Biomarker guided combinations for treating high-risk bladder cancer

Bladder cancer (BC) is a common cancer of the urinary tract. While low-grade tumors have a good prognosis, two-thirds of patients with high-grade BC have tumors invading the bladder wall muscle and beyond (MIBC). Patients with MIBC are at high-risk for metastasis, significant morbidity, and mortality. Cystectomy (bladder removal) is the primary treatment for MIBC. Many patients with MIBC receive treatment before surgery (neoadjuvant) to downstage the tumor and to treat micrometastases. However, half of these patients develop metastasis within two years. Although immunotherapy is approved for treatment, the response rate is ~ 25%, leaving chemotherapy as the main treatment. Gemcitabine (Gem)-based combination treatments are used in the neoadjuvant, and adjuvant/salvage settings for better tolerability. Sequential Gem-based bladder instillations are increasingly being used to delay/prevent recurrence in patients with high-grade non-MIBC (NMIBC). However, Gem combinations are empirical, not without toxicity and few consider Gem-resistance. The goal of this study is to evaluate two evidence-based Gem combinations to improve outcome in patients with NMIBC and MIBC. Chase is the first of its kind in humans that cleaves chondroitin sulfate from proteoglycans. Chase was discovered to drive bladder tumorigenesis, tumor growth, metastasis, and Gem resistance. Chase and its molecular signaling pathway that induces Gem resistance are expressed in bladder tumor specimens. We found two well-characterized compounds with potential to overcome Chase-induced Gem resistance. While one compound inhibited the Chase activity, another inhibited its downstream signaling pathway. Combination of Gem with either compound re-sensitized Gem-resistant pre-clinical BC models to Gem. The project is designed to test the hypothesis that inhibition of Chase or its signaling abolishes Gem resistance. Furthermore, the development of Gem combinations with one or both compounds, together with the evaluation of Chase and Chase-signaling for predicting response to Gem-based treatments, will enable the clinical translation of these combinations for the treatment of advanced BC. In BC models, we will investigate the molecular mechanism of ablating Chase- induced Gem resistance by either of the two compounds (inhibitor of Chase or of Chase-signaling) (Aim 1). We will evaluate Chase-related molecules to predict treatment response, optimize the dose of the combinations and validate their favorable tolerability and target specificity (Aim 2). We will use advanced BC and patient-derived xenograft models to compare the efficacy of Gem combination with each compound and with the current Gem- based treatments (Aim 3). Impact: Few studies have evaluated Gem resistance, and how to overcome it. Evaluation of evidenced-based novel combinations that target Chase-induced Gem resistance, and of Chase-related molecules as predictors of response to Gem-based treatments, should reveal which combination is superior and who could receive it.