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.
Invasive-bladder cancer results in substantial morbidity, mortality, and economic cost. Because experimental studies have shown that high levels of insulin may contribute to bladder cancer growth, we will examine whether medical conditions characterized by insulin resistance (diabetes and obesity), and biomarkers of insulin resistance, predict for poor outcomes in patients with invasive bladder cancer. Results from these studies could improve patient selection for more aggressive therapy and lead to interventional studies testing whether lowering insulin levels in patients with bladder cancer results in improved outcomes, thereby informing a more personalized approach to the treatment of bladder cancer.
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