Enhancing Translational Science via Prospective Investigation

描述（由申请人提供）：肾细胞癌是一种主要临床需求未得到满足的癌症，其发病率稳步上升，并日益成为一种多学科疾病。我们对影响这种癌症患者临床结局的潜在遗传和分子因素的理解已经发展到应用于临床决策的阶段。提高对导致疾病复发和死亡的分子和遗传事件的理解，将显著提高我们将患者分为临床相关类别的能力，制定降低风险的策略，并确定治疗这种癌症患者的新方法。 我们以前已经通过我们的翻译工作确定了这些癌症的几个重要生物学特征，这对区分肾脏癌症的途径具有指导意义。我建议将这些特征作为生物标志物扩展到四个项目的不同发展阶段，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）前瞻性生物标志物评估和纵向临床数据收集，用于预后生物标志物验证。2)评价肾切除术前使用帕唑帕尼进行新辅助治疗的临床获益，并前瞻性开发反应预测生物标志物。3)使用MR-PET阐明基因组肿瘤内异质性与肿瘤灌注和代谢特性的功能关系。4)评估激酶生物标志物表达谱以区分患者对达沙替尼的反应。该提案将提供一系列最佳的临床注释数据集，用于开发生物学和药理学关系，并作为一个平台，通过初级教师和同伴指导关系的参与，开发一个多学科的骨干研究人员。除了为这一奋进提供地面支持外，这项提案的支持将使我有受保护的时间和平台，继续和扩大我目前以患者为导向的研究工作，以及初级教师，研究员和居民以及研究生的指导工作，专注于医学博士-博士生为医生-科学家职业道路做准备。这项工作将提供关键的见解，使药物开发，更准确的疾病风险评估，建议可能的治疗策略，并建立负责肾肿瘤发生的常见分子和遗传变化的生物学模型，同时继续建立一个强大的多学科团队。此外，这些研究非常适合发展职业生涯 为初级教师和临床实习生提供培训，并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.