An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.
Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy.
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. evanguelosxylinas@hotmail.com.|Institut National de la Santé et de la Recherche médicale (Inserm) Unit U955 Eq07, CHU Henri Mondor, Créteil 94010, France. evanguelosxylinas@hotmail.com.
Evanguelos
E
Xylinas
Department of Urology, Medical University of Vienna, Vienna 1090, Austria. melanie.hassler@meduniwien.ac.at.
Melanie R
MR
Hassler
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. dz100005@gmail.com.
Dazhong
D
Zhuang
Canada's Michael Smith Genome Sciences Center, Cancer Research Center, Vancouver, BC V5Z4S6, Canada. martink@bcgsc.ca.
Martin
M
Krzywinski
Institute of Cancer Research, Department of Medicine 1, Medical University of Vienna, Vienna 1090, Austria. zeynep.erdem@meduniwien.ac.at.
Zeynep
Z
Erdem
Department of Pathology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. brr2006@med.cornell.edu.
Brian D
BD
Robinson
Division of Physiology and Biophysics, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. ole2001@med.cornell.edu.
Olivier
O
Elemento
Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. thomas.clozel@gmail.com.
Thomas
T
Clozel
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. shahrokh.shariat@meduniwien.ac.at.|Department of Urology, Medical University of Vienna, Vienna 1090, Austria. shahrokh.shariat@meduniwien.ac.at.|Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY 10065, USA. shahrokh.shariat@meduniwien.ac.at.|Department of Urology, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA. shahrokh.shariat@meduniwien.ac.at.
Shahrokh F
SF
Shariat
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D000077209:Decitabine; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057890:Epigenomics; D005047:Etoposide / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008745:Methylation; D020360:Neoadjuvant Therapy; D011401:Promoter Regions, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology; D000077337:Vorinostat
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; C097899:homeobox protein HOXA9; D000077337:Vorinostat; D014747:Vinblastine; D005047:Etoposide; D000077209:Decitabine; D004317:Doxorubicin; D001374:Azacitidine; D002945:Cisplatin
HOXA9; decitabine; drug resistance; neoadjuvant therapy; urinary bladder neoplasms