Bladder Cancer is the tenth most common malignancy globally, and is the thirteenth most common cause of tumor associate morbidity. Bladder cancer is largely stratified into two categories: Non-Muscle Invasive Bladder Cancer (NMIBC) and Muscle Invasive Bladder Cancer (MIBC). NMIBC represents disease localized to the urinary bladder, and can be stratified into low and high-grade disease. MIBC represents an aggressive class of bladder cancer, with invasion into the underlying muscle layers of the bladder.
MIBC can be classified as either non-metastatic MIBC, with disease localized to the bladder corpus, or metastatic MIBC, with disease spreading to sites beyond the bladder corpus. High grade NMIBC presents significant risk for progression to MIBC, and collectively both high grade NMIBC and MIBC bladder cancers demonstrate poor prognostic outcomes in clinical settings in terms of responses to therapy, recurrence risks, and overall survival. Hexaminolevulinate is a precursor of Protoporphyrin IX (PpIX) in the heme biosynthetic pathway. Hexaminolevulinate has been FDA approved under the trade name Cysview for diagnostic usage in blue light cystoscopies for fluorescence mediated visualization of disease along the bladder wall.
I demonstrate that in addition to its diagnostic utility, Cysview and blue light irradiation can be utilized clinical as a potential therapeutic modality. I demonstrate the significant selective cytotoxicity of Cysview in combination with blue light against patient derived organoids (PDOs) from primary bladder cancers. My results determine that Cysview and blue light induce a rapid cell death program mediated by an influx in Reactive Oxygen Species (ROS) production, resulting in less than 5% viability within 24 hrs of treatment. This massive loss in viability is observed in low and high grade NMIBC, as well as MIBC derived PDOs with diverse mutational profiles.
The results of this work demonstrate that PDOs are a significant platform for assessing therapy responses for correlation with the large patient population. Furthermore, the work identifies photodynamic therapy with Cysview and blue light irradiation as a putative therapeutic modality for localized bladder cancers, with the potential for significant improvement in patient outcomes. The identification and characterization of the therapeutic effects of Cysview come at a critical time during a global shortage of conventional therapeutics for localized bladder cancer, and presents a pathway for patients affected by these shortages.
Progression in bladder cancer has been understood to be driven by processes governing subpopulation and cell state and lineage transformation. Previous studies identify phenotypic plasticity within a subset of bladder cancers and have correlated this phenomenon with an increased risk for disease progression from NMIBC to MIBC. In previous work, a subset of PDOs derived from luminal primary tumors demonstrated significant degrees of luminal to basal plasticity in vitro. In my analysis of these PDOs using transcriptomic and chromatin accessibility data, I identified a transcriptomic and epigenetic signature unique to plastic PDOs.
Furthermore, I identified HNF1B, GRHL2, GATA6, and SNAI2 as putative regulators of luminal to basal plasticity in bladder cancer. Using these molecular profiles, I correlated the plasticity phenotype with reduction in overall survival using data from published bladder cancer patient cohorts. Finally, I developed a novel transcriptomic subtypes classification scheme and an accompanying R package to classify epithelial heterogeneity in bladder cancer, based on the transcriptomic subtypes I identified in bladder cancer PDOs.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/2ez7-wd96 |
| Date | January 2024 |
| Creators | Syed, Talal Ahsan |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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