Capitalizing on a New Biomarker Signature for Cancer Prognosis

利用新的生物标志物特征进行癌症预测

• 批准号: 8688972
• 负责人: KATHARINE S ULLMAN
• 金额: $ 15.72万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688972
• 关键词: Antibodies; Biological; Biological Markers; Biology; Breast Cancer Cell; Cancer Prognosis; Cancer cell line; Cells; Characteristics; Clinical; Clinical Management; Data Set; Detection; Development; Disease; Disease-Free Survival; Enzymes; Gene Expression; Genes; Goals; Growth; Hand; Investigation; Knowledge; Learning; Literature; Malignant Neoplasms; Messenger RNA; Methylation; Methyltransferase; Mining; Modeling; Molecular; Molecular Profiling; Mutate; Non-Malignant; Normal tissue morphology; Outcome; Pathway interactions; Patients; Post-Translational Protein Processing; Premalignant; Prognostic Marker; Protein Methyltransferases; Proteins; RNA Sequences; Relative (related person); Reporting; Research; Role; Sampling; Site; Staging; Testing; Tumor Biology; Tumor Suppressor Proteins; Work; Xenograft Model; Xenograft procedure; cancer cell; cellular engineering; clinical application; cohort; experimental analysis; improved; insight; malignant breast neoplasm; mutant; novel; novel therapeutics; outcome forecast; prognostic; public health relevance; tool; treatment strategy; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The main goals of this research are to learn more about the biology of two biomarkers, newly-identified to have prognostic utility when considered together, and how to apply this knowledge for clinical benefit. Specifically, mRNA co-expression of the protein methyltransferase PRMT5 and a newly-discovered target of this enzyme, PDCD4, corresponds to poor prognosis in breast cancer. In an orthotopic xenograft model, cancer cells engineered to express elevated levels of these two proteins displayed significantly accelerated tumor growth. A recently developed antibody that specifically recognizes the methylated form of PDCD4 now provides the opportunity to directly detect activity of this novel pathway in cancer cells, presenting the possibility of a unique bioactive prognostic marker. Further, the reported activity of PDCD4 as a tumor suppressor suggests a novel hypothesis for the contribution of this pathway to tumor progression. The specific prediction is that PDCD4 function can keep aspects of tumorigenesis in check, but when PRMT5 levels become elevated as well, PDCD4 tumor suppressive function is abrogated by methylation and the two proteins cooperate to accelerate tumor growth. Here, clinical samples will be used to test and improve the prognostic power of these biomarkers, as well as to determine how their expression corresponds to tumor progression. The goals of the research proposed are to use tumor microarrays to rigorously assess both PDCD4 and PRMT5 protein levels and the direct detection of methylated PDCD4 as prognostic markers. Clinical samples will also be used to test the model that acquisition of PRMT5 in the presence of PDCD4 corresponds to tumor progression. Concurrently, these biomarkers will be investigated experimentally to elucidate their role in tumorigenesis. This complementary goal will involve identifying 1) protein partners that interact preferentially with methylated PDCD4 and 2) the gene expression changes that lie downstream of PDCD4-PRMT5 co-expression. This experimental analysis will give new and unbiased insight into how the PDCD4-PRMT5 pathway contributes to aggressive tumor growth. Together, the results of these studies will set the stage for the development of a new prognostic cancer biomarker that may be paired rationally with a particular treatment strategy.

描述（由申请人提供）：本研究的主要目标是更多地了解两种生物标志物的生物学特性，新发现的两种生物标志物在一起考虑时具有预后效用，以及如何将这些知识应用于临床益处。具体来说，蛋白甲基转移酶PRMT5和该酶新发现的靶标PDCD4的mRNA共表达与乳腺癌预后不良有关。在原位异种移植模型中，经过工程改造表达这两种蛋白水平升高的癌细胞显示出肿瘤生长明显加快。最近开发的一种特异性识别PDCD4甲基化形式的抗体，现在提供了直接检测癌细胞中这种新途径活性的机会，提出了一种独特的生物活性预后标记物的可能性。此外，报道的PDCD4作为肿瘤抑制因子的活性为该途径对肿瘤进展的贡献提供了一个新的假设。具体预测是PDCD4功能可以控制肿瘤发生的各个方面，但当PRMT5水平升高时，PDCD4的抑瘤功能被甲基化取消，两种蛋白合作加速肿瘤生长。在这里，临床样本将用于测试和改善这些生物标志物的预后能力，以及确定它们的表达如何与肿瘤进展相对应。该研究的目标是使用肿瘤微阵列严格评估PDCD4和PRMT5蛋白水平，并直接检测甲基化PDCD4作为预后标志物。临床样本也将用于测试在PDCD4存在下获得PRMT5与肿瘤进展相对应的模型。同时，这些生物标志物将被实验研究以阐明其在肿瘤发生中的作用。这个互补的目标将包括确定1)优先与甲基化PDCD4相互作用的蛋白伴侣和2)PDCD4- prmt5共表达下游的基因表达变化。这项实验分析将为PDCD4-PRMT5通路如何促进侵袭性肿瘤生长提供新的和公正的见解。总之，这些研究的结果将为开发一种新的预后癌症生物标志物奠定基础，这种生物标志物可能与特定的治疗策略合理配对。