Dataset Information

Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma.

ABSTRACT: Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had ARID1A mutations. ARID1A mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant ARID1A-mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies ARID1A loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.

SUBMITTER: Gupta S

PROVIDER: S-EPMC6350908 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Histone Deacetylase Inhibition Has Targeted Clinical Benefit in <i>ARID1A</i>-Mutated Advanced Urothelial Carcinoma.

Gupta Sumati S Albertson Daniel J DJ Parnell Timothy J TJ Butterfield Andrew A Weston Alexis A Pappas Lisa M LM Dalley Brian B O'Shea John M JM Lowrance William T WT Cairns Bradley R BR Schiffman Joshua D JD Sharma Sunil S

Molecular cancer therapeutics 20181009 1

Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responder ...[more]

PMID: 30301863

Similar Datasets

Project description:Canine urothelial carcinoma (cUC) is the most common tumor of the lower urinary tract in dogs. Although chemotherapy and radical surgery have improved the overall survival, most dogs with cUC succumb to metastasis or recurrence. Therefore, the development of an effective systematic therapy is warranted. In this study, a comprehensive drug screening test using a cUC cell line was performed and the anti-tumor effect of a histone deacetylase (HDAC) inhibitor was evaluated. Comprehensive drug screening was performed on cUC cells. Based on this screening, the anti-proliferation effect of vorinostat, an HDAC inhibitor clinically applied in humans, was evaluated using several cUC cell lines in sulforhodamine B and flow cytometry assays. Western blot analysis was also performed to evaluate the degree of acetylation of histone H3 as well as the expression and phosphorylation of cell cycle-related molecules. The anti-tumor effect of vorinostat in vivo was evaluated using a xenograft model. Finally, immunohistochemistry was performed on acetyl-histone H3 in cUC and the relationship between the degree of acetylation and prognosis was examined using Kaplan-Meier survival analysis. Drug screening revealed that HDAC inhibitors consistently inhibited the growth of cUC cells. Vorinostat inhibited the growth of 6 cUC cell lines in a dose-dependent manner and induced G0/G1 cell cycle arrest. Western blot analysis showed that vorinostat mediated the acetylation of histone H3, the dephosphorylation of p-Rb, and the upregulation of p21 upon exposure to vorinostat. Furthermore, inhibition of tumor growth was observed in the xenograft model. In clinical cUC cases, neoplastic urothelium showed significant deacetylation of histones compared to the normal control, where lower histone acetylation levels were associated with a poor prognosis. In conclusion, the therapeutic potential of vorinostat was demonstrated in cUC. Histone deacetylation may be related to cUC tumor progression.

Dataset Information

Histone Deacetylase Inhibition Has Targeted Clinical Benefit in ARID1A-Mutated Advanced Urothelial Carcinoma.

Publications

Histone Deacetylase Inhibition Has Targeted Clinical Benefit in <i>ARID1A</i>-Mutated Advanced Urothelial Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets