Type II TGF Beta Receptor and RCC Progression

II 型 TGF β 受体与 RCC 进展

• 批准号: 7267945
• 负责人: ALEXANDER S PARKER
• 金额: $ 11.14万
• 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 2009-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267945
• 关键词: Abdomen; Adjuvant Therapy; Age; Algorithms; Anchorage-Independent Growth; Area; Attenuated; Biological Markers; Categories; Cell Line; Cell Proliferation; Cells; Characteristics; Clear Cell; Clinic; Clinical; Collaborations; Complementary DNA; Data; Diagnostic Neoplasm Staging; Dipeptidases; Disease; Disease Progression; Disease regression; Distant Metastasis; Dry Ice; Event; Excision; Freezing; Gender; Genomics; Goals; Histologic; Image; Immunohistochemistry; Incidence; Integrins; Intervention; Investigation; Kidney; Laboratories; Link; Localized; Localized Disease; Malignant Epithelial Cell; Malignant neoplasm of kidney; Measures; Mediating; Messenger RNA; Metastatic Renal Cell Cancer; Methods; Microdissection; Modification; Molecular; Molecular Analysis; Necrosis; Neoplasm Metastasis; Nephrectomy; Normal tissue morphology; Nuclear Grade; Operative Surgical Procedures; Pathogenesis; Pathologic; Patient Care; Patients; Phenotype; Polymerase Chain Reaction; Population; Prognostic Factor; Proteins; Protocols documentation; Publishing; RNA; Rate; Recurrence; Regional Lymph Node Involvement; Registries; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research Personnel; Risk; Role; Sampling; Score; Shipping; Ships; Signal Transduction; Staining method; Stains; Survival Rate; Testing; Therapeutic Intervention; Thinking; Time; Tissue Sample; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Treatment Protocols; Tumor Markers; Tumor Tissue; Tumor stage; Vital Status; Western Blotting; anticancer research; base; cohort; experience; follow-up; improved; indexing; innovation; member; membrane dipeptidase; mouse model; novel; outcome forecast; receptor; repository; response; restoration; size; tissue processing; transforming growth factor-beta type II receptor; tumor

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 (3 receptor (T(3R2) 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 T(3R2 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 TpR2 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 T0R2 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 T|3R2 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，其中局限性肿瘤的报告增幅最大。到目前为止，治疗局限性肾细胞癌的主要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%的肾癌患者在手术时没有转移的证据，随后会发生远处转移(即疾病进展)，其中大约三分之二将发生在手术后第一年内。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布了预测肾癌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，它们只是决定肿瘤侵袭性的潜在分子特征的替代指标，因此它们本身并不提供治疗干预的潜在靶点。这一局限性强调了明确的需要确定分子预后因素，这些因素不仅有可能改善肾癌进展的预测，而且还为临床干预提供了潜在的靶点。最近，我们的研究团队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(3)受体(T(3R2))的表达缺失是肾癌转移表型获得的重要事件。此外，这些阵列数据已经得到验证(实时聚合酶链式反应、免疫组织化学、小鼠模型)，并与其他先前的研究一致，这些研究也表明T丢失(3R2是肾癌进展中的一个重要事件)。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，确定TpR2的表达是否与肾癌的进展有关，在2000年1月1日至2003年12月31日期间，在梅奥诊所罗切斯特接受手术治疗的369名局部肾癌患者中，TpR2的表达与肾癌进展有关。明确地说，我们将检验这样的假设，即在单变量和多变量环境中，T0R2表达降低与肾癌进展的风险增加有关。作为二次分析的一部分，我们还将研究T|3R2信号的五个下游靶标的表达在我们的基因组图谱研究中也被确认为异常调控的作用。综上所述，我们将评估关于肾癌进展的分子决定因素的创新的翻译假说，以更好地理解这种疾病的发病机制，并潜在地为新的治疗方案提供信息。