This K23 proposal will provide Nicholas G. Cost, MD with the protected time, mentorship, training, and experience to become an independent surgeon-scientist. Dr. Cost is a board-certified urologist with a unique practice focused on pediatric urologic oncology developed after fellowship training in both urologic oncology and pediatric urology. His long-term vision is to minimize the impact of pediatric cancer care on long-term urologic outcomes. Specifically, he is focused on studying the impact of chemotherapy on bladder function. This involves studying the epidemiology of bladder dysfunction (BD) in childhood cancer survivors and investigating alterations in bladder physiology induced by chemotherapy. This will mature into studying mechanisms behind this pathophysiology and identifying biomarkers of chemotherapy-induced BD. Skills that he will acquire during the award, include: 1) didactic and ?hands on? education in epidemiology, 2) advanced laboratory skills in the study of bladder physiology, and 3) investigation into urinary proteomics and biomarkers. This grant proposes to objectively describe the prevalence and extent of chemotherapy-induced pediatric BD, as well as explain the mechanisms of dysfunction in order to prevent chemotherapy-induced BD. While chemotherapy is the foundation for treating childhood cancer, these therapies are known to have a variety of deleterious side effects. There is much known about their most common side effects, but there has been no investigation into how chemotherapy impacts bladder function. In connecting chemotherapy to potential BD, there are two widely used agents in pediatric oncology, Vincristine (VCR) and Doxorubicin (DOX), which are known to cause peripheral neuropathy (VCR) and myotoxicity (DOX). Such neurotoxicity and myotoxicity could rationally induce BD. This grant proposes to address this gap in knowledge with three specific aims: 1) To evaluate the symptoms of BD in children treated with VCR and/or DOX; 2) To determine the mechanisms underlying BD after VCR and/or DOX using a murine model; 3) To evaluate the urinary proteome, as well as levels of known urinary biomarkers of BD, in children exposed to VCR and/or DOX.
The first aim will leverage a large pediatric cancer survivorship population at Dr. Cost's institution. The second and third aim will be supported by Dr. Cost's mentors who have a strong track record of innovative research in bladder physiology. The proposed work has high potential to make a significant clinical impact. It will be the first description of this clinical phenomenon and represents the necessary initial steps in a career-long investigation into understanding and preventing chemotherapy-induced pediatric BD. Based on Dr. Cost's initial work, past productivity, and strong mentorship team, the proposed work is realistic and feasible within the award period and will provide Dr. Cost the skills necessary to compete for future R01 or equivalent funding. This award comes at an ideal time in Dr. Cost's career to provide the necessary support to enable him to become a successful independent surgeon-scientist.
Children with cancer are often treated with chemotherapy that while curative, may cause long term side effects. We are investigating the effects on bladder function of two specific chemotherapies, vincristine and doxorubicin, which are known to cause neurotoxicity and myotoxicity, respectively. Surveying children treated with these agents for symptoms of bladder dysfunction and studying bladder physiology in a murine model of vincristine and doxorubicin exposure will allow us to take the first steps in understanding chemotherapy- induced pediatric bladder dysfunction.
