Identification of Biomarkers for Early Detection of Renal Cell Carcinoma

描述（由申请人提供）：2007年，美国肾细胞癌（RCC）的发病率预计将达到56，000例/年，自1970年以来，男性和女性以及白人和黑人的发病率一直在上升。提高生存率与RCC的早期检测有关。目前，约30%的肾癌患者在诊断时存在转移性疾病，这些患者的5年生存率约为5%。早期诊断，而疾病仍然是局部增加生存率接近50- 95%。但是，即使早期发现，接受治疗性肾切除术的局部疾病患者也有20-50%的机会局部或全身复发，并有对侧肾患肾癌的长期风险。 转移性RCC靶向治疗的最新进展开辟了一系列新的可能性和问题，迫切需要开发可靠的RCC生物标志物。例如，小分子抑制剂治疗的持续时间、多组临床试验中的组间患者交叉、小分子合理组合的测试以及辅助治疗患者的选择可以通过使用RCC特异性生物标志物评估疾病活性来促进和加速。此外，生物标志物可以检测微小残留疾病已经存在于肾切除术后似乎局部疾病或早期复发。靶向/抗血管生成治疗可能对最小残留比临床可检测疾病更有效。 Von Hippel Lindau（VHL）肿瘤抑制基因的失活和由此产生的缺氧诱导因子（HIF）的组成性上调是大多数透明细胞RCC的标志，也是这种癌症中最早已知的信号转导缺陷。VHL的丢失也与RCC中蛋白水解活性的增加有关。我们利用VHL缺陷的人RCC细胞系的可用性来询问与VHL功能丧失相关的全局基因表达变化，作为RCC生物标志物发现的第一步。然后，我们选择，作为候选生物标志物，特定的基因与限制成人组织表达的VHL的损失上调。我们发现，当与从同一个体获得的匹配的正常肾实质相比时，这些细胞系衍生的生物标志物（CDB）在检查的所有患者RCC肿瘤中也上调。 该提案的总体目标是验证CDB作为RCC中肿瘤活性的循环生物标志物。我们还建议使用从RCC患者和荷瘤小鼠获得的血液和尿液来发现其他RCC生物标志物。由于RCC肿瘤中蛋白水解活性增加，我们建议选择性地调查尿液中的肽组，并将这些发现与RCC相关的血浆肽组和蛋白质组变化进行交叉参考。最后，我们描述了我们将如何制定一个统计规则，RCC复发的早期检测。 该提案是Iliopoulos实验室（马萨诸塞州总医院癌症中心）和巴内特化学和化学生物学研究所（东北大学）之间的合作成果。这项合作还包括Steve Skates博士（MGH生物统计学系）和帕特里克斯卢斯（生殖内分泌学实验室）。 公共卫生相关性：这种标志物识别的影响与公众直接相关。肾细胞癌的可用生物标志物或生物标志物集可允许具有局部和/或全身复发高风险且无临床明显疾病的患者获得预防其疾病复发的额外治疗。此外，它们可以用作对治疗反应的替代标志物，并允许生物治疗或靶向分子治疗的早期变化，以防后者不起作用。

DESCRIPTION (provided by applicant): The incidence of renal cell carcinoma (RCC) in United States has been projected to reach 56,000 cases/year in 2007 and has been rising since 1970 for both men and women and for whites as well as blacks. Improved survival rates are associated with early detection of RCC. Currently, about 30% of kidney cancer patients present with metastatic disease at the time of diagnosis and the 5-year survival rate for these patients is approximately 5%. Early diagnosis while the disease is still localized increases the rate of survival to close to 50-95%. But even if detected early, patients with localized disease undergoing curative nephrectomy have a 20-50% chance of local or systemic relapse and a long-term risk of kidney cancer in the contralateral kidney. Recent advances in targeted therapy of metastatic RCC have opened a new set of possibilities and questions that urgently call for the development of reliable RCC biomarkers. For example, the duration of treatment for small molecule inhibitors, patient crossover among arms in multi-arm clinical trials, testing of rational combinations of small molecules, and selection of patients for adjuvant therapy could be facilitated and expedited by evaluating disease activity with RCC-specific biomarker(s). Furthermore, biomarkers may detect minimal residual disease already present after nephrectomy for seemingly localized disease or an early relapse. Targeted/anti-angiogenic therapy may be more efficient against minimal residual than clinically detectable disease. Inactivation of the Von Hippel Lindau (VHL) tumor suppressor gene and the resulting constitutive upregulation of hypoxia inducible factor (HIF) are hallmarks of the majority of clear cell RCC and the earliest known signal transduction defect in this cancer. Loss of VHL is also associated with increased proteolytic activity in RCC. We took advantage of the availability of human RCC cell lines deficient in VHL to interrogate the global gene expression changes linked to loss of VHL function as a first step in RCC biomarker discovery. We then selected, as candidate biomarkers, specific genes with restricted adult tissue expression that are upregulated by loss of VHL. We found that these cell line derived biomarkers (CDBs) are also upregulated in all patient RCC tumors examined when compared to matched normal renal parenchyma obtained from the same individual. The overall goal of this proposal is to validate the CDBs as circulating biomarkers of tumor activity in RCC. We also propose to use blood and urine obtained from RCC patients and tumor bearing mice to discover additional RCC biomarkers. Because of increased proteolytic activity in RCC tumors we propose to survey selectively the peptidome of urine and to cross-reference these findings with RCC related plasma peptidome and proteome changes. Finally we describe how we will develop a statistical rule for early detection of RCC relapse. This proposal is a collaborative effort between the Iliopoulos Laboratory (Massachusetts General Hospital Cancer Center) and the Barnett Institute of Chemistry and Chemical Biology (Northeastern University). This collaboration also includes Drs. Steve Skates (MGH Department of Biostatistics) and Patrick Sluss (Laboratory of Reproductive Endocrinology). PUBLIC HEALTH RELEVANCE: The impact of such marker identification is of direct interest to the public. Available biomarker or set of biomarkers for renal cell carcinoma may allow patients at high risk for local and/or systemic relapse and without clinically obvious disease to get additional therapy that prevents recurrence of their disease. In addition they may be used as surrogate markers for response to therapy and allow for early changes in biotherapy or targeted molecular therapy in case these latter ones do not work.