Expression-Based Multi-Gene Signatures for CRC Recurrence and Chemoselection

总结 结直肠癌（CRC）是美国和西方世界癌症死亡的第二大原因。尽管 增加筛查和治疗方面的进步，死亡率（约50 000/年）和高国民保健水平 CRC的负担可能仍然很高，除非开发出更有效的方法来预测复发， 对放化疗的反应例如，CRC的五年生存率为90%，超过70%。 不复发的患者（即使没有治疗）。然而，非局部转移性CRC的发生率 （mCRC）下降到仅10%。CRC治疗和患者的结果可以显着改善，如果它可以 只关注那些需要和最有可能从治疗中受益的患者。为此 NCI已经将发现新的预后指标和可能性作为一个关键目标， 对化疗和放疗的反应（NCI结肠直肠癌进展评论的建议 （PRG），2000年）。 作为第二阶段的结果，AmberGen开发了一种基于多基因的有前途的CRC肿瘤检测方法。 表达谱，称为Praxis-CRCTM。本试验旨在准确预测以下可能性： CRC复发和对用于治疗手术后CRC患者的治疗的反应，包括主要 化疗和外照射放疗。在第II阶段开发和评价的初始试验 仅需4个基因即可预测复发（mCRC），准确率超过95%，并需4个基因即可预测缓解 5-氟尿嘧啶（5-FU）治疗的准确性超过91%，如提案中所述。相比之下 涉及开发用于乳腺癌的商业测定，例如OncoDxTM（GenomicHealth 25个以上的基因，但准确性要低得多。Praxis-CRCTM签名开发的新步骤 包括：i）获取具有已知临床结果数据的高质量新鲜冷冻CRC肿瘤样品， ii）低噪声基因表达微阵列数据的测量和分析，iii） iv）通过RT-PCR对FFPE样品验证优先基因列表， 5年以上的已知结果，v）在工业标准384孔RTPCR上开发最终测定 平台 二期桥梁项目旨在加速Praxis-CRCTM的商业化。这将涉及 进一步改进和评估特征以预测常见疗法的结果，例如folfox、folfiri 和外部辐射，使用300个记录良好的临床FFPE肿瘤样本。该项目涉及一个 AmberGen与生物医学检测产品的全球领导者建立了合作伙伴关系， 2008年的营业收入和9,000名员工。由于第二阶段项目的成功， 有机会获得SBIR第二阶段的桥梁资金，该公司将提供至少600万美元的资金， 商业化的额外成本，包括大规模多机构验证研究、FDA监管 PRAXIS-CRCTM的批准和全球上市。该项目还包括安大略省的参与 癌症研究所（OICR），达纳法伯癌症研究所和UCSD莫里斯癌症中心， 高质量CRC肿瘤样本的主要来源，Ananomouse，Corp，（分包商）开发商 PRAXISTM，用于收集和分析微阵列基因表达数据的先进软件，以及 WaferGen生物系统公司，SmartChip实时PCR系统的开发商，该系统将用于 改进的初始生物标志物发现。

Summary Colorectal cancer (CRC) is the second leading cause of cancer deaths in the U.S and Western world. Despite increased screening and advances in treatment, the mortality rate (~50,000/year) and high national health-care burden for CRC is likely to remain high unless more effective methods are developed to predict recurrence and response to chemo-radiation therapy. For example, the five-year survival rate of CRC is 90% for the over 70% of patients who do not recur (even without therapy). However, this rate for non-local metastasized CRC (mCRC) drops to only 10%. CRC treatment and the patient outcome could be significantly improved if it could be focused on only those patients who need and are most likely to benefit from the therapy. For this reason the NCI has made as a critical goal the ¿Discovery of new indicators of prognosis and the likelihood of response to chemotherapy and radiation¿ (Recommendations of the NCI Colorectal Cancer Progress Review Group (PRG), 2000). As a result of the Phase II, AmberGen has developed a promising CRC tumor assay based on multi-gene expression profiling, termed the Praxis-CRCTM. This assay is designed to accurately predict the likelihood of CRC recurrence and response to therapies used to treat post-surgical CRC patients including major chemotherapies and external beam radiotherapy. The initial assay developed and evaluated in Phase II requires only 4 genes to predict recurrence (mCRC) with over 95% accuracy and 4 genes to predict response to 5-fluorouracil (5-FU) therapy with over 91% accuracy as described in the proposal. This compares favorably to commercial assays developed for breast cancer such as OncoDxTM (Genomic Health) which utilize a panel of over 25 genes with much less accuracy. Novel steps in the development of the Praxis-CRCTM signature include: i) Acquisition of high-quality fresh-frozen CRC tumor samples with known clinical outcome data going back 5 years, ii) Measurement and analysis of low-noise gene expression microarray data, iii) Generation of priority gene list by Meta-Analysis, iv) Validation of the priority gene list by RT-PCR on FFPE samples with known outcome for over 5 years, v) Development of the final assay on an industry standard 384-well RTPCR platform. This Phase II Bridge project is aimed at accelerating the commercialization of Praxis-CRCTM. This will involve further refinement and evaluation of signatures to predict outcome of common therapies such as folfox, folfiri and external radiation using 300 well-documented clinical FFPE tumor samples. The project involves a partnership between AmberGen and a global leader in biomedical assay products with over $1.7 billion in revenue in 2008 and a total of 9,000 employees. As a result of the success of the Phase II project and the opportunity to receive SBIR Phase II Bridge funding, this company will provide at least $6M in funds for the additional costs of commercialization including a large-scale multi-institution validation study, FDA regulatory approval and world-wide marketing of PRAXIS-CRCTM. The project also includes participation by the Ontario Institute of Cancer Research (OICR), Dana Farber Cancer Institute and the UCSD Morris Cancer Center, major sources of high quality CRC tumor samples, Ananomouse, Corp, (subcontractor) the developer of PRAXISTM, advanced software for the collection and analysis of microarray gene expression data, and WaferGen Biosystems, Inc., developer of SmartChip¿ Real-Time PCR System which will be used for improved initial biomarker discovery.