Design and Validation of a Biomarker-enhanced System to Predict RCC Progression

预测 RCC 进展的生物标志物增强系统的设计和验证

• 批准号: 8433450
• 负责人: ALEXANDER S PARKER
• 金额: $ 35.81万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8433450
• 关键词: Abdomen; Adjuvant; Adjuvant Therapy; Algorithms; American Cancer Society; Archives; Biological Markers; Biology; Cancer Center; Cell Line; Cessation of life; Characteristics; Clear Cell; Clinic; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Progression; Distant Metastasis; Drops; Ensure; Evaluation; Excision; Future; Generations; Genomics; Goals; Hand; Image; Incidence; Individual; Institution; Intervention; Investigation; KOC1 gene; Kidney; Localized Disease; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Metastatic to; Methods; Molecular; National Cancer Institute; Necrosis; Neoplasm Metastasis; Nephrectomy; Operative Surgical Procedures; Organ; Outcome; Pathogenesis; Pathologic; Patients; Population; Postoperative Period; Primary Neoplasm; Prognostic Factor; Prognostic Marker; Progress Review Group; Publishing; Recurrence; Renal Cell Carcinoma; Reporting; Resources; Review Literature; Risk; Sampling; Site; Staining method; Stains; Stratification; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Translations; Tumor Tissue; Tumor stage; Validation; Work; base; cancer recurrence; cohort; combinatorial; design; experience; high risk; improved; indexing; interest; member; mortality; novel; novel therapeutics; patient population; patient registry; prognostic; response; success; survivin; tool; trend; tumor

PROJECT/SUMMARY ABSTRACT Incidence rates for renal cell carcinoma (RCC) have risen steadily over the past three decades, with the majority of this increase seen among localized tumors. Hallmark features of RCC include a predominance of clear cell subtype (ccRCC), a variable clinical course, and limited treatment options beyond surgical excision. Of interest, approximately 35% of patients treated surgically for localized ccRCC will experience disease progression (i.e. develop distant metastases) and most of these will occur within one year of surgery. Related to this, in 2003 we published the Mayo Clinic Progression (PROG) Score, an algorithm that is used to help predict which ccRCC patients will progress after surgery. While the PROG score has demonstrable prognostic value for patients with localized ccRCC, it is based entirely on information from pathologic indices and therefore represents only a surrogate measure of the underlying molecular characteristics that ultimately determine tumor aggressiveness. As such, the PROG score does not provide complete patient stratification nor does it inform on the biology of ccRCC aggressiveness or identify potential targets for therapeutic intervention. These limitations underscore the need to identify molecular prognostic factors that, in isolation or in combination with existing prognostic tools, not only improve prediction of ccRCC progression but also provide potential targets for clinical intervention. In direct response to this need, members of our investigative team employed a variety of discovery methods to identify a panel of seven tumor-based biomarkers of ccRCC aggressiveness (survivin, B7-H1, B7-H4, Ki-67, IGF-IR, IMP3 and CA-IX). More importantly, we have published individual preliminary investigations showing that tumor expression levels of each of these biomarkers are associated with an increased risk of ccRCC progression following surgery for localized disease. Herein, we propose to continue the translation of our biomarker discovery efforts by (1) generating a novel biomarker-based scoring algorithm to predict ccRCC progression, which when integrated with our existing PROG score will result in a more robust and accurate scoring system (BioPROG); (2) externally validating the prognostic value of this new scoring system in two independent populations of ccRCC patients and (3) exploring for the first time the expression of our seven biomarkers in metastatic ccRCC tissues and examining their ability to predict time to death following diagnosis of metastatic disease. To do this, we propose to harness high-quality clinical data and biospecimen resources available through ongoing large patient registries at our institutions. In summation, our overarching goal is to improve prognostic stratification following surgery for patients with localized ccRCC as well as inform on the underlying biology of ccRCC progression. This effort will ultimately enhance patient management/surveillance, allow for more appropriate clinical trial design, inform the molecular underpinnings of ccRCC pathogenesis, provide the rationale for novel therapeutic strategies, and represent a logical platform for the evaluation of patient response to emerging adjuvant therapeutics.

项目/摘要摘要 在过去的三十年中，肾细胞癌（RCC）的发病率稳步上升 大多数这种增加在局部肿瘤中。 RCC的标志性功能包括 透明细胞亚型（CCRCC），可变的临床过程，以及手术切除以外的有限治疗选择。 令人感兴趣的是，大约35％接受手术治疗的局部CCRC的患者会患疾病 进展（即发展遥远的转移），其中大多数将在手术后一年内发生。有关的 为此，我们在2003年发布了梅奥诊所的进度（PROG）评分，该算法用于帮助 预测手术后哪些CCRCC患者将进展。虽然前编得分具有可证明的预后 对于局部CCRCC患者的价值，它完全基于病理指数的信息和 因此，仅代表对基本分子特征的替代度量 确定肿瘤的侵略性。因此，POG分数无法提供完整的患者分层 它也不会告知CCRC侵略性的生物学或确定治疗的潜在靶标 干涉。这些限制强调了确定分子预后因素的需求，这些因素是孤立或 结合现有的预后工具，不仅可以改善CCRC的进展预测 提供临床干预的潜在目标。为了直接响应这种需求，我们的调查成员 团队采用各种发现方法来识别CCRCC的七个基于肿瘤的生物标志物的面板 侵略性（Survivin，B7-H1，B7-H4，KI-67，IGF-IR，IMP3和CA-IX）。更重要的是，我们有 已发表的个人初步研究表明，每种肿瘤表达水平 生物标志物与局部疾病手术后CCRC进展的风险增加有关。 在此，我们建议通过（1）产生小说来继续对生物标志物发现工作的翻译 基于生物标志物的评分算法可以预测CCRCC的进展，当与我们现有 PROG评分将导致更健壮，更准确的评分系统（Bioprog）； （2）外部验证 在两个独立的CCRCC患者中，该新评分系统的预后价值和（3） 首次探索我们的七个生物标志物在转移性CCRCC组织中的表达并检查 他们在诊断转移性疾病后预测死亡时间的能力。为此，我们建议 线束高质量的临床数据和通过正在进行的大型患者登记处获得的生物测量资源 在我们的机构。总而言之，我们的总体目标是改善手术后的预后分层 适用于局部CCRCC的患者，并了解CCRCC进展的潜在生物学。这项努力 最终将增强患者管理/监视，允许更合适的临床试验设计，告知 CCRCC发病机理的分子基础为新型治疗策略提供了理由， 并代表评估患者对新兴辅助治疗剂的反应的逻辑平台。