Presentation Authors: Bryan A Smith, Nikolas G Balanis, Brandon Tsai, Jung-Wook Park, Hanwei Zhang, Jonathan W Said, Thomas G Graeber, Owen N Witte, Arnold I Chin*, Los Angeles, CA
Introduction: Small cell bladder cancer is a rare yet highly lethal histological variant that lacks viable treatment options. High-throughput genomic analyses have shed light into driver alterations and therapeutic targets for bladder cancer. Molecular information is lacking for the small cell phenotype.
Methods: High-throughput RNA sequencing was performed on formalin fixed archived tissue from histologically defined small cell (n = 11) and urothelial (n = 10) muscle-invasive bladder cancer. Bioinformatic analyses were performed to identify enriched gene sets and transcriptional regulators specific for the respective cancer phenotypes. PD-L1 immunohistochemistry was performed on the bladder cancer cohort. To identify potential targets amenable to immunotherapeutic strategies, a computational analysis was utilized to mark cell surface markers overexpressed on small cell bladder cancer samples. A pan-small cell analysis identified cell surfaces markers potentially enriched in small cell cancer from other epithelial tissues.
Results: Clustering analyses separated small cell and non-small cell muscle-invasive bladder cancers into their respective histological phenotypes. Differential expression analysis between small cell and muscle invasive bladder cancer samples revealed overexpression of genes and transcription factors associated with neuronal development in the small cell phenotype. PD-L1 immunohistochemistry was expressed on approximately 80% (>1% PD-L1 expression) of our small cell bladder cancer samples with the expression confined to the tumor-infiltrated immune cells. Furthermore, we found that small cell bladder cancers overexpress a distinct set of cell surface markers compared to non-small cell neuroendocrine bladder cancers. Interestingly, a number of these cell surface markers were also overexpressed on small cell neuroendocrine cancers from the prostate and lung.
Conclusions: Our findings shed light into the molecular mechanisms common to small cell bladder cancer and provide insight into potential immunotherapeutic targets to treat this aggressive malignancy.
Source of Funding: Hal Gaba Broad Stem Center Research Center Innovation Award, Perkins Foundation