File Download
Supplementary

postgraduate thesis: In vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia

TitleIn vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia
Authors
Advisors
Advisor(s):Leung, AYHNg, RK
Issue Date2016
PublisherThe 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.
AbstractAn 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.
DegreeDoctor of Philosophy
SubjectAcute myeloid leukemia - Treatment
Alkaloids - Therapeutic use
Dept/ProgramMedicine
Persistent Identifierhttp://hdl.handle.net/10722/265355

 

DC FieldValueLanguage
dc.contributor.advisorLeung, AYH-
dc.contributor.advisorNg, RK-
dc.contributor.authorLam, Sze-yuen-
dc.contributor.author林思遠-
dc.date.accessioned2018-11-29T06:22:25Z-
dc.date.available2018-11-29T06:22:25Z-
dc.date.issued2016-
dc.identifier.citationLam, 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.urihttp://hdl.handle.net/10722/265355-
dc.description.abstractAn 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.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshAcute myeloid leukemia - Treatment-
dc.subject.lcshAlkaloids - Therapeutic use-
dc.titleIn vitro drug screening identified homoharringtonine (omacetaxine mepesuccinate) as an effective adjunct for treatment of FLT3-ITD acute myeloid leukaemia-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2018-
dc.identifier.mmsid991044058176503414-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats