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

简介(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。尽管增加了筛查并在治疗方面取得了进展，但除非开发出更有效的方法来预测复发和化疗放射治疗的反应，否则结直肠癌的死亡率(约50,000/年)和沉重的国家保健负担可能仍然很高。例如，结直肠癌的五年存活率为90%，超过70%的患者没有复发(即使没有治疗)。然而，非局部转移性结直肠癌(MCRC)的这一比例下降到只有10%。如果只关注那些需要并最有可能从治疗中受益的患者，结直肠癌的治疗和患者结局可能会得到显著改善。为此，NCI将发现新的预后指标以及对化疗和放射治疗的反应可能性作为一个重要目标(NCI结直肠癌进展审查小组(PRG)2000年的建议)。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景的CRC肿瘤分析方法，称为Praxis-CRCTM。这项检测旨在准确预测结直肠癌复发的可能性和对用于治疗术后结直肠癌患者的治疗反应，包括主要化疗和外照射。在第二阶段开发和评估的初步试验只需要4个基因来预测复发(MCRC)，准确率超过95%，只需要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%，如提案中所述。这与为乳腺癌开发的商业分析相比是有利的，例如OncoDxTM(基因组健康)，后者使用了超过25个基因的面板，但准确性要低得多。PRADXIS-CRCTM标志物开发的新步骤包括：i)获取具有5年前已知临床结果数据的高质量新鲜冷冻CRC肿瘤样本，ii)测量和分析低噪声基因表达微阵列数据，iii)通过Meta分析生成优先基因列表，iv)通过RT-PCR对具有超过5年已知结果的FFPE样本进行优先基因列表验证，v)在行业标准的384孔RTPCR平台上开发最终分析方法。这一二期桥梁项目旨在加快Praxis-CRCTM的商业化进程。这将涉及进一步改进和评估签名，以使用300个有良好记录的临床FFPE肿瘤样本来预测常见疗法的结果，如FOLFOX、FOLFIRI和外照射。该项目涉及AmberGen与一家生物医学检测产品的全球领先者之间的合作伙伴关系，该公司2008年的收入超过17亿美元，员工总数为9000人。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。该项目还包括安大略省癌症研究所(OICR)、Dana Farber癌症研究所和UCSD Morris癌症中心、高质量CRC肿瘤样本的主要来源、用于收集和分析微阵列基因表达数据的高级软件PraxisTM的开发商Anonomouse公司(分包商)以及将用于改进初始生物标记物发现的SmartChip实时PCR系统的开发商WaferGen BiosSystems，Inc.。 公共卫生相关性：目前迫切需要一种准确的结直肠癌(CRC)复发和治疗反应预后分析方法。CRC是美国癌症相关死亡的第二大原因。AmberGen寻求资金，为加速Praxis-CRCTM的商业化提供关键支持，Praxis-CRCTM是在第二阶段开发的一种基于基因表达的CRC肿瘤复发和反应分析。这种分析将显著影响治疗、生活质量，并降低与CRC相关的高昂医疗成本。

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.