Abstract 1610: Development and characterization of a novel semi-spontaneous bladder cancer model by pathological evaluation, single cell sequencing and proteomic profiling of urine and serum

Abstract

Abstract Bladder cancer continues to be a healthcare challenge and for many years there have been very few new therapies providing benefit for patients either with non-muscle or muscle invasive bladder cancer. The molecular profiling of bladder cancer has evolved over the last years and different classifications systems have arisen; however, there is still a lack of knowledge on the prognostic or predictive therapeutic value based on these stratification methods. The clinical heterogeneity of the disease impacts the use of the molecular tools; in addition to that, the heterogeneity in the tumor microenvironment may hamper therapeutic strategies based on monotherapy approaches. As check-point blocking antibodies have entered the clinic for the treatment of muscle-invasive bladder cancer, and as novel therapeutic approaches are gaining interest in the non-muscle invasive treatment schedule, we may have novel therapeutic options for these patients ahead of us. But to be successful we also need to understand how to combine these therapies to improve overall survival and to impact relapse and progression of the disease. To enable an improved understanding of the landscape of the bladder cancer therapies we have developed a novel model based on a transgenic mouse with overexpression of Hgf and a dysregulated cell cycle. When exposing this transgenic strain to OH-BBN in drinking water these mice develop a non-muscle invasive bladder cancer that differ from a wt C57BL/6 mouse exposed to OH-BBN. The tumors are of squamous differentiated Tis/T1 type after a course of 10 weeks OH-BBN exposure. After another 5-10 weeks there is a noted muscle invasive squamous-like bladder cancer. The tumors show a strong inflammatory reaction. The muscle-invasive stage also leads to a marked change in the urine proteomic profile (as measured by the Proximity Extension Assay [PEA 92]). We have profiled both the micro and macro-hematuria and the time-course proteomic changes along with the pathology in this model. In addition, we recently performed single-cell sequencing on tumors from the non-muscle and muscle invasive model to dissect the molecular profile, immune landscape along with the heterogeneity. Thus, we can compare this novel model to the frequently used syngeneic MB49 tumor model. We are also currently assessing anti-PD1 therapy in the novel semi-spontaneous tumor model to evaluate the responsiveness to check-point blocking therapy. Ahead we will process the single cell sequencing data and dissect out what type of targeted therapies along with immunotherapies that should be combined, to improve the understanding of how to resolve the progression from a non-muscle invasive to a muscle-invasive deadly disease, with a hope to translate this into a clinically relevant therapeutic strategy. Citation Format: Iliana Kerzeli, Ramy Elgendy, Ivan Stepanek, Milena Doroszko, Aikaterini Chourlia, Sven Nelander, Per-Uno Malmstrom, Ulrika Segersten, Anca Dragomir, Martin Lord, Sara Mangsbo. Development and characterization of a novel semi-spontaneous bladder cancer model by pathological evaluation, single cell sequencing and proteomic profiling of urine and serum [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1610.