title: Top2a identifies and provides epigenetic rationale for novel combination therapeutic strategies for aggressive prostate cancer.
abstract: Progression of aggressive prostate cancers (PCa) with androgen receptor splice variants or neuroendrocrine features is currently untreatable in the clinic. Therefore novel therapies are urgently required. We conducted RNA-seq using tumors from a unique murine transplant mouse model which spontaneously progresses to metastatic disease. Differential gene expression analysis revealed a significant increase of topoisomerase IIα, Top2a (Top2a) in metastatic tumors. Interrogation of human data revealed that increased Top2a expression in primary tumors selected patients with more aggressive disease. Further, significant positive correlation was observed between Top2a and the histone methyltransferase, Ezh2. Combination of the Top2 poison etoposide with the Ezh2 inhibitor GSK126 or DZNep significantly increased cell death in vitro in murine and human prostate cancer cell lines. Additionally, combination therapy extended time to progression and increased therapeutic efficacy in vivo. Overall, our studies demonstrate that patients screened for Top2a and Ezh2 expression would exhibit significant response to a combinational treatment involving low dose etoposide combined with Ezh2 inhibition. In addition, our data suggests that this combination therapeutic strategy is beneficial against aggressive PCa, and provides strong rationale for continued clinical development.
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Kirk
authors.affiliation: Department of Medicine, University of Szeged, Hungary.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schaarschuch
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Zafardjan
authors.initials: Z
authors.lastname: Dalimov
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Lasorsa
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Cancer Prevention and Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: ShengYu
authors.initials: S
authors.lastname: Ku
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Ramakrishnan
authors.affiliation: Department of Bioinformatics and Statistics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Gissou
authors.initials: G
authors.lastname: Azabdaftari
authors.affiliation: Department of Bioinformatics and Statistics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.affiliation: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Ellis
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D000075223:Poly-ADP-Ribose Binding Proteins; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011728:Pyridones / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C577920:GSK-2816126; D007211:Indoles; D000075223:Poly-ADP-Ribose Binding Proteins; D011728:Pyridones; D012333:RNA, Messenger; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse