Enhancing Translational Science via Prospective Investigation

描述(申请人提供)：肾细胞癌是一种主要的临床需求未得到满足的癌症，其发病率正在稳步上升，并日益成为一种多学科疾病。我们对决定这种癌症患者临床结果的潜在遗传和分子因素的了解已经发展到了将其应用于临床决策的阶段。加强对导致疾病复发和死亡的分子和遗传事件的了解，将显著提高我们将患者划分为临床相关类别的能力，设计策略以实现降低风险，并找到治疗这种癌症患者的新方法。 我们之前已经通过我们的翻译努力确定了这些癌症的几个重要的生物学特征，这些特征对区分肾脏中的癌症途径具有指导意义。我建议将这些功能扩展为四个处于不同开发阶段的项目中的生物标记物，作为向我们临床团队的初级成员介绍前瞻性研究的独特潜力的工具。简而言之，这四个项目是：1)前瞻性生物标记物评估和用于预后生物标记物验证的纵向临床数据收集。2)评价肾切除术前应用帕佐帕尼新辅助治疗的临床益处，并展望预测疗效的生物标志物的发展。3)用MR-PET研究肿瘤基因组内异质性与肿瘤血流灌注和代谢特性之间的功能关系。4)评估激酶生物标记物的表达谱，以分层患者对达沙替尼的反应。这项建议将为发展生物学和药理学关系提供一系列最佳的临床注释数据集，并作为一个平台，通过初级教员和同事指导关系的参与，发展一支由多学科研究人员组成的老牌研究队伍。除了为这项工作提供基层支持外，这项提案的支持将使我有受保护的时间和平台，以继续和扩大我目前以患者为导向的研究努力，以及初级教员、研究员和住院医生以及研究生的指导努力，重点是医学博士学生为医生-科学家的职业道路做准备。这项工作将提供关键的见解，以支持药物开发，更准确的疾病风险评估，建议可能的治疗策略，并对导致肾脏肿瘤发生的常见分子和基因变化的生物学进行建模，同时继续建立一个强大的多学科团队。此外，这些研究非常适合职业发展。 它是初级教员和临床实习生的基础，将作为我的学员进行研究的起点。

DESCRIPTION (provided by applicant): Renal cell carcinoma is a cancer with major unmet clinical needs for which the incidence is steadily rising, and which is increasingly becoming a multidisciplinary disease. Our understanding of the underlying genetic and molecular factors which shape the clinical outcomes for patients with this cancer has advanced to a stage where application to clinical decision-making is imperative. An enhanced understanding of the molecular and genetic events which contribute to disease recurrence and death would significantly improve our ability to stratify patients into clinically relevant classes, devise strategies to achieve risk reduction and identify novel methods to treat patients with this cancer. We have previously identified several important biological features of these cancers through our translational efforts, which are instructional in discriminating the pathways to cancer in the kidney. I propose to extend these features as biomarkers in four projects in various stages of development as vehicles to introduce junior members of our clinical team to the unique potential of prospective investigation. In brief, the four projects are: 1) Prospective biomarker assessment and longitudinal clinical data collection for prognostic biomarker validation. 2) Evaluation of clinical benefit to neoadjuvant treatment with pazopanib prior to nephrectomy, with prospective development of response - predictive biomarkers. 3) Elucidation of the functional relationship of genomic intratumoral heterogeneity with tumor perfusion and metabolic properties using MR-PET. 4) Evaluation of a kinase biomarker expression profile to stratify patients for response to dasatinib. This proposal will provide a series of optimal clinically annotated datasets for developing biological and pharmacological relationships as well as serving as a platform for developing a multidisciplinary cadre of established investigators through the involvement of junior faculty and fellow mentoring relationships. In addition to providing ground-level support fo this endeavor, the support of this proposal will allow me to have the protected time and a platform from which to continue and expand my current patient-oriented research efforts as well as the mentoring efforts of junior faculty, fellows and residents, as well as post-graduate students, focusing on MD-PhD student preparation for the physician- scientist career path. This work will provide key insights to enable drug development, more accurate disease risk assessment, suggest possible therapeutic strategies, and model the biology of common molecular and genetic changes responsible for renal oncogenesis while continuing to build a robust multidisciplinary team. Further, these studies are ideally suited for developing the careers of junior faculty and clinical trainees, and will serve as the launching point for studies to be implemented by my mentees.