Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development.
Development of an integrated genomic classifier for a novel agent in colorectal cancer: approach to individualized therapy in early development.
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DOI：
10.1158/1078-0432.ccr-09-3191
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发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Eckhardt SG
中科院分区：
文献类型：
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作者：
Pitts TM;Tan AC;Kulikowski GN;Tentler JJ;Brown AM;Flanigan SA;Leong S;Coldren CD;Hirsch FR;Varella-Garcia M;Korch C;Eckhardt SG
过多的药物处于结直肠癌的早期发展阶段，包括靶向胰岛素样生长因子受体（IGF 1 R）途径的药物。在目前众多癌症靶点的环境下，必须制定患者选择策略，以便在I期试验的后期阶段进行初步测试。本研究的目的是开发和表征IGF 1 R酪氨酸激酶抑制剂OSI-906的预测生物标志物，该生物标志物可应用于该药物的结直肠癌（CRC）特异性研究。将27个CRC细胞系暴露于OSI-906，并根据IC 50值分为敏感（< 1.5μM）或耐药（>5μM）。对细胞系进行效应蛋白的免疫印迹和免疫组织化学、通过FISH的IGFIR拷贝数、KRAS/BRAF/PI 3 K突变状态和基线基因阵列分析。最敏感和抗性的细胞系用于基因阵列和途径分析，沿着高等级基因的shRNA敲低。然后针对8个人CRC外植体在体内测试所得的整合基因组分类器。来自细胞系和异种移植物的基线基因阵列数据用于开发k-顶级评分对（k-TSP）分类器，其与IGFIR FISH和KRAS突变状态组合，能够以100%的准确度预测患者来源的CRC异种移植物的测试集。这些结果表明，开发个体化治疗的综合方法是可行的，应在新药开发的早期应用，最好与后期I期试验结合使用。
A plethora of agents are in early stages of development for colorectal cancer, including those that target the insulin-like growth factor receptor (IGF1R) pathway. In the current environment of numerous cancer targets, it is imperative that patient selection strategies be developed with the intent of preliminary testing in the latter stages of phase I trials. The goal of this study was to develop and characterize predictive biomarkers for an IGF1R tyrosine kinase inhibitor, OSI-906, that could be applied in colorectal cancer (CRC)-specific studies of this agent. Twenty-seven CRC cell lines were exposed to OSI-906 and classified according to IC50 value as sensitive (< 1.5μM), or resistant (>5μM). Cell lines were subjected to immunoblotting and immunohistochemistry for effector proteins, IGFIR copy number by FISH, KRAS/BRAF/PI3K mutation status, and baseline gene array analysis. The most sensitive and resistant cell lines were utilized for gene array and pathway analyses, along with shRNA knockdown of highly ranked genes. The resulting integrated genomic classifier was then tested against 8 human CRC explants in vivo. Baseline gene array data from cell lines and xenografts was used to develop a k-Top Scoring Pair (k-TSP) classifier, which in combination with IGFIR FISH and KRAS mutational status, was able to predict with 100% accuracy a test set of patient-derived CRC xenografts. These results indicate that an integrated approach to the development of individualized therapy is feasible and should be applied early in the development of novel agents, ideally in conjunction with late-stage phase I trials.