Monitoring response of neoadjuvant therapy in primary bladder cancer using hyperpolarized 13C MRI

PROJECT SUMMARY / ABSTRACT The goal of this proposal titled “Monitoring response of neoadjuvant therapy in primary bladder cancer using hyperpolarized 13C MRI” is to develop a metabolic imaging biomarker to assess neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC), a previously unexplored translational opportunity. This will be accomplished by using novel quantitative hyperpolarized (HP) 13C pyruvate magnetic resonance imaging (MRI) to assess changes in glycolysis in response to anti-cancer therapy using patient derived xenografts derived from previously untreated tumors. NAC has been associated with a pathologic response in 40% of patients with a complete response in up to 25%, there is significant overtreatment of non-responders. Identifying patients who are chemosensitive would not only provide a benefit to them but would spare unnecessary toxicity and a possibly fatal delay in radical cystectomy for patients who are chemotherapy resistant. Although cross-sectional imaging is a cornerstone in the management of patients with MIBC at initial staging and during follow-up it has not been applied successfully for monitoring response to NAC. Lack of specific and sensitive non-invasive means to monitor response currently limits clinical application and value of NAC for MIBC. In Aim 1 we will employ 6 PDX of known response to gemcitabine and cisplatin, the most commonly prescribed NAC regimen, to evaluate the ability of quantitative imaging marker kPL, the apparent rate of conversion of pyruvate to lactate, reflecting glycolysis, to monitor the response to said combinatorial chemotherapy, using HP MRI. Aim 2 will lay the groundwork for providing a biological basis for the value of kPL as an imaging biomarker of treatment response or resistance and also as a predictive marker. Additionally, we will explore other basal metabolites and pathways that are informative of treatment effect and to develop complimentary imaging markers in the future. Given rapidly expanding clinical studies of HP MRI, positive preclinical results can be swiftly translated to a clinical trial.