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: 7990176
• 负责人: ALEXANDER S PARKER
• 金额: $ 22.59万
• 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/7990176
• 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; 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; public health relevance; response; success; survivin; tool; trend; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: In our proposed application, we will build upon our published work with seven individual biomarkers of ccRCC aggressiveness to develop and externally validate a second generation, biomarker-enhanced scoring system for predicting progression among patients with localized ccRCC (BioPROG). We will then extend the scope of our previous work by examining for the first time the expression of our seven biomarkers in paired samples of primary and metastatic ccRCC and estimating their association with time to death. The short-term clinical benefits of this effort include more appropriate ccRCC patient surveillance/management and clinical trial design, while more long-term benefits include a biologically relevant platform for evaluating response to emerging adjuvant therapeutics and for designing novel combinatorial therapies.

描述（由申请人提供）：在过去的三十年中，肾细胞癌（RCC）的发病率稳步上升，大部分增加了局部肿瘤。 RCC的标志性特征包括透明细胞亚型（CCRCC），可变的临床课程以及超出手术切除以外的有限治疗选择。有趣的是，大约35％的患者接受了手术治疗的局部CCRCC患者会经历疾病的进展（即发展遥远的转移），其中大多数将在手术后的一年内发生。与此相关的是，在2003年，我们发布了Mayo诊所进展（PROG）评分，该算法用于帮助预测哪些CCRCC患者在手术后将进展。尽管对局部CCRC的患者的POG评分具有可证明的预后价值，但它完全基于病理指数的信息，因此仅代表了基本分子特征的替代度量，最终决定了肿瘤侵袭。因此，POG评分无法提供完整的患者分层，也不会告知CCRCC侵略性的生物学或确定治疗干预的潜在靶标。这些局限性强调了确定分子预后因素的需求，这些因素是孤立或与现有的预后工具结合的，不仅可以改善CCRCC进展的预测，而且还为临床干预提供了潜在的靶标。为了直接响应这种需求，我们的调查小组的成员采用了各种发现方法来识别CCRCC侵略性的七个基于肿瘤的生物标志物（Survivin，B7-H1，B7-H4，KI-67，IGF-IR，IMP3和CA-IX）。更重要的是，我们已经发表了个体初步研究，表明这些生物标志物的肿瘤表达水平与手术后CCRCC进展的风险增加有关。在此，我们建议通过（1）生成一种新型的基于生物标志物的评分算法来预测CCRCC的进展，以继续对生物标志物发现工作进行翻译，当与我们现有的ProG得分集成时，它将导致更强大，更准确的评分系统（Bioprog）； （2）在两名CCRCC患者的独立人群中，外部验证了该新评分系统的预后价值，（3）首次探索我们在转移性CCRCC组织中七个生物标志物的表达，并检查了他们在转移性疾病诊断后预测其死亡时间的能力。为此，我们建议利用我们机构中正在进行的大型患者注册机构可用的高质量临床数据和生物循环资源。总而言之，我们的总体目标是改善局部CCRC患者手术后的预后分层，并告知CCRCC进展的潜在生物学。这项工作最终将增强患者的管理/监测，允许更合适的临床试验设计，为CCRCC发病机理的分子基础提供信息，为新型治疗策略提供了理由，并代表了评估患者对新兴辅助治疗剂的反应的逻辑平台。 公共卫生相关性：在我们提出的应用程序中，我们将建立我们已发表的工作，与七个单独的CCRCC侵略性生物标志物开发和外部验证了第二代生物标志物增强得分系统，以预测局部CCRCC患者的进展（Bioprog）。然后，我们将通过首次在原代和转移性CCRCC的配对样品中检查我们的七个生物标志物的表达，并估算它们与死亡时间的关联，从而扩展了先前工作的范围。这项工作的短期临床益处包括更合适的CCRCC患者监视/管理和临床试验设计，而更长期的益处包括一个与生物学相关的平台，用于评估对新兴辅助治疗疗法的反应以及设计新型组合疗法的反应。