File Download
Supplementary
-
Citations:
- Appears in Collections:
postgraduate thesis: In vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia
Title | In vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia |
---|---|
Authors | |
Advisors | |
Issue Date | 2016 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Lam, S. [林思遠]. (2016). In vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | An in vitro drug-screening platform was developed and validated with a view to design personalised treatment for relapsed or chemo-refractory acute myeloid leukaemia (AML). A pilot study was conducted to test the effects of 25 carefully selected drugs on 96 primary AML samples in both conditioned medium and autologous human serum culture systems. Unbiased clustering and correlation of drug response showed that a protein translation inhibitor, homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential anti-leukaemia effect on AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). As FLT3 signalling proteins were known to have short half-lives, the preferential effect of HHT on FLT3-ITD AML was attributed to addiction to high protein synthesis rates in this AML subtype. Synergism between HHT and FLT3 inhibitors could be demonstrated in vitro.
Combination of HHT with sorafenib (S+HHT) was tested in a phase II clinical trial in FLT3-ITD AML patients. Compared with a historical cohort of patients receiving sorafenib monotherapy, combination treatment resulted in high remission rate, greater reduction of ITD allelic burden, longer leukaemia-free (LFS) and overall survivals. AML samples from patients before S+HHT treatment showed a significantly greater in vitro response to sorafenib and HHT than those obtained at the time of leukaemia progression. The in vitro response of clinical samples from treatment-naive patient was also correlated with their subsequent LFS. This study has validated the principle and clinical relevance of in vitro drug testing, and also set a new paradigm for the treatment of FLT3-ITD AML.
|
Degree | Doctor of Philosophy |
Subject | Acute myeloid leukemia - Treatment Alkaloids - Therapeutic use |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/265355 |
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Leung, AYH | - |
dc.contributor.advisor | Ng, RK | - |
dc.contributor.author | Lam, Sze-yuen | - |
dc.contributor.author | 林思遠 | - |
dc.date.accessioned | 2018-11-29T06:22:25Z | - |
dc.date.available | 2018-11-29T06:22:25Z | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Lam, S. [林思遠]. (2016). In vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/265355 | - |
dc.description.abstract | An in vitro drug-screening platform was developed and validated with a view to design personalised treatment for relapsed or chemo-refractory acute myeloid leukaemia (AML). A pilot study was conducted to test the effects of 25 carefully selected drugs on 96 primary AML samples in both conditioned medium and autologous human serum culture systems. Unbiased clustering and correlation of drug response showed that a protein translation inhibitor, homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential anti-leukaemia effect on AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). As FLT3 signalling proteins were known to have short half-lives, the preferential effect of HHT on FLT3-ITD AML was attributed to addiction to high protein synthesis rates in this AML subtype. Synergism between HHT and FLT3 inhibitors could be demonstrated in vitro. Combination of HHT with sorafenib (S+HHT) was tested in a phase II clinical trial in FLT3-ITD AML patients. Compared with a historical cohort of patients receiving sorafenib monotherapy, combination treatment resulted in high remission rate, greater reduction of ITD allelic burden, longer leukaemia-free (LFS) and overall survivals. AML samples from patients before S+HHT treatment showed a significantly greater in vitro response to sorafenib and HHT than those obtained at the time of leukaemia progression. The in vitro response of clinical samples from treatment-naive patient was also correlated with their subsequent LFS. This study has validated the principle and clinical relevance of in vitro drug testing, and also set a new paradigm for the treatment of FLT3-ITD AML. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Acute myeloid leukemia - Treatment | - |
dc.subject.lcsh | Alkaloids - Therapeutic use | - |
dc.title | In vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044058176503414 | - |
dc.date.hkucongregation | 2018 | - |
dc.identifier.mmsid | 991044058176503414 | - |