Novel Mechanistic Approaches in Prevention, Treatment and Non-Invasive Assessment of Radiation Cystitis in Mice

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ABSTRACT Pelvic organ tumors in men and women are projected to account for 40% and 18%, respectively, of new cancers diagnosed, and 31% and 26%, respectively, of cancer related deaths in the United States in 2020, according to the American Cancer Society’s Cancer Facts & Figures 2020. While nearly half of all pelvic cancer patients receive radiation therapy, the dose is limited and fractionated over weeks due to the potential for developing radiation cystitis. This is a debilitating secondary condition that can lead to disruption of the urothelium, inflammation, neurogenic detrusor overactivity (NDO), hemorrhagic cystitis and chronic fibrosis that may require a cystectomy. Current therapies such as cystoscopic fulguration, intravesical formalin and hyperbaric oxygen are often ineffective and focus on restricting hemorrhage rather than urological consequences. Thus, there is a critical need for preclinical models to better understand the pathophysiology of radiation cystitis, design novel mechanistic approaches in its prevention and treatment and non-invasive monitoring of these outcomes using clinically viable imaging methods. In our mouse models, bladders are either externalized or instilled with an infrared dye for selective irradiation (10Gy; 1Gy=100rad) to cause radiation cystitis with an acute phase (1- 3days) characterized by urothelial cell (UC) apoptosis and disruption of barrier function, and a chronic phase (8wks) with inflammation, afferent sensitization, NDO, and eventually collagen deposition, fibrosis and decreased bladder wall compliance. We propose to test mechanistically different classes of therapeutic and contrast agents for which we have strong preliminary data: 1) Mitochondrial targeted free radical scavenger, XJB-5-131, to decrease reactive oxygen species that inhibit mitophagy; 2) p75 neurotrophin receptor (p75NTR) modulator, LM11A-31, to decrease urothelial cell apoptosis and barrier disruption; 3) soluble guanylyl cyclase (sGC) activator, cinaciguat, to decrease inflammation, afferent sensitization and collagen deposition to treat NDO and fibrosis; and 4) intravesical infrared dye and novel contrast media mixture, gadobutrol/ferumoxytol, to selectively irradiate the bladder within the abdomen and to enhance the capabilities of magnetic resonance imaging (MRI) for non-invasive assessment of fibrosis in the bladder wall, respectively. As LM11A-31 and cinaciguat have passed phase 1 clinical safety trials for non-urological pathologies, they have considerable clinical relevance in the prevention and treatment of radiation cystitis. The overall goals of the proposal are to better characterize the pathophysiology of radiation cystitis and to design clinically relevant treatment protocols utilizing the proposed agents individually or in combination. Progress toward this goal will be monitored using decerebrate or awake (telemetric) cystometrogram (CMG) recordings, MRI, histological and molecular approaches, mitophagy reporter (mt-keima) mice, and conditional knockout mice for NADPH cytochrome b5 reductase 3 (CyB5R3) in smooth muscle or nerves which renders sGC unresponsive to NO• in these cells.