Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy.
<h4>Background</h4>Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, wa...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089750&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850189975710072832 |
|---|---|
| author | Anne Hansen Ree Marie Grøn Saelen Erta Kalanxhi Ingrid H G Østensen Kristina Schee Kathrine Røe Torveig Weum Abrahamsen Svein Dueland Kjersti Flatmark |
| author_facet | Anne Hansen Ree Marie Grøn Saelen Erta Kalanxhi Ingrid H G Østensen Kristina Schee Kathrine Røe Torveig Weum Abrahamsen Svein Dueland Kjersti Flatmark |
| author_sort | Anne Hansen Ree |
| collection | DOAJ |
| description | <h4>Background</h4>Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, was designed to evaluate both clinical and novel biomarker endpoints, the latter relating to pharmacodynamic indicators of vorinostat action in clinical radiotherapy.<h4>Patients and methods</h4>Potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of study patients' peripheral blood mononuclear cells (PBMC), sampled at baseline (T0) and on-treatment two and 24 hours (T2 and T24) after the patients had received vorinostat.<h4>Results</h4>This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of identified genes were implicated in gene regulation, the cell cycle, and chromatin biology. Gene expression was validated both in patients' PBMC and in vorinostat-treated human carcinoma xenograft models, and transient repression of MYC was consistently observed.<h4>Conclusion</h4>Within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat action in fractionated radiotherapy, possibly underscoring the role of MYC in this therapeutic setting. |
| format | Article |
| id | doaj-art-54fbe20779b64e22906b6e19c487e96a |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-54fbe20779b64e22906b6e19c487e96a2025-08-20T02:15:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8975010.1371/journal.pone.0089750Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy.Anne Hansen ReeMarie Grøn SaelenErta KalanxhiIngrid H G ØstensenKristina ScheeKathrine RøeTorveig Weum AbrahamsenSvein DuelandKjersti Flatmark<h4>Background</h4>Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, was designed to evaluate both clinical and novel biomarker endpoints, the latter relating to pharmacodynamic indicators of vorinostat action in clinical radiotherapy.<h4>Patients and methods</h4>Potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of study patients' peripheral blood mononuclear cells (PBMC), sampled at baseline (T0) and on-treatment two and 24 hours (T2 and T24) after the patients had received vorinostat.<h4>Results</h4>This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of identified genes were implicated in gene regulation, the cell cycle, and chromatin biology. Gene expression was validated both in patients' PBMC and in vorinostat-treated human carcinoma xenograft models, and transient repression of MYC was consistently observed.<h4>Conclusion</h4>Within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat action in fractionated radiotherapy, possibly underscoring the role of MYC in this therapeutic setting.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089750&type=printable |
| spellingShingle | Anne Hansen Ree Marie Grøn Saelen Erta Kalanxhi Ingrid H G Østensen Kristina Schee Kathrine Røe Torveig Weum Abrahamsen Svein Dueland Kjersti Flatmark Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy. PLoS ONE |
| title | Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy. |
| title_full | Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy. |
| title_fullStr | Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy. |
| title_full_unstemmed | Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy. |
| title_short | Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy. |
| title_sort | biomarkers of histone deacetylase inhibitor activity in a phase 1 combined modality study with radiotherapy |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089750&type=printable |
| work_keys_str_mv | AT annehansenree biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT mariegrønsaelen biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT ertakalanxhi biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT ingridhgøstensen biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT kristinaschee biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT kathrinerøe biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT torveigweumabrahamsen biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT sveindueland biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy AT kjerstiflatmark biomarkersofhistonedeacetylaseinhibitoractivityinaphase1combinedmodalitystudywithradiotherapy |