A phase II study of RO4929097 in metastatic colorectal cancer.
A phase II study of RO4929097 in metastatic colorectal cancer.
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DOI：
10.1016/j.ejca.2012.02.056
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Sullivan D
中科院分区：
文献类型：
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作者：
Strosberg JR;Yeatman T;Weber J;Coppola D;Schell MJ;Han G;Almhanna K;Kim R;Valone T;Jump H;Sullivan D
Notch 信号通路在多种恶性肿瘤中被激活，并与结直肠癌的进展有关。 Notch 通路激活的第一步是由 γ-分泌酶介导的，γ-分泌酶是一种蛋白水解酶，可产生激活的细胞内 Notch (ICN)。 RO4929097 是 γ-分泌酶的选择性抑制剂。我们测试了 RO4929097 在转移性难治性结直肠癌患者中的活性。先前至少接受过两次全身化疗的转移性结直肠癌患者被纳入该研究。患者接受 RO4929097 治疗，推荐 II 期剂量为每天 20 毫克，连续用药 3 天，停药 4 天。周期长度为28天。每两个周期进行一次成像。对档案组织标本进行免疫组织化学染色，以检测 Notch 通路的组成部分：Notch1、ICN 和下游靶标 HES1。招募了 37 名患者，其中 33 名可进行毒性和反应评估。对档案组织的免疫组织化学分析表明，大多数患者的 notch 受体以及细胞内 notch 和下游基因 HES1 呈阳性染色。然而，在该组中没有观察到客观的放射学反应，并且只有 6 名患者的最佳反应是疾病稳定。中位 PFS 为 1.8 个月，中位 OS 为 6.0 个月。在这项对难治性转移性结直肠癌患者进行 RO4929097 的研究中，没有看到放射学反应，并且进展时间很短，这表明在研究剂量和时间表下的 RO4929097 在这种恶性肿瘤中具有最小的单药活性。
The Notch signaling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by γ-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of γ-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer. Patients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3 days on and 4 days off continuously. Cycle length was 28 days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN, and the downstream target HES1. 37 patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only 6 patients had stable disease as their best response. Median PFS was 1.8 months and median OS was 6.0 months. In this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.