gsk-2816126 and Prostatic-Neoplasms

Upregulation of EZH2 is associated with advanced stage and poor prognosis of prostate cancer; therefore, it is likely to be a promising therapeutic target. Metformin, a drug that has been used to treat type 2 diabetes, was found to have antineoplastic activity in different cancers. Herein, we report that the combination of metformin and the EZH2 inhibitor GSK126 exerts synergistic inhibition on prostate cancer cell growth, both

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Synergism; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic; Humans; Indoles; Male; Metformin; Mice; MicroRNAs; Promoter Regions, Genetic; Prostatic Neoplasms; Pyridones; Receptors, Androgen; Transcriptional Activation; Xenograft Model Antitumor Assays

Androgen deprivation therapy is the mainstay of treatment of advanced prostate cancer (PCa). However, a significant portion of patients experience disease relapse and tumors ultimately evolve into castration resistant prostate cancer (CRPC), for which there is no cure in the clinic. The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in CRPC. It is unclear whether EZH2 can be a therapeutic target in CRPC. Here, we demonstrated that chemo- and radiotherapy agents such as camptothecin (CPT) and γ irradiation decrease EZH2 expression in various PCa cell lines. We provided evidence that functional p53 and RB proteins are required for CPT- and irradiation-induced downregulation of EZH2 in CRPC cells. We demonstrated that EZH2-specific small molecule inhibitors mitigate CRPC cell growth. We further showed that the EZH2 inhibitor GSK126 inhibits both Polycomb-dependent and -independent functions of EZH2 in PCa cells. Importantly, we found that inhibition of EZH2 by genetic and pharmacological means sensitizes CRPC cells to CPT-induced apoptotic death and growth inhibition in culture and in mice. Our data suggest that concomitant administration of small molecule inhibitors of EZH2 may significantly increase the anti-tumor efficacy of conventional chemo- and radiotherapies in CRPC.

Topics: Animals; Apoptosis; Blotting, Western; Cell Movement; Cell Proliferation; Chemoradiotherapy; Enhancer of Zeste Homolog 2 Protein; Humans; Immunoenzyme Techniques; Indoles; Male; Mice; Mice, Inbred NOD; Mice, SCID; Prostatic Neoplasms; Pyridones; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Line, Tumor; Disease-Free Survival; DNA Topoisomerases, Type II; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Indoles; Male; Mice, Inbred C57BL; Poly-ADP-Ribose Binding Proteins; Polycomb Repressive Complex 2; Precision Medicine; Predictive Value of Tests; Prostatic Neoplasms; Pyridones; RNA, Messenger; Time Factors; Topoisomerase II Inhibitors; Up-Regulation; Xenograft Model Antitumor Assays