INDIVIDUALIZING COLON CANCER THERAPY USING HYBRID RNA AND DNA MOLECULAR SIGNATURE

利用混合 RNA 和 DNA 分子特征进行个体化结肠癌治疗

• 批准号: 8283832
• 负责人: DEEPAK K AGRAWAL
• 金额: $ 60万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2013-06-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283832
• 关键词: Accounting; Algorithms; Alleles; BRAF gene; Biological Assay; Cancer Patient; Cetuximab; Characteristics; Clinical; Clinical Data; Clinical Trials; Collaborations; Colon Carcinoma; Colorectal Cancer; Complex; DNA; Data; Development; Diagnostic; Ensure; Environment; Epidermal Growth Factor Receptor; Experimental Designs; Failure; Formalin; Freezing; Future; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Determinism; Genome; Genomics; Goals; Health Care Costs; Healthcare; Hybrids; Investigational Therapies; Laboratories; Measures; Molecular; Molecular Profiling; Mutate; Mutation; Nature; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Population; Prevalence; Progression-Free Survivals; Protocols documentation; RNA; Reading; Regimen; Reproducibility; Resistance; Risk; Role; Sampling; Seasons; Sensitivity and Specificity; Sequence Analysis; Signal Transduction; Specimen; System; Testing; Toxic effect; Training; Translations; Validation; base; cancer care; cancer therapy; clinical application; clinical phenotype; cohort; cost; cost effective; exome; improved; mutant; novel; oncology; response; success; therapeutic target; tumor; tumor progression

DESCRIPTION (provided by applicant): Predicting which cancer patients will best respond to therapy is an enormous health care issue. It has been recently suggested, based on early reads of whole exome sequencing data, that there may only be ~12 molecular pathways that drive the development and progression of cancer. Many experimental therapies are now targeting these pathways. We believe that gene expression signatures may be one of the best ways to judge the activation of a particular molecular pathway, by providing a "molecular summary" of the activity of many genes. Moreover, we believe that the selective addition of mutational assessment may improve the resolving power of a hybrid, multi-analyte (DNA + RNA) test that may be used to guide patients to the most effective drugs. We have recently developed gene expression signatures to measure the activation of two of the most important pathways in colon cancer, RAS and PI3K, for which there is an increasing availability of pathway targeted therapeutics. Due to the complex nature of these pathways, simple analysis of canonical single gene mutations only identifies the response characteristics of a proportion (<30%) of the population. Here, we propose to technically validate the existing RAS and PI3K signatures and to refine their activity through novel mutational assessment. Multi-analyte signatures/ algorithms will be clinically validated in a CLIA environment with a cohort of colorectal cancer patients treated with cetuximab therapy. This approach will prepare signatures for clinical application in the near future. PUBLIC HEALTH RELEVANCE: This proposal seeks to identify a reliable means to identify the right drugs for the right cancer patients. Current approaches over treat many patients to help an unknown few, with substantial costs and toxicities. The application of molecular signatures to individualize therapy holds significant promise to personalize cancer care, improve response rates, reduces toxicity and associated costs. Here we will combine RNA gene expression signatures with gene mutation assessments to identify responders and non-responders to cetuximab therapy.

描述（由申请人提供）：预测哪些癌症患者对治疗的反应最好是一个巨大的卫生保健问题。最近有人提出，基于全外显子组测序数据的早期读数，可能只有约12种分子途径驱动癌症的发展和进展。许多实验性疗法现在都针对这些途径。我们相信，基因表达的签名可能是最好的方式来判断一个特定的分子途径的激活，通过提供一个“分子总结”的活动，许多基因。此外，我们认为，选择性地增加突变评估可以提高杂交多分析物（DNA + RNA）测试的分辨率，该测试可用于指导患者使用最有效的药物。我们最近开发了基因表达特征来测量结肠癌中两个最重要的通路RAS和PI 3 K的激活，对于这两个通路，靶向治疗的可用性越来越高。由于这些途径的复杂性，对典型单基因突变的简单分析只能确定一部分（<30%）人群的反应特征。在这里，我们建议从技术上验证现有的RAS和PI 3 K签名，并通过新的突变评估来完善它们的活性。多分析物特征/算法将在CLIA环境中使用接受西妥昔单抗治疗的结直肠癌患者队列进行临床验证。这种方法将在不久的将来为临床应用准备签名。 公共卫生相关性：该提案旨在确定一种可靠的方法，为合适的癌症患者确定合适的药物。目前的方法过度治疗许多患者，以帮助未知的少数人，具有巨大的成本和毒性。分子标记在个体化治疗中的应用为个性化癌症护理、提高响应率、降低毒性和相关成本带来了重大希望。在这里，我们将联合收割机RNA基因表达特征与基因突变评估相结合，以识别西妥昔单抗治疗的应答者和无应答者。