Grant: Project Grant

Radical cystectomy remains the standard of care for muscle-invasive bladder cancer (MIBC). This surgery entails complete removal of the bladder and surrounding organs, leading to a serious impact on the quality of life (QoL) of patients and associated with a 5-year overall survival of only 50 %. Radiation therapy (RT), which preserves the bladder, would be a more appropriate treatment modality if we could improve efficacy, as lack of local control remains problematic. As part from its direct tumor cell killing potential, there is increasing evidence that RT also leads to significant alterations in the tumor microenvironment, which inflammation being one of the most important factors modulating radiation responsiveness of tumors. During the acute phase of inflammation, neutrophils are one of the first-line responders of inflammatory cells to migrate towards the site of inflammation. Recently, it has been shown neutrophils can exhibit dual behaviors and are increasingly being seen as important players in cancer progression. Neutrophils can expel DNA studded with various proteins to form web-like structures known as neutrophil extracellular traps (NET), which has been shown to be associated with tumor progression and metastasis. Our preliminary findings strongly indicate NET are implicated in radioresistance. Determining the NET-related molecular and cellular mechanisms underlying response to radiation will have direct clinical relevance to better select patients who will benefit most from bladder preservation therapy. The novel approach of the proposal herein can bring transformative changes in developing novel strategies in bladder cancer (BC) therapy as it has the potential to transfer from the bench to the patient, an unquestionably, positive impact on survival and quality of life of MIBC patients.