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

描述（由申请人提供）：肾细胞癌（RCC）的发病率在过去三十年中稳步上升，其中大部分增加见于局部肿瘤。RCC的标志性特征包括透明细胞亚型（ccRCC）占优势、可变的临床病程和手术切除以外的有限治疗选择。值得关注的是，大约35%的局部ccRCC手术治疗患者将经历疾病进展（即发生远处转移），其中大多数将在手术后一年内发生。与此相关，我们在2003年发表了马约临床进展（PROG）评分，这是一种用于帮助预测哪些ccRCC患者在手术后会进展的算法。虽然PROG评分对局部ccRCC患者具有明显的预后价值，但它完全基于病理指标的信息，因此仅代表最终决定肿瘤侵袭性的潜在分子特征的替代指标。因此，PROG评分不能提供完整的患者分层，也不能提供ccRCC侵袭性的生物学信息或识别治疗干预的潜在靶点。这些局限性强调了识别分子预后因素的必要性，这些因素单独或与现有的预后工具相结合，不仅可以改善对ccRCC进展的预测，而且还可以为临床干预提供潜在的靶点。为了直接满足这一需求，我们的研究团队成员采用了各种发现方法来鉴定一组七种基于肿瘤的ccRCC侵袭性生物标志物（生存素，B7-H1，B7-H4，Ki-67，IGF-IR，IMP3和CA-IX）。更重要的是，我们已经发表了单独的初步研究，表明这些生物标志物中每一种的肿瘤表达水平与局部疾病手术后ccRCC进展的风险增加相关。在此，我们建议通过（1）产生新的基于生物标志物的评分算法来预测ccRCC进展，当与我们现有的PROG评分整合时，将产生更稳健和准确的评分系统（BioPROG）;（2）在两个独立的ccRCC患者群体中外部验证该新评分系统的预后价值，以及（3）首次探索我们的七种生物标志物在转移性ccRCC组织中的表达，并检查它们预测转移性疾病诊断后死亡时间的能力。为此，我们建议利用我们机构正在进行的大型患者登记处提供的高质量临床数据和生物标本资源。总之，我们的总体目标是改善局部ccRCC患者手术后的预后分层，并了解ccRCC进展的基础生物学。这一努力最终将加强患者管理/监测，允许更适当的临床试验设计，告知ccRCC发病机制的分子基础，为新的治疗策略提供理论基础，并代表评估患者对新兴辅助治疗的反应的逻辑平台。 公共卫生相关性：在我们提出的申请中，我们将利用ccRCC侵袭性的七种单独生物标志物来开发和外部验证第二代生物标志物增强的评分系统，用于预测局部ccRCC患者的进展（BioPROG）。然后，我们将通过首次检查我们的七种生物标志物在原发性和转移性ccRCC配对样本中的表达，并估计它们与死亡时间的相关性，来扩展我们先前工作的范围。这一努力的短期临床益处包括更适当的ccRCC患者监测/管理和临床试验设计，而更长期的益处包括用于评估对新兴辅助疗法的反应和设计新型组合疗法的生物学相关平台。

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.