Evaluation of Patient-Matched Primary and Metastatic Samples to Identify and Vali

描述(申请人提供)：导致肾细胞癌转移的分子事件仍然知之甚少，这是三十多年来肾细胞癌死亡率缓慢上升的一个主要因素。事实上，目前批准用于转移性ccRCC的药物旨在针对已报道的在原发ccRCC肿瘤中常见的分子改变，但不一定针对转移性ccRCC肿瘤。因此，尽管转移性肾细胞癌的治疗方法在过去十年中稳步增加，但五年生存率仍不到10%也就不足为奇了。因此，一个关键的临床问题是需要询问ccRCC转移性肿瘤，以确定转移性肿瘤特有的分子变化。正是这些改变最有可能增强预后预测，预测对当前治疗的反应，并为新的靶向治疗的发展提供信息。为了直接响应这一需求，我们的多学科研究团队使用Affymetrix基因阵列分析了14例患者匹配的原发和转移性ccRCC肿瘤(所有转移到肺)，并确定了7个在转移性和原发ccRCC中差异表达的新候选基因：DCN、SLIT2、LUM、LAMA2、ADAMTS12、CEACAM6和LMO3。在此，我们建议通过以下方式扩展我们的试点工作：(1)在大量与患者匹配良好的原发和转移性ccRCC肿瘤(包括肺以外的其他转移部位)的独立队列中验证这些候选基因，(2)评估这些基因在转移性肿瘤中的表达与生存和治疗反应的相关性，以及(3)扩大我们现有的努力，包括探索与转移后预后相关的其他转移性基因改变。综上所述，我们的总体目标是更好地了解肾癌转移的发病机制，以帮助集中力量进行三级预防和治疗。通过识别与ccRCC从原发肿瘤进展到致命转移疾病相关的基因变异，该项目最终将有可能为ccRCC进展的生物学机制提供信息，改善预后和对治疗努力的反应，并为新的治疗方法提供合理的靶点。

DESCRIPTION (provided by applicant): The molecular events that cause ccRCC metastasis remain poorly understood and this is a major contributing factor to why ccRCC mortality rates have been slowly rising for more than three decades. Indeed, current drugs approved for metastatic ccRCC are designed to target molecular alterations that have been reported to be common in primary ccRCC tumors, but not necessarily in metastatic ccRCC tumors specifically. As such, it is not surprising that despite a steady increase over the past decade in therapeutics for metastatic ccRCC, the five year survival is still less than 10%. Thus, a key clinical issue is the need to interrogate ccRCC metastatic tumors in order to identify molecular alterations that are unique to metastatic tumors. It is these alterations that will have the highest probability to enhance prognostic forecasting, predict response to current therapies, and inform the development of novel, targeted therapeutics. In direct response to this need, our multidisciplinary team of investigators has used Affymetrix gene arrays to analyze 14 patient-matched primary and metastatic ccRCC tumors (all metastases are to lung) and identified seven novel candidate genes that are differentially expressed in metastatic versus primary ccRCC: DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. Herein, we propose to expand on our pilot work by (1) validating these candidates in a large independent cohort of well annotated patient-matched primary and metastatic ccRCC tumors that include other metastatic sites in addition to lung, (2) evaluating the association of expression of these genes in the metastatic tumors with survival and treatment response, and (3) expanding our existing efforts to include the exploration of additional metastatic genetic alterations that are associated with prognosis after metastasis. In summary, our overall goal is to better understand the pathogenesis of RCC metastasis in order to help focus tertiary prevention and treatment efforts. By identifying genetic variants that are associated with ccRCC progression from primary tumor to lethal metastatic disease, this project will ultimately have the potential to inform the biologyof ccRCC progression, improve prognostic and response to treatment efforts as well as provide rationale targets for novel therapeutics.