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Tumor-independent host secretomes induced by angiogenesis and immune-checkpoint inhibitors
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2018-04-25 , DOI: 10.1158/1535-7163.mct-17-1066 Michalis Mastri , Christina R. Lee , Amanda Tracz , Robert S. Kerbel , Melissa Dolan , Yuhao Shi , John M.L. Ebos
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2018-04-25 , DOI: 10.1158/1535-7163.mct-17-1066 Michalis Mastri , Christina R. Lee , Amanda Tracz , Robert S. Kerbel , Melissa Dolan , Yuhao Shi , John M.L. Ebos
The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor “host” treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral “side effects” of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare “off-target” host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or “therasomes”) may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602–12. ©2018 AACR.
中文翻译:
血管生成和免疫检查点抑制剂诱导的肿瘤非依赖性宿主分泌组
各种循环血液蛋白的水平会随着癌症治疗而改变。监测治疗诱导的分泌组 (TIS) 可能用作建立最佳生物效应(例如剂量)或识别毒性和耐药性来源的生物标志物。尽管 TIS 可以直接源自肿瘤细胞,但非肿瘤“宿主”治疗反应也会影响全身分泌程序。对于肿瘤微环境的靶向抑制剂,包括抗血管生成和免疫检查点疗法,宿主 TIS 可以解释治疗的意外附带“副作用”。在这里,我们描述了用 VEGF、cMet/ALK 和 PD-1 通路的抗体和受体酪氨酸激酶抑制剂 (RTKI) 治疗的无癌小鼠的组织和血浆中宿主 TIS 的比较转录组学和蛋白质组学分析。我们发现,所有癌症疗法都引发 TIS,与肿瘤生长无关,与抗体相比,RTKI 中的全身性分泌基因变化强度更高。我们的结果表明,宿主 TIS 特征在药物靶标、药物类别和剂量之间存在差异。值得注意的是,蛋白质和基因宿主 TIS 特征并不总是相互预测,这表明仅转录组学方法对循环蛋白质的临床生物标志物开发存在局限性。总之,这些是第一项评估和比较 VEGF 和 PD-1 通路抑制的“脱靶”宿主分泌效应的研究,这些效应独立于肿瘤分期或肿瘤对治疗的反应。测试治疗对正常组织的影响以建立宿主介导的 TIS 特征(或“治疗体”)对于识别疾病不可知生物标志物以预测药物组合方法的益处(或局限性)可能很重要。摩尔癌症治疗; 17(7); 1602-12。©2018 AACR。
更新日期:2018-04-25
中文翻译:
血管生成和免疫检查点抑制剂诱导的肿瘤非依赖性宿主分泌组
各种循环血液蛋白的水平会随着癌症治疗而改变。监测治疗诱导的分泌组 (TIS) 可能用作建立最佳生物效应(例如剂量)或识别毒性和耐药性来源的生物标志物。尽管 TIS 可以直接源自肿瘤细胞,但非肿瘤“宿主”治疗反应也会影响全身分泌程序。对于肿瘤微环境的靶向抑制剂,包括抗血管生成和免疫检查点疗法,宿主 TIS 可以解释治疗的意外附带“副作用”。在这里,我们描述了用 VEGF、cMet/ALK 和 PD-1 通路的抗体和受体酪氨酸激酶抑制剂 (RTKI) 治疗的无癌小鼠的组织和血浆中宿主 TIS 的比较转录组学和蛋白质组学分析。我们发现,所有癌症疗法都引发 TIS,与肿瘤生长无关,与抗体相比,RTKI 中的全身性分泌基因变化强度更高。我们的结果表明,宿主 TIS 特征在药物靶标、药物类别和剂量之间存在差异。值得注意的是,蛋白质和基因宿主 TIS 特征并不总是相互预测,这表明仅转录组学方法对循环蛋白质的临床生物标志物开发存在局限性。总之,这些是第一项评估和比较 VEGF 和 PD-1 通路抑制的“脱靶”宿主分泌效应的研究,这些效应独立于肿瘤分期或肿瘤对治疗的反应。测试治疗对正常组织的影响以建立宿主介导的 TIS 特征(或“治疗体”)对于识别疾病不可知生物标志物以预测药物组合方法的益处(或局限性)可能很重要。摩尔癌症治疗; 17(7); 1602-12。©2018 AACR。