast-Enhanced Magnetic Resonance [DCEMRI], transcriptomic and pathology.Initial treatment response showed significant overall decrease in DCE-MRI median K-trans, angiogeinc factors such ESM1 and FLT1, and proliferation. However, it also revealed great heterogeneity, spanning from downregulation of blood vessel density and central necrosis to continued growth with new vasculature. Crucially, significantly upregulated pathways leading to resistance included glycolysis and pH adaptation, PI3K-Akt and immune checkpoint signaling, for which inhibitors exist, making a strong case to investigate such combinations.These findings support that anti-angiogenesis trials should incorporate initial enrichment of patients with high K-trans, and a range of targeted therapeutic options to meet potential early resistance pathways. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but our results suggest this needs to be further modified by much earlier adaptation when using drugs affecting the tumor microenvironment. (C) 2016 The Authors. Published by Elsevier B.V.