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

描述（由申请人提供）：结直肠癌（CRC）是美国和西方世界癌症死亡的第二大原因。尽管筛查增加和治疗进展，但CRC的死亡率（约50，000/年）和高国家卫生保健负担可能仍然很高，除非开发出更有效的方法来预测复发和对化疗-放疗的反应。例如，对于超过70%的不复发（即使没有治疗）的患者，CRC的五年生存率为90%。然而，非局部转移性CRC（mCRC）的这一比率下降到仅10%。CRC治疗和患者的结果可以显着改善，如果它可以集中在那些谁需要和最有可能受益于治疗的患者。因此，NCI将发现预后的新指标以及对化疗和放疗的反应可能性作为关键目标（NCI结肠直肠癌进展审查组（PRG）的建议，2000）。 作为第二阶段的结果，AmberGen开发了一种基于多基因表达谱的有前途的CRC肿瘤检测方法，称为Praxis-CRCTM。该检测旨在准确预测CRC复发的可能性和对用于治疗术后CRC患者的治疗的反应，包括主要化疗和外照射放疗。如提案中所述，在II期开发和评估的初始检测仅需要4个基因来预测复发（mCRC），准确率超过95%，4个基因来预测对5-氟尿嘧啶（5-FU）治疗的反应，准确率超过91%。这与为乳腺癌开发的商业测定法（例如OncoDxTM（Genomic Health））相比是有利的，OncoDxTM（Genomic Health）利用一组超过25个基因，准确性低得多。开发Praxis-CRCTM签名的新步骤包括：i）获取高质量的新鲜冷冻CRC肿瘤样品，其具有可追溯到5年前的已知临床结果数据，ii）测量和分析低噪声基因表达微阵列数据，iii）通过荟萃分析生成优先基因列表，iv）在FFPE样品上通过RT-PCR验证优先基因列表，具有超过5年的已知结果。V）在工业标准384孔RTPCR平台上开发最终测定。 二期桥梁项目旨在加速Praxis-CRCTM的商业化。这将涉及使用300份记录良好的临床FFPE肿瘤样本进一步细化和评估特征，以预测常见疗法（如folfox、folfiri和外部放射）的结果。该项目涉及AmberGen与生物医学检测产品的全球领导者之间的合作，该公司2008年的收入超过17亿美元，共有9，000名员工。由于第二阶段项目的成功和获得SBIR第二阶段桥梁资金的机会，该公司将提供至少600万美元的资金用于商业化的额外成本，包括大规模多机构验证研究，FDA监管批准和PRAXIS-CRCTM的全球营销。该项目还包括参与安大略癌症研究所（OICR），达纳法伯癌症研究所和加州大学圣地亚哥分校莫里斯癌症中心，高质量CRC肿瘤样本的主要来源，Ananomouse公司，（分包商）PRAXISTM的开发商，用于收集和分析微阵列基因表达数据的先进软件，和WaferGen生物系统公司，SmartChip实时PCR系统的开发商，该系统将用于改进初始生物标志物的发现。 公共卫生相关性：目前迫切需要一种准确的复发和对治疗预后的反应测定方法，用于结直肠癌（CRC），这是美国癌症相关死亡的第二大原因。AmberGen寻求资金，为PRAXIS-CRCTM的加速商业化提供关键支持，PRAXIS-CRCTM是一种在II期开发的基于基因表达的CRC肿瘤复发和反应测定方法。该检测将显著影响治疗，生活质量，并降低与CRC相关的高医疗保健成本。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: There exists an urgent need for an accurate recurrence and response to treatment prognostic assay for colorectal cancer (CRC), the second leading cause of cancer-related death in the U.S. AmberGen seeks funds to provide critical support for accelerated commercialization of PRAXIS-CRCTM, a gene expression-based CRC tumor recurrence and response assay developed during Phase II. This assay will significantly impact the treatment, quality of life and reduce the high health-care costs associated with CRC.