Novel approaches for targeting BRCA2-deficient tumour cells
<p>Defects in homologous recombination (HR) repair are associated with significant mortality and improved therapies for HR-deficient tumours are therefore urgently needed. This work aimed to address this unmet need and utilised pharmacological approaches to investigate several methods for the...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2015
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| _version_ | 1797090196139802624 |
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| author | Tacconi, E |
| author2 | Tarsounas, M |
| author_facet | Tarsounas, M Tacconi, E |
| author_sort | Tacconi, E |
| collection | OXFORD |
| description | <p>Defects in homologous recombination (HR) repair are associated with significant mortality and improved therapies for HR-deficient tumours are therefore urgently needed. This work aimed to address this unmet need and utilised pharmacological approaches to investigate several methods for the targeting of BRCA2-deficient tumour cells. Parallel lines of investigation demonstrated the selective and effective targeting of BRCA2-deficient cells via both chemical G-quadruplex stabilisation and ERK inhibition. These studies provide impetus for the further development of specific and clinically relevant inhibitors. Further, pharmacological screens generated a body of data relevant to the selective targeting of BRCA2-deficiency. In particular, screening studies demonstrated that targeting the kinase GSK3 selectively kills BRCA2-deficient cells. Moreover, pharmacological screens revealed for the first time that disulfiram, an aldehyde dehydrogenase inhibitor currently in clinical use as an alcohol-aversive agent, induces replicative stress and DNA damage, selectively reducing the viability of BRCA2-deficient human tumour cells. Together, these data reveal a greater dependency of BRCA2-deficient human tumour cells on certain pro-proliferative pathways than their wild type counterparts and demonstrate the vulnerability of BRCA2-deficient cells to replicative stress. Importantly, this work delivers clear rationale for the further study and clinical development of several novel approaches relevant to the treatment of HR-deficient tumours and thus has the potential to help reduce the burden of these devastating diseases in the future.</p> |
| first_indexed | 2024-03-07T03:15:01Z |
| format | Thesis |
| id | oxford-uuid:b582633a-92cd-4aa4-b63d-36b9c922859e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:15:01Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | oxford-uuid:b582633a-92cd-4aa4-b63d-36b9c922859e2022-03-27T04:33:55ZNovel approaches for targeting BRCA2-deficient tumour cellsThesishttp://purl.org/coar/resource_type/c_db06uuid:b582633a-92cd-4aa4-b63d-36b9c922859eEnglishORA Deposit2015Tacconi, ETarsounas, MRyan, A<p>Defects in homologous recombination (HR) repair are associated with significant mortality and improved therapies for HR-deficient tumours are therefore urgently needed. This work aimed to address this unmet need and utilised pharmacological approaches to investigate several methods for the targeting of BRCA2-deficient tumour cells. Parallel lines of investigation demonstrated the selective and effective targeting of BRCA2-deficient cells via both chemical G-quadruplex stabilisation and ERK inhibition. These studies provide impetus for the further development of specific and clinically relevant inhibitors. Further, pharmacological screens generated a body of data relevant to the selective targeting of BRCA2-deficiency. In particular, screening studies demonstrated that targeting the kinase GSK3 selectively kills BRCA2-deficient cells. Moreover, pharmacological screens revealed for the first time that disulfiram, an aldehyde dehydrogenase inhibitor currently in clinical use as an alcohol-aversive agent, induces replicative stress and DNA damage, selectively reducing the viability of BRCA2-deficient human tumour cells. Together, these data reveal a greater dependency of BRCA2-deficient human tumour cells on certain pro-proliferative pathways than their wild type counterparts and demonstrate the vulnerability of BRCA2-deficient cells to replicative stress. Importantly, this work delivers clear rationale for the further study and clinical development of several novel approaches relevant to the treatment of HR-deficient tumours and thus has the potential to help reduce the burden of these devastating diseases in the future.</p> |
| spellingShingle | Tacconi, E Novel approaches for targeting BRCA2-deficient tumour cells |
| title | Novel approaches for targeting BRCA2-deficient tumour cells |
| title_full | Novel approaches for targeting BRCA2-deficient tumour cells |
| title_fullStr | Novel approaches for targeting BRCA2-deficient tumour cells |
| title_full_unstemmed | Novel approaches for targeting BRCA2-deficient tumour cells |
| title_short | Novel approaches for targeting BRCA2-deficient tumour cells |
| title_sort | novel approaches for targeting brca2 deficient tumour cells |
| work_keys_str_mv | AT tacconie novelapproachesfortargetingbrca2deficienttumourcells |