Proteomic analysis of chemoresistance in bladder cancer
Final Report Abstract
Bladder cancer (BC) is a prevalent global concern causing over 570,000 annual diagnoses and 212,000 deaths. Most cases present as non-muscle-invasive (NMIBC) with favorable outcomes, but approximately 25% are more aggressive muscle-invasive (MIBC) demonstrating only a 50-60% 5-year survival. Current guideline-recommended treatment involves platinum-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), but only a minority of patients responds to NAC. Molecular markers for therapeutic guidance in MIBC are lacking, prompting ongoing trials. Transcriptomic subtypes and DNA damage repair (DDR) gene mutations have shown to impact response in various studies. Notably, proteomic studies on MIBC are limited, hindering understanding of NAC mechanisms. Utilizing mass spectrometry for the analysis of the proteome on formalin-fixed paraffin-embedded specimens we analyzed pre-NAC and post-NAC tumour samples in MIBC patients and were able to offer insights into potential biomarkers and chemo-resistance mechanisms, forming a foundation for future exploration. The study involved 107 muscle-invasive bladder cancer (MIBC) patients from Vancouver and Bern cohort. Tissue samples were collected before and after platinum-based chemotherapy and proteomic and transcriptomic analyses were performed. Proteomic clusters pre- and postchemotherapy were identified using established bioinformatic methods. Multivariable analysis, survival studies and immunohistochemistry were conducted, forming a comprehensive platform for future exploration. The pre-NAC MIBC proteome revealed four clusters (CC1 to CC4) with distinct characteristics and clinical outcomes. CC1 (luminal subtype) exhibited high metabolic activity, favorable NAC responses, and superior overall survival (OS). CC2 (enriched for nuclear features) had promising outcomes, influenced by a small sample size. CC3 (basal subtype) displayed basal differentiation, immune enrichment and the worst prognosis. CC4 (stroma-rich) featured elevated stroma-related proteins and immune infiltration. Comparison with non-muscle-invasive bladder cancer (NMIBC) and benign urothelium demonstrated a high degree of overlap with CC1. Immunohistochemical validation of cluster-defining proteins correlated in part with clinical outcomes. Post-NAC tissue proteomic analysis revealed four additional clusters associated with distinct biological features and outcomes. Intra-tumor heterogeneity (ITH) analysis of pre-NAC samples suggested higher ITH correlated with poorer NAC response and survival outcomes. Integrating proteomic and transcriptomic data revealed concordance between pre-NAC clusters and RNA subtypes and further lead to the identification of potential therapeutic targets and suggesting ITH as a biomarker for NAC resistance.
Publications
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Not “If”, but “When” and “How”: Testing Antibody-Drug Conjugates in Patients with Non–muscle-invasive Bladder Cancer. European Urology, 81(2), 143-144.
Reike, Moritz J.; Adar, Roy & Black, Peter C.
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Assessment of complications after transperineal and transrectal prostate biopsy using a risk-stratified pathway identifying patients at risk for post-biopsy infections. Scandinavian Journal of Urology, 57(1-6), 41-46.
Berg, Sebastian; Tully, Karl Heinrich; Hoffmann, Vincent; Bahlburg, Henning; Roghmann, Florian; Müller, Guido; Noldus, Joachim & Reike, Moritz
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Biological Stratification of Invasive and Advanced Urothelial Carcinoma. Urologic Clinics of North America, 50(1), 69-80.
Reike, Moritz J.; Contreras-Sanz, Alberto & Black, Peter C.
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Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III. Urologic Oncology: Seminars and Original Investigations, 41(5), 211-218.
Reike, M.J.; Ingersoll, M.A.; Müller, D.C.; Zuiverloon, T.C.M.; Strandgaard, T.; Kamat, A.M.; Williams, S.B.; Seiler, R.; Todenhöfer, T.; Dyrskjøt, L.; Nawroth, R.; Goebell, P.; Schmitz-Dräger, B.; Sfakianos, J.P.; Meeks, J.; Horowitz, A. & Black, P.C.
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Harninkontinenz nach radikaler Prostatektomie beim Prostatakarzinom – aktuelle Daten von 17.149 Patienten aus 125 zertifizierten Zentren. Die Urologie, 63(1), 67-74.
Kowalski, Christoph; Sibert, Nora Tabea; Hammerer, Peter; Wesselmann, Simone; Feick, Günter; Carl, Ernst-Günther; Klotz, Theodor; Apel, Hendrik; Dieng, Sebastian; Nyarangi-Dix, Joanne; Knoll, Thomas; Reike, Moritz Johannes; Duwe, Gregor; Bartolf, Elisabeth; Steiner, Thomas; Borowitz, Rainer; Lümmen, Gerd; Seitz, Anna Katharina; Pfitzenmaier, Jesco ... & Burchardt, Martin
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Proteomic profiling of muscle invasive bladder cancer treated with neoadjuvant chemotherapy. European Urology Open Science, 48, S11.
Contreras-Sanz, A.; Reike, M.J.; Negri, G.L.; Oo, H.Z.; Spencer, Miko S.; Nielsen, K.; Roberts, M.E.; Scurll, J.; Ikeda, K.; Wang, G.; Seiler, R.; Morin, G.B. & Black, P.
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A systematic review of nanocarriers for treatment of urologic cancers. Urologic Oncology: Seminars and Original Investigations, 42(4), 75-101.
Wang, Amy J.Y.; Yan, Cathy; Reike, Moritz J.; Black, Peter C. & Contreras-Sanz, Alberto
