High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097
High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097
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DOI：
10.1016/j.molonc.2011.01.001
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发表时间：
2011-06-01
影响因子：
6.6
通讯作者：
Boylan, John F.
中科院分区：
文献类型：
--
作者：
He, Wei;Luistro, Leopoldo;Boylan, John F.
人们对早期应用患者选择标记物来前瞻性地识别可能从癌症治疗中表现出临床益处的患者的兴趣继续增加。假设的产生和临床策略通常开始于临床前阶段，在此阶段，应答和无应答的肿瘤细胞系首先被识别和表征。在本研究中，我们研究了体内对γ分泌酶抑制剂RO4929097耐药的驱动因素。从组织培养水平开始，我们发现肿瘤细胞系对RO4929097有明显的il - 6和il - 8表达差异。我们在临床前疗效水平上验证了这一分子特征，并鉴定了对RO4929097体内作用产生抗性的其他异种移植物模型。我们的数据表明，对于IL6和IL8过表达的肿瘤，RO4929097不再影响血管生成或肿瘤相关成纤维细胞的浸润。这些临床前数据为在服用RO4929097之前预先选择具有低水平IL6和IL8的患者提供了依据。将这一假设扩展到临床，我们在第一阶段给药RO4929097之前监测了患者il - 6和il - 8的血清水平。有趣的是，一小部分从RO4929097获得某种临床益处的患者呈现出较低的il - 6和il - 8基线水平。我们的数据支持对RO4929097和其他类型的Notch抑制剂进行早期临床评估的患者选择标记的持续研究。(c) 2011年欧洲生化学会联合会。Elsevier B.V.版权所有。
Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the gamma-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation. (c) 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.