Type II TGF Beta Receptor and RCC Progression

II 型 TGF β 受体与 RCC 进展

• 批准号: 7142092
• 负责人: ALEXANDER S PARKER
• 金额: $ 11.48万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-21 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142092
• 关键词: clinical research; metastasis; neoplasm /cancer; nephrectomy; receptor; surgery; tissues

DESCRIPTION (provided by applicant): Incidence rates for renal cell carcinoma (RCC) have risen steadily over the past three decades with the greatest increases reported for localized tumors. To date, the mainstay of treatment for patients with localized RCC remains surgical excision. Unfortunately, despite aggressive surgical therapy, over 30% of RCC patients with no evidence of metastasis at time of surgery will subsequently develop distant metastases (i.e. disease progression) and roughly two-thirds of those will occur within the first year after surgery. Therefore, an important and controversial issue in renal cancer research is the identification of prognostic factors that correlate with risk of progression following surgery for localized disease. While some investigators have recently published sophisticated scoring algorithms that predict risk of RCC progression, these algorithms are based entirely on clinical and pathologic indices. As such, they represent only surrogate measures for the underlying molecular characteristics that determine tumor aggressiveness and for that reason themselves do not provide potential targets for therapeutic intervention. This limitation underscores a clear need to identify molecular prognostic factors that have the potential to not only improve prediction of RCC progression but also provide potential targets for clinical intervention. Recently, members of our investigative team published compelling genomic array data that implicates loss of expression of the type II transforming growth factor beta receptor (TbetaR2) as a significant event in the acquisition of metastatic phenotype for RCC. Moreover, these array data have been validated (real time PCR, immunohistochemistry, mouse model) and are consistent with other previous studies that also suggest loss of TbetaR2 is an important event in RCC progression. In this investigation, we propose to translate these compelling laboratory data to a clinical population by determining if TbetaR2 expression is associated with RCC progression in a cohort of 369 patients treated surgically for localized RCC at the Mayo Clinic Rochester between January 1, 2000 and December 31, 2003. Explicitly, we will test the hypothesis that lower TbetaR2 expression is associated with an increased risk of RCC progression in both a univariate and multivariate setting. As part of our secondary analyses, we will also examine the role of expression of five downstream targets of TbetaR2 signaling that were also identified as aberrantly regulated in our genomic profiling study. In summary, we will evaluate an innovative translational hypothesis regarding molecular determinants of RCC progression in order to better understand the pathogenesis of this disease and potentially inform on novel treatment regimens.

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，据报道局部肿瘤的发病率上升幅度最大。迄今为止，局部RCC患者的主要治疗方法仍然是手术切除。不幸的是，尽管进行了积极的手术治疗，但超过30%的在手术时没有转移证据的RCC患者随后会发生远处转移（即疾病进展），其中大约三分之二将在手术后第一年内发生。因此，肾癌研究中一个重要且有争议的问题是确定与局部疾病手术后进展风险相关的预后因素。虽然一些研究人员最近发表了预测RCC进展风险的复杂评分算法，但这些算法完全基于临床和病理指标。因此，它们仅代表决定肿瘤侵袭性的潜在分子特征的替代测量，并且由于该原因，它们本身不提供治疗干预的潜在靶标。这种局限性强调了明确需要识别分子预后因素，这些因素不仅有可能改善RCC进展的预测，而且还为临床干预提供了潜在的靶点。最近，我们的研究小组成员发表了令人信服的基因组阵列数据，表明II型转化生长因子β受体（TbetaR2）的表达缺失是RCC转移表型获得的重要事件。此外，这些阵列数据已经过验证（真实的时间PCR、免疫组织化学、小鼠模型），并且与也表明TbetaR2的丢失是RCC进展中的重要事件的其它先前研究一致。在这项研究中，我们建议将这些令人信服的实验室数据转化为临床人群，通过确定TbetaR2表达是否与2000年1月1日至2003年12月31日期间在马约诊所罗切斯特接受局部RCC手术治疗的369例患者队列中的RCC进展相关。我们将在单变量和多变量环境中检验TbetaR2表达降低与RCC进展风险增加相关的假设。作为我们二次分析的一部分，我们还将研究TbetaR2信号传导的五个下游靶点表达的作用，这些靶点在我们的基因组分析研究中也被确定为异常调节。总之，我们将评估一个关于RCC进展的分子决定因素的创新翻译假设，以更好地了解这种疾病的发病机制，并可能为新的治疗方案提供信息。