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postgraduate thesis: Anti-tumor effects of polo-like kinase 4 inhibitor in epithelial ovarian cancer
Title | Anti-tumor effects of polo-like kinase 4 inhibitor in epithelial ovarian cancer |
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Authors | |
Advisors | |
Issue Date | 2021 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Tse, K. [謝嘉瑜]. (2021). Anti-tumor effects of polo-like kinase 4 inhibitor in epithelial ovarian cancer. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Epithelial ovarian cancer (EOC) is characterised by chromosomal instability. Different histological subtypes have different genetic mutations and copy number changes, and many of these are related to cell cycle control. Polo-like kinase (PLK) 4 regulates centriole duplication and mitosis, and is crucial in maintaining the genomic stability in cancer cells. Its depletion leads to cell cycle arrest, and its accumulation leads to polyploidy. This study aims to examine the prognostic implications of PLK4 in EOC, to investigate the anti-tumoral effects of CFI-400945 that targets PLK4, and to elicit the mechanisms of PLK4 inhibition on tumor growth.
Comparing to normal ovarian tissues, ovarian cancer tissues had a significantly higher PLK4 mRNA expression level. Its overexpression was associated with shorter progression-free survival (PFS) which was confirmed by multivariate analysis. Hence, PLK4 appeared to be a vulnerable target for cancer therapy in EOC. Next the efficacy of CFI-400945 in EOC cell lines was evaluated. CFI-400945 could not only inhibit cell proliferation and induce apoptosis, it could also lead to polyploidy, which caused additional burden on cancer cells that already had chromosomal instability. In addition, the centriole deregulation caused DNA damage, yet this was not accompanied by an increased homologous recombination repair. The net imbalance resulted in cell death. The anti-tumoral effects of CFI-400945 were further demonstrated in mice where growth inhibition and apoptosis were observed. These results were further confirmed in organoid models that were developed from tumors and ascites.
Because of the significant anti-proliferative effect of CFI-400945 shown in the above experiments, I was prompted to study how PLK4 inhibition would have led to this. It was found that the efficacy of CFI-400945 was correlated with the mTOR and p70S6K mRNA expression. CFI-400945 also downregulated AKT / mTOR / p70S6K at transcriptional level. This suggested that there was a relationship between PLK4 and the AKT / mTOR / p70S6K pathway. More experiments are under way to investigate this further.
In order to explore whether there were other mechanisms of CFI-400945, transcriptome was performed which demonstrated a senescence-associated secretory phenotype (SASP). While acute senescence can be beneficial as the cell cycle arrest can attract more immune cells to kill the cancer cells, chronic senescence and the components in its associated SASP can promote cancer growth. The therapy-induced senescence after CFI-400945 provided a secondary target where complementary therapy can be added to clear the remaining senescent cells. As previous studies showed that metformin possessed senomorphic effects, it was used to combine with CFI-400945 where a marginal synergistic effect was observed in one cell line. Metformin has a long history and is well tolerated. This combination regimen can be considered for further evaluation in clinical trials.
Based on the above results, it is clear that CFI-400945 is a promising therapeutics in EOC by causing synthetic lethality on tumor cells that have already harboured chromosomal aberrations. Finally, organoid culture is shown to be an integral part in current precision medicine era by providing more human-like evidence compared to the traditional in vitro and in vivo models.
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Degree | Doctor of Philosophy |
Subject | Ovaries - Cancer Protein kinases |
Dept/Program | Pathology |
Persistent Identifier | http://hdl.handle.net/10722/323432 |
DC Field | Value | Language |
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dc.contributor.advisor | Wong, CCL | - |
dc.contributor.advisor | Mak, TW | - |
dc.contributor.advisor | Ngan, HYS | - |
dc.contributor.author | Tse, Ka-yu | - |
dc.contributor.author | 謝嘉瑜 | - |
dc.date.accessioned | 2022-12-23T09:47:26Z | - |
dc.date.available | 2022-12-23T09:47:26Z | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Tse, K. [謝嘉瑜]. (2021). Anti-tumor effects of polo-like kinase 4 inhibitor in epithelial ovarian cancer. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/323432 | - |
dc.description.abstract | Epithelial ovarian cancer (EOC) is characterised by chromosomal instability. Different histological subtypes have different genetic mutations and copy number changes, and many of these are related to cell cycle control. Polo-like kinase (PLK) 4 regulates centriole duplication and mitosis, and is crucial in maintaining the genomic stability in cancer cells. Its depletion leads to cell cycle arrest, and its accumulation leads to polyploidy. This study aims to examine the prognostic implications of PLK4 in EOC, to investigate the anti-tumoral effects of CFI-400945 that targets PLK4, and to elicit the mechanisms of PLK4 inhibition on tumor growth. Comparing to normal ovarian tissues, ovarian cancer tissues had a significantly higher PLK4 mRNA expression level. Its overexpression was associated with shorter progression-free survival (PFS) which was confirmed by multivariate analysis. Hence, PLK4 appeared to be a vulnerable target for cancer therapy in EOC. Next the efficacy of CFI-400945 in EOC cell lines was evaluated. CFI-400945 could not only inhibit cell proliferation and induce apoptosis, it could also lead to polyploidy, which caused additional burden on cancer cells that already had chromosomal instability. In addition, the centriole deregulation caused DNA damage, yet this was not accompanied by an increased homologous recombination repair. The net imbalance resulted in cell death. The anti-tumoral effects of CFI-400945 were further demonstrated in mice where growth inhibition and apoptosis were observed. These results were further confirmed in organoid models that were developed from tumors and ascites. Because of the significant anti-proliferative effect of CFI-400945 shown in the above experiments, I was prompted to study how PLK4 inhibition would have led to this. It was found that the efficacy of CFI-400945 was correlated with the mTOR and p70S6K mRNA expression. CFI-400945 also downregulated AKT / mTOR / p70S6K at transcriptional level. This suggested that there was a relationship between PLK4 and the AKT / mTOR / p70S6K pathway. More experiments are under way to investigate this further. In order to explore whether there were other mechanisms of CFI-400945, transcriptome was performed which demonstrated a senescence-associated secretory phenotype (SASP). While acute senescence can be beneficial as the cell cycle arrest can attract more immune cells to kill the cancer cells, chronic senescence and the components in its associated SASP can promote cancer growth. The therapy-induced senescence after CFI-400945 provided a secondary target where complementary therapy can be added to clear the remaining senescent cells. As previous studies showed that metformin possessed senomorphic effects, it was used to combine with CFI-400945 where a marginal synergistic effect was observed in one cell line. Metformin has a long history and is well tolerated. This combination regimen can be considered for further evaluation in clinical trials. Based on the above results, it is clear that CFI-400945 is a promising therapeutics in EOC by causing synthetic lethality on tumor cells that have already harboured chromosomal aberrations. Finally, organoid culture is shown to be an integral part in current precision medicine era by providing more human-like evidence compared to the traditional in vitro and in vivo models. | - |
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 | Ovaries - Cancer | - |
dc.subject.lcsh | Protein kinases | - |
dc.title | Anti-tumor effects of polo-like kinase 4 inhibitor in epithelial ovarian cancer | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Pathology | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2022 | - |
dc.identifier.mmsid | 991044494002803414 | - |