Insulin resistance in the development and progression of invasive bladder cancer

 描述(由申请者提供)：此申请建议为宾夕法尼亚大学肿瘤学医学助理教授颁发职业发展奖，该奖项旨在了解宿主因素及其修改对泌尿生殖系癌症结果的作用。在这个奖项的过程中，他将确定肌肉浸润性膀胱癌患者不良预后的代谢预测因子。这一奖项将使他能够发展成为一名独立的调查者，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。在一个横跨流行病学、肿瘤学和内分泌学领域的5年职业发展计划中，将获得新的技能和进一步的知识，途径是：(1)流行病学和生物统计学的高级培训；(2)翻译研究方法的新培训； (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；以及(5)原创研究的表现。为了实现这些目标，候选人组建了一支具有临床流行病学、膀胱癌护理、新陈代谢、翻译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，而且在各自的领域都是成功的导师和领导者。肌肉浸润性肿瘤是膀胱癌发病率和死亡率的主要原因。术前化疗与提高存活率有关，但只有30%-40%的患者有反应。目前预测膀胱癌复发的方法依赖于肿瘤病理学，只有在手术(膀胱切除术)后才能使用，因此不能在膀胱切除术前决定是否使用化疗。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到一定作用。这项研究将首先使用一个新的数据库来进行一项病例对照研究，评估临床胰岛素抵抗，即被诊断为糖尿病和/或肥胖，作为膀胱癌切除后复发的风险因素(AIM 1)。接下来，候选人将在接受膀胱切除术的患者中进行一项前瞻性队列研究，以检查通过稳态模型评估(HOMA)测量的膀胱癌复发风险与亚临床胰岛素抵抗(AIM 2)的关系。这些研究的结果可以应用于临床实践，以改善个体化预测和选择可能受益于降低风险的术前化疗的患者。最后， 候选人将创建一个来自登记的队列患者的膀胱癌样本和血液样本的生物库，用于以后与申请者当前和未来的假设相关的生物标记物发现研究。此培训将使应聘者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。提出了一项有严格指导的科学研究的结构化培训计划，以在五年结束时为独立候选人定位。

 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.