Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy
Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Published: |
Impact Journals
2017
|
| Subjects: | |
| Online Access: | https://eprints.nottingham.ac.uk/49754/ |
| _version_ | 1848798070073982976 |
|---|---|
| author | Hay, Jodie F. Lappin, Katrina Liberante, Fabio Kettyle, Laura M. Matchett, Kyle B. Thompson, Alexander Mills, Ken I. |
| author_facet | Hay, Jodie F. Lappin, Katrina Liberante, Fabio Kettyle, Laura M. Matchett, Kyle B. Thompson, Alexander Mills, Ken I. |
| author_sort | Hay, Jodie F. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML. |
| first_indexed | 2025-11-14T20:13:55Z |
| format | Article |
| id | nottingham-49754 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:13:55Z |
| publishDate | 2017 |
| publisher | Impact Journals |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-497542020-05-04T19:06:35Z https://eprints.nottingham.ac.uk/49754/ Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy Hay, Jodie F. Lappin, Katrina Liberante, Fabio Kettyle, Laura M. Matchett, Kyle B. Thompson, Alexander Mills, Ken I. Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML. Impact Journals 2017-09-15 Article PeerReviewed Hay, Jodie F., Lappin, Katrina, Liberante, Fabio, Kettyle, Laura M., Matchett, Kyle B., Thompson, Alexander and Mills, Ken I. (2017) Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy. Oncotarget, 8 (40). pp. 67891-67903. ISSN 1949-2553 acute myeloid leukaemia Vorinostat HDAC epigenetics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620222/ 10.18632/oncotarget.18910 10.18632/oncotarget.18910 10.18632/oncotarget.18910 |
| spellingShingle | acute myeloid leukaemia Vorinostat HDAC epigenetics Hay, Jodie F. Lappin, Katrina Liberante, Fabio Kettyle, Laura M. Matchett, Kyle B. Thompson, Alexander Mills, Ken I. Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy |
| title | Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy |
| title_full | Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy |
| title_fullStr | Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy |
| title_full_unstemmed | Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy |
| title_short | Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy |
| title_sort | integrated analysis of the molecular action of vorinostat identifies epi-sensitised targets for combination therapy |
| topic | acute myeloid leukaemia Vorinostat HDAC epigenetics |
| url | https://eprints.nottingham.ac.uk/49754/ https://eprints.nottingham.ac.uk/49754/ https://eprints.nottingham.ac.uk/49754/ |