ABSTRACT Cancer survivors are a growing population in the United States, though many of them pay a heavy price for their survivorship status due to long-term side effects from cancer therapies. Radiation cystitis (RC) results from radiation therapy for pelvic cancers. RC is a debilitating and progressive bladder condition with no effective therapy that may be life-threatening. Thus, the treatment that killed the cancer, may ultimately kill the cancer survivor as well. Research in cancer survivorship is highly significant and represent a great unmet need. This grant proposal is greatly innovative and results from our studies may lead to new diagnosis and treatment for radiation cystitis. The PI, Bernadette Zwaans, PhD, completed a successful and productive NIDDK K01 training award. The KO1 was focused on a systematic research on better understanding of radiation cystitis using SARRP at the capable and resourceful environment at Beaumont Research Institute. We developed an RC preclinical model that closely mimics the human condition. In this model, we identified that RC is a biphasic condition, characterized by urothelial damage in the weeks after radiation therapy (=acute RC), and by chronic fibrosis, vascular damage, and loss of detrusor muscle in months to years after radiation therapy (= chronic RC). We have identified Amphiregulin (AREG) to be significantly elevated after radiation therapy, and to continue to grow in abundance over time. AREG is a member of the epidermal growth factor family that binds the EGF receptor. It has been implicated in many processes including tissue regeneration, cancer, tissue fibrosis, and cellular senescence. AREG is present throughout the body but is most prominently expressed in the bladder urothelium. We hypothesize that AREG mediates radiation-induced bladder fibrosis and can serve as a potential therapeutic target. We further hypothesize that AREG can serve as a predictive urine biomarker to identify patients that are at risk for developing chronic RC. Our hypothesis will be tested through three specific aims: 1. Determine the expression pattern of AREG and its importance in maintaining urothelial integrity in normal and irradiated bladder; 2. Determine the role of AREG in mediating radiation-induced fibrosis; 3. Assess AREG as a predictive biomarker for RC. Given our experience with RC preclinical models our team is well-suited to successfully complete these aims. This study is investigating the first potential therapeutic target for RC and its use as a predictive urine biomarker. The outcomes of our studies can significantly improve the quality of life of many cancer survivors suffering from severe bladder complications due to radiation therapy. Thus, this study falls within the mission statement of the NIDDK to improve health and quality of life of cancer survivors.

NARRATIVE Radiation cystitis is a severely debilitating chronic fibrotic bladder condition that results from radiation therapy for cancers in the pelvis for which no safe and effective treatment exists to date. Amphiregulin is a pro-fibrotic protein that is highly expressed in the bladder after radiation therapy and thus we hypothesize that amphiregulin mediates radiation-induced bladder fibrosis and can serve as a predictive marker for radiation cystitis. The successful outcomes of this study will determine if amphiregulin is a viable therapeutic target for radiation-induced fibrosis which will also be relevant for other benign bladder conditions characterized by a fibrotic bladder.