Capitalizing on a New Biomarker Signature for Cancer Prognosis

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，这两种生物标志物是新发现的，当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获益。具体而言，蛋白质甲基转移酶PRMT 5和这种酶的新发现的靶点PDCD 4的mRNA共表达对应于乳腺癌的不良预后。在原位异种移植模型中，经工程改造以表达升高水平的这两种蛋白质的癌细胞显示出显著加速的肿瘤生长。最近开发的一种特异性识别PDCD 4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，这可能是一种独特的生物活性预后标志物。此外，报道的PDCD 4作为肿瘤抑制因子的活性表明了该途径对肿瘤进展的贡献的新假设。具体的预测是，PDCD 4功能可以控制肿瘤发生的各个方面，但是当PRMT 5水平也升高时，PDCD 4肿瘤抑制功能被甲基化废除，这两种蛋白质合作加速肿瘤生长。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对应于肿瘤进展。该研究的目标是使用肿瘤微阵列严格评估PDCD 4和PRMT 5蛋白水平，并直接检测甲基化PDCD 4作为预后标志物。临床样品也将用于测试在PDCD 4存在下PRMT 5的获得对应于肿瘤进展的模型。同时，这些生物标志物将进行实验研究，以阐明其在肿瘤发生中的作用。该互补目标将涉及鉴定1）优先与甲基化PDCD 4相互作用的蛋白质伴侣和2）位于PDCD 4-PRMT 5共表达下游的基因表达变化。这项实验分析将为PDCD 4-PRMT 5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，这种生物标志物可以与特定的治疗策略合理配对。

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.