Blood-based monitoring of bladder-sparing trimodality therapy for muscle-invasive bladder cancer

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PROJECT SUMMARY/ABSTRACT Although radical cystectomy is often recommended for muscle-invasive bladder cancer (MIBC), a well-tolerated alternative called bladder-sparing trimodality therapy (TMT), consisting of chemoradiation therapy (CRT) follow- ing transurethral resection of bladder tumor (TURBT), has equivalent long-term outcomes to cystectomy while preserving the patient’s native bladder. However, 20-30% of patients treated with TMT require a salvage cystec- tomy due to recurrent disease, and there is an unmet need for molecular biomarkers to precisely identify appro- priate candidates and to monitor for recurrences after therapy. We recently developed methods for the microflu- idic isolation and molecular characterization of circulating tumor cells (CTCs) from blood, which have potential as non-invasive, serial “liquid biopsies” to predict and monitor therapeutic responses. Our long-term goal is to develop predictive molecular biomarkers that can precisely guide the individualized care of patients with bladder cancer. The overall objectives of this application are to (i) optimize CTC and tumor molecular signatures for the prediction of therapeutic responses and longitudinal monitoring of patients treated with TMT, and (ii) to elucidate molecular mechanisms of treatment resistance based on the evolution of CTC and tumor molecular profiles after CRT. Our central hypothesis is that CTC molecular signatures, in combination with tumor molecular profiles, can predict and monitor therapeutic responses after bladder preservation therapy in patients with MIBC. The rationale for this project is that the development of molecular biomarkers will enable the tailored selection of therapy and accurate monitoring of treatment response for MIBC patients. The central hypothesis will be tested by pursuing three specific aims: 1) Identify pretreatment CTC molecular signatures that, combined with tumor molecular profiles, correlate with prognosis after TMT; 2) Identify CTC molecular signatures to monitor for early detection of recurrence after TMT; and 3) Evaluate dynamic changes in CTC and tumor molecular profiles before and after TMT to elucidate mechanisms of therapeutic resistance. In the first aim, we will optimize pretreatment CTC and tumor predictive signatures in MIBC patients undergoing TMT, followed by validation in MIBC patients enrolled in the SWOG/NRG 1806 clinical trial. In the second aim, we will optimize a CTC RNA signature for early detection of recurrence after TMT in a cohort of MIBC patients, followed by validation in patients enrolled in SWOG/NRG 1806. In the third aim, we will analyze CTC and tumor transcriptional profiles collected longitudinally from TMT patients who develop recurrent disease to identify molecular signatures associated with therapeutic resistance. The research proposed in this application is innovative because it will develop novel molecular assays based on the microfluidic isolation and RNA expression profiling of CTCs in bladder cancer patients. The proposed re- search is significant because it will yield clinically useful biomarkers for the precise selection of patients appro- priate for bladder-sparing TMT and the non-invasive monitoring of these patients, while also advancing our un- derstanding of molecular determinants of response and resistance to CRT in bladder cancer.