Gleason-based mRNA and Metabolomic Profiling to Predict Prostate Cancer Progress

基于格里森的 mRNA 和代谢组学分析可预测前列腺癌进展

• 批准号: 9313629
• 负责人: Massimo Loda
• 金额: $ 26.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-19 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313629
• 关键词: Area; Biological; Biological Markers; Biopsy; Biopsy Specimen; Clinic; Clinical; Dana-Farber Cancer Institute; Data; Decision Making; Diagnosis; Disease; Disease Progression; Gene Chips; Gene Expression; Gene Expression Profiling; Genes; Gleason Grade for Prostate Cancer; Goals; Indolent; Institutes; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Metabolic Marker; Metabolic Pathway; Metabolism; Modeling; Molecular Profiling; Monitor; Operative Surgical Procedures; Outcome; Pathway interactions; Patient Monitoring; Patients; Pattern; Preparation; Prostate; Pyrimidine; Radical Prostatectomy; Research Personnel; Sampling; Serum; Specimen; Testing; Time; Tissue Differentiation; Tissue Sample; Tissues; Tumor Tissue; base; beta-Alanine; clinical application; clinical decision-making; clinically relevant; genetic signature; improved; men; metabolomics; outcome prediction; tool; tumor

Clinicians and researchers are currently unable to distinguish at diagnosis with sufficient confidence men with indolent prostate cancer (CaP) from those who have aggressive disease. At present, the strongest predictor of lethal CaP is Gleason score. Utilizing gene expression array data, we previously identified a 157 gene mRNA signature that distinguished high from low Gleason score. This signature significantly improved prediction of lethal disease among men with clinically heterogeneous Gleason score 7. The signature may have clinical utility, but before applying it to patients it must be further refined and then tested in biopsy specimens to determine if the predictive accuracy is sufficient to influence treatment decisions at the time of diagnosis. This mRNA study also identified metabolic pathways differentially enriched in high and low grade disease, generating hypotheses for biological mechanisms that may underlie CaP differentiation and clinical progression. Since different types of biological data may add to the mRNA signature as well as provide different biological information, it is worthwhile to further investigate the metabolic pathways identified. We therefore propose to build upon our promising expression profiling findings with the following Specific Aims: 1) Preparation and testing of Gleason signature of lethal disease for clinical use -To determine if the mRNA signature can be applied in the clinic, we will further validate it by testing its predictive accuracy in biopsy specimens at the time of diagnosis. We hypothesize that within Gleason score 7, the signature's ability to predict lethal disease may improve if applied specifically to the grade 3 or grade 4 focus of the tumor 2) Metabolomics bf Gleason grade In tumor as predictor of lethal disease - Our mRNA study identified metabolic pathways (pyrimidine, propanoate, and beta-alanine metabolism) differentially enriched in high and low grade tumors. Our preliminary data suggests these same pathways may be differentially enriched using metabolomic data; we hypothesize that metabolites may themselves be associated with Gleason score and lethal disease. 3) Metabolomics of Gleason grade in serum as biomarker for upgrading - We hypothesize that metabolites in serum associated with Gleason grade may indicate the presence of higher-grade tumor not detected at biopsy and could serve as a biomarker for monitoring disease progression of active surveillance patients.

临床医生和研究人员目前无法在诊断时以足够的信心区分患有惰性前列腺癌（CaP）的男性和患有侵袭性疾病的男性。目前，致死性CaP的最强预测因子是Gleason评分。利用基因表达阵列数据，我们以前确定了157个基因mRNA的签名，区分高，低Gleason评分。该特征显著改善了临床异质性Gleason评分7的男性中致死性疾病的预测。该签名可能具有临床实用性，但在将其应用于患者之前，必须进一步细化，然后在活检标本中进行测试，以确定预测准确性是否足以影响诊断时的治疗决策。这项mRNA研究还确定了在高级别和低级别疾病中差异富集的代谢途径，产生了可能是CaP分化和临床进展基础的生物学机制的假设。由于不同类型的生物学数据可能会添加到mRNA签名中，并提供不同的生物学信息，因此值得进一步研究所确定的代谢途径。因此，我们提出以我们有希望的表达谱发现为基础，具有以下具体目的：1）制备和测试用于临床使用的致死性疾病的格里森签名-为了确定mRNA签名是否可以应用于临床，我们将通过在诊断时测试其在活检标本中的预测准确性来进一步验证它。我们假设在Gleason评分7内，如果特异性地应用于肿瘤的3级或4级病灶，则标记预测致死性疾病的能力可以提高。2）肿瘤中Gleason等级的代谢组学作为致死性疾病的预测因子-我们的mRNA研究鉴定了在高和低等级肿瘤中差异富集的代谢途径（嘧啶、丙酸和β-丙氨酸代谢）。我们的初步数据表明，这些相同的途径可能是差异富集使用代谢组学数据，我们假设，代谢物本身可能与格里森评分和致死性疾病。3)血清中Gleason分级的代谢物组学作为升级的生物标志物-我们假设血清中与Gleason分级相关的代谢物可能表明存在活检时未检测到的更高级别肿瘤，并且可以作为监测主动监测患者疾病进展的生物标志物。