Transcriptomic and protein analysis of small cell bladder cancer (SCBC) identifies prognostic biomarkers and DLL3 as a relevant therapeutic target

Transcriptomic profiling can shed light on the biology of SCBC, nominating biomarkers and novel therapeutic targets.

Sixty-three SCBC patients had small cell histology confirmed and quantified by a genitourinary pathologist.

Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody-drug conjugate (ADC).

Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most "normal-like" pattern of gene expression had longer OS compared to the other 3 clusters while patients with the most "metastasis-like" pattern had the shortest OS (p=0.047). Expression of DLL3, PDL1, ASCL1 and CD56 was confirmed by IHC in 68%, 30%, 52% and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (p=0.03 each). A DLL3-targeting ADC showed durable anti-tumor efficacy in a SCBC PDX model.

Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Oct 16 [Epub ahead of print]

Vadim S Koshkin, Jorge A Garcia, Jordan P Reynolds, Paul Elson, Cristina Magi-Galluzzi, Jesse K McKenney, Kumiko Isse, Evan Bishop, Laura R Saunders, Aysegul Balyimez, Summya Rashid, Ming Hu, Andrew J Stephenson, Amr F Fergany, Byron H Lee, Georges-Pascal Haber, Afshin Dowlati, Timothy Gilligan, Moshe C Ornstein, Brian I Rini, Omar Y Mian, Petros Grivas

Hematology and Medical Oncology, Cleveland Clinic., Solid Tumor Oncology and Urology, Cleveland Clinic., Anatomic Pathology, Cleveland Clinic., Department of Quantitative Health Sciences, Cleveland Clinic., Anatomical Pathology, Cleveland Clinic Foundation., Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic., AbbVie Stemcentrx LLC., Abbvie Stemcentrx., Molecular Biology, Abbvie Stemcentrx., Translational Hematology & Oncology Research (THOR), Cleveland Clinic., Quantitative Health Sciences, Cleveland Clinic., Glickman Urological Institute, Cleveland Clinic., Urology, Cleveland Clinic., Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation., Hematology and Oncology, University Hospitals Cleveland Medical Center., Hematology and Medical Oncology, Cleveland Clinic Foundation., Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute., Hematology/Oncology, Cleveland Clinic Taussig Cancer Institute., Translational Hematology & Oncology Research (THOR) and Radiation Oncology, Cleveland Clinic ., Medicine (Division of Oncology), University of Washington.

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