Insulin resistance in the development and progression of invasive bladder cancer

 描述（由申请人提供）：本申请为宾夕法尼亚大学肿瘤学医学助理教授提供职业发展奖，该教授对了解宿主因素及其修饰对泌尿生殖系统癌症结局的作用具有科学兴趣。在这个奖项的过程中，他将确定肌肉浸润性膀胱癌患者预后不良的代谢预测因素。该奖项将使他能够发展成为一名独立的研究者，进行以人群为基础和以患者为导向的研究，为泌尿生殖系统癌症治疗提供更个性化的方法。新的技能和进一步的知识将在5年的职业发展计划，跨越流行病学，肿瘤学和内分泌学领域通过（1）流行病学和生物统计学的高级培训获得;（2）转化研究方法的新培训; (3)前瞻性观察研究的新实践经验;（4）与资深科学家的密集指导和合作;（5）原创研究的表现。为了实现这些目标，候选人组建了一个具有临床流行病学，膀胱癌护理，代谢，转化科学和生物统计学专业知识的指导团队，他们不仅是有成就的研究人员，而且是各自领域的成功导师和领导者。 肌层浸润性肿瘤是膀胱癌发病和死亡的主要原因。术前化疗与提高生存率相关，但仅在30-40%的患者中观察到反应。目前用于预测膀胱癌复发的方法依赖于肿瘤病理学，该病理学仅在手术（cycloplasty）后可用，因此不能告知关于在cycloplasty之前使用化疗的决定。与肿瘤复发相关的宿主相关因素尚未确定，尽管胰岛素抵抗可能起作用。这项研究将首先采用一个新的数据库进行一项病例对照研究，评估临床胰岛素抵抗，定义为糖尿病和/或肥胖症的诊断，作为膀胱癌术后复发的风险因素（AIM 1）。接下来，候选人将在接受cytokine治疗的患者中进行前瞻性队列研究，以检查膀胱癌复发与亚临床胰岛素抵抗（AIM 2）相关的风险，通过稳态模型评估（HOMA）进行测量。这些研究的结果可以应用于临床实践，以改善个体化的诊断和选择可能从降低风险的术前化疗中获益的患者。最后 候选人将创建来自入组队列患者的膀胱肿瘤标本和血液样本的生物库，其将可用于与申请人当前和未来假设相关的后续生物标志物发现研究。 该培训将使候选人能够在面向人群和面向患者的方法之间无缝过渡，选择最适合回答每个问题的设计。提出了一个有严格指导的科学研究的结构化培训计划，以便在五年结束时定位独立候选人。

 DESCRIPTION (provided by applicant): This application proposes a career development award for an Assistant Professor of Medicine in Oncology at the University of Pennsylvania with scientific interest in understanding the role of host factors, and their modification, on genitourinary cancer outcomes. During the course of this award, he will identify metabolic predictors of poor outcome in patients with muscle-invasive bladder cancer. This award will enable him to evolve into an independent investigator, conducting both population-based and patient-oriented research to inform a more personalized approach to genitourinary cancer therapy. New skills and further knowledge will be obtained in a 5-year career development plan that spans the fields of epidemiology, oncology, and endocrinology through (1) advanced training in epidemiology and biostatistics; (2) new training in translational research methodology; (3) new hands-on experience in prospective observational research; (4) intensive mentorship and collaboration with senior scientists; and (5) the performance of original research. To achieve these goals, the candidate has assembled a mentoring team with expertise in clinical epidemiology, bladder cancer care, metabolism, translational science, and biostatistics, all of whom are not only accomplished researchers but also successful mentors and leaders in their respective fields. Muscle-invasive tumor is the major cause of morbidity and mortality from bladder cancer. Pre-operative chemotherapy is associated with improved survival, but responses are seen in only 30-40% of patients. Current methods for predicting bladder cancer recurrence rely on tumor pathology, which is available only after surgery (cystectomy) and therefore cannot inform decisions about use of chemotherapy prior to cystectomy. Host-related factors associated with tumor recurrence have not yet been identified, although insulin resistance may play a role. This research will first employ a novel database to conduct a case-control study assessing clinical insulin resistance, defined as a diagnosis with diabetes and/or obesity, as a risk factor for the development of bladder cancer recurrence after cystectomy (AIM 1). Next, the candidate will conduct a prospective cohort study in patients treated with cystectomy to examine risk of bladder cancer recurrence in relation to subclinical insulin resistance (AIM 2), measured by homeostatic model assessment (HOMA). Results from these studies could be implemented into clinical practice to improve individualized prognostication and selection of patients likely to benefit from risk-reducing pre-operative chemotherapy. Finally, the candidate will create a biobank of bladder tumor specimens and blood samples from enrolled cohort patients which will be available for later biomarker discovery studies related to the applicant's current and future hypotheses. This training will enable the candidate to transition seamlessly between population- and patient-oriented methods, selecting the design best suited to answer each question. A structured training plan with rigorously mentored scientific study is proposed to position the candidate for independence at the end of five years.