Detailed Abstract
[E-poster]
[EP201] HDAC-targeting epigenetic drug screening for biliary tract cancer
Christian MAYR1, 2, Tobias KIESSLICH1, 2, Sara ERBER1, Dino BEKRIC1, Heidemarie DOBIAS1, Markus RITTER1, 3, Tarkan J횳ER4, Bettina NEUMAYER5, 6, Paul WINKELMANN5, 6, Eckhard KLIESER5, 6, Daniel NEUREITER*5, 6
1Institute for Physiology and Pathophysiology, Paracelsus Medical University, Austria
2Department of Internal Medicine I, University Clinics Salzburg, Paracelsus Medical University, Austria
3Ludwig Boltzmann Institute for Arthritis und Rehabilitation, Paracelsus Medical University, Austria
4Department of Surgery, University Clinics Salzburg, Paracelsus Medical University, Austria
5Institute of Pathology, University Clinics Salzburg, Paracelsus Medical University, Austria
6Institute of Pathology, Cancer Cluster Salzburg, Austria
Introduction : Although molecular insights about biliary tract cancer (BTC) increased in the last decade, new therapeutic strategy like inhibition of histone deacetylases (HDACs) could additionally improve the still dismal outcome of this tumor entity.
Methods : Therefore, we performed comprehensive investigation of HDAC expression and pharmacological inhibition in a panel of eight established BTC cell lines and in a cohort resected native BTC specimens (n=78).
Results : HDAC profiling revealed a heterogeneous expression of HDACs across the studied cell lines and the BTC cancer specimen. Cytotoxicity of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis was dose- as well as cell line-dependent and did not show a statistical correlation with HDAC isoform expression. Romidepsin (a class II HDACi), induced the highest reduction of cell viability and apoptosis in BTC cells which was paralleled by reducing HDAC1/2 activity and increasing histone 3 lysine 9 acetylation. Furthermore, non-toxic concentrations of romidepsin could augment the cytotoxic effect of the standard chemotherapeutic cisplatin. Related to the clinical tumor specimen, HDAC expression pattern correlated with the tumor grading and the survival of BTC patients.
Conclusions : In conclusion, in-vitro-experiments provide clear evidence that the HDAC class I inhibitor romidepsin is effective for BTC alone and acts supportively in combination with standard chemotherapeutics. Additionally, the observed HDAC expression in BTC specimens could serve as a predictive and prognostic biomarker for BTC patients.
Methods : Therefore, we performed comprehensive investigation of HDAC expression and pharmacological inhibition in a panel of eight established BTC cell lines and in a cohort resected native BTC specimens (n=78).
Results : HDAC profiling revealed a heterogeneous expression of HDACs across the studied cell lines and the BTC cancer specimen. Cytotoxicity of six established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis was dose- as well as cell line-dependent and did not show a statistical correlation with HDAC isoform expression. Romidepsin (a class II HDACi), induced the highest reduction of cell viability and apoptosis in BTC cells which was paralleled by reducing HDAC1/2 activity and increasing histone 3 lysine 9 acetylation. Furthermore, non-toxic concentrations of romidepsin could augment the cytotoxic effect of the standard chemotherapeutic cisplatin. Related to the clinical tumor specimen, HDAC expression pattern correlated with the tumor grading and the survival of BTC patients.
Conclusions : In conclusion, in-vitro-experiments provide clear evidence that the HDAC class I inhibitor romidepsin is effective for BTC alone and acts supportively in combination with standard chemotherapeutics. Additionally, the observed HDAC expression in BTC specimens could serve as a predictive and prognostic biomarker for BTC patients.
SESSION
E-poster
E-Session 3/25 ~ 3/27 ALL DAY