The role of SPRTN protease in colorectal cancer chemotherapy
<p>Colorectal cancer (CRC) currently represents one of the most commonly diagnosed tumors, accounting for 10% of all cancer diagnoses and cancer-related deaths. The first-line treatment of metastatic colorectal cancer (mCRC) is frequently based on combination chemotherapeutic regimens, where 5...
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| Format: | Thesis |
| Language: | English |
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2023
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| _version_ | 1797111965348265984 |
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| author | Peron, C |
| author2 | Ramadan, K |
| author_facet | Ramadan, K Peron, C |
| author_sort | Peron, C |
| collection | OXFORD |
| description | <p>Colorectal cancer (CRC) currently represents one of the most commonly diagnosed tumors, accounting for 10% of all cancer diagnoses and cancer-related deaths. The first-line treatment of metastatic colorectal cancer (mCRC) is frequently based on combination chemotherapeutic regimens, where 5-fluorouracil is either associated with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). Both these regiments present similar level of efficacy, and both irinotecan and oxaliplatin have been reported as drugs with the potential to induce relevant amounts of DNA-protein crosslinks (DPCs), a heterogeneous form of DNA lesion in which proteins end up being covalently bound to the DNA. At the moment we are currently lacking reliable methods to predict which patients are more likely to respond to FOLFIRI or FOLFOX, which would allow us to choose the most appropriate therapy for each patient. In order to address this need, the role of SPRTN in colorectal cancer chemotherapy is investigated for the first time in this thesis.</p>
<p>SPRTN was recently identified as a metalloprotease involved in the repair of DPCs. To address SPRTN potential role in the repair of DPCs induced by irinotecan and oxaliplatin, two main approaches have been attempted in this thesis. First, a preclinical study with three different colorectal cancer cell lines was performed to address if SPRTN depletion could make cells more sensitive to the aforementioned drugs. However, despite presenting an increased amount of DNA damage, CRC cells appeared to survive the deleterious effects of SPRTN depletion, thanks to the expression of alternative DPC proteases and the upregulation of anti-apoptotic genes. Secondly, clinical mCRC samples obtained from the MRC FOCUS trial were analyzed to determine if SPRTN overexpression measured by immunohistochemistry could represent a useful predictive biomarker to determine the efficacy of FOLFIRI vs FOLFOX chemotherapy. In line with the preclinical data, however, SPRTN was not confirmed to represent a valuable biomarker in CRC chemotherapy.</p> |
| first_indexed | 2024-03-07T08:16:10Z |
| format | Thesis |
| id | oxford-uuid:c5c3d34c-c63d-4967-a1ce-c5e7bb76569e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:16:10Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:c5c3d34c-c63d-4967-a1ce-c5e7bb76569e2024-01-04T14:20:50ZThe role of SPRTN protease in colorectal cancer chemotherapyThesishttp://purl.org/coar/resource_type/c_db06uuid:c5c3d34c-c63d-4967-a1ce-c5e7bb76569eCancerOncologyEnglishHyrax Deposit2023Peron, CRamadan, KMaughan, TMiddleton, MTrusolino, L<p>Colorectal cancer (CRC) currently represents one of the most commonly diagnosed tumors, accounting for 10% of all cancer diagnoses and cancer-related deaths. The first-line treatment of metastatic colorectal cancer (mCRC) is frequently based on combination chemotherapeutic regimens, where 5-fluorouracil is either associated with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). Both these regiments present similar level of efficacy, and both irinotecan and oxaliplatin have been reported as drugs with the potential to induce relevant amounts of DNA-protein crosslinks (DPCs), a heterogeneous form of DNA lesion in which proteins end up being covalently bound to the DNA. At the moment we are currently lacking reliable methods to predict which patients are more likely to respond to FOLFIRI or FOLFOX, which would allow us to choose the most appropriate therapy for each patient. In order to address this need, the role of SPRTN in colorectal cancer chemotherapy is investigated for the first time in this thesis.</p> <p>SPRTN was recently identified as a metalloprotease involved in the repair of DPCs. To address SPRTN potential role in the repair of DPCs induced by irinotecan and oxaliplatin, two main approaches have been attempted in this thesis. First, a preclinical study with three different colorectal cancer cell lines was performed to address if SPRTN depletion could make cells more sensitive to the aforementioned drugs. However, despite presenting an increased amount of DNA damage, CRC cells appeared to survive the deleterious effects of SPRTN depletion, thanks to the expression of alternative DPC proteases and the upregulation of anti-apoptotic genes. Secondly, clinical mCRC samples obtained from the MRC FOCUS trial were analyzed to determine if SPRTN overexpression measured by immunohistochemistry could represent a useful predictive biomarker to determine the efficacy of FOLFIRI vs FOLFOX chemotherapy. In line with the preclinical data, however, SPRTN was not confirmed to represent a valuable biomarker in CRC chemotherapy.</p> |
| spellingShingle | Cancer Oncology Peron, C The role of SPRTN protease in colorectal cancer chemotherapy |
| title | The role of SPRTN protease in colorectal cancer chemotherapy |
| title_full | The role of SPRTN protease in colorectal cancer chemotherapy |
| title_fullStr | The role of SPRTN protease in colorectal cancer chemotherapy |
| title_full_unstemmed | The role of SPRTN protease in colorectal cancer chemotherapy |
| title_short | The role of SPRTN protease in colorectal cancer chemotherapy |
| title_sort | role of sprtn protease in colorectal cancer chemotherapy |
| topic | Cancer Oncology |
| work_keys_str_mv | AT peronc theroleofsprtnproteaseincolorectalcancerchemotherapy AT peronc roleofsprtnproteaseincolorectalcancerchemotherapy |