To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy
Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vi...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2024
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| _version_ | 1811139655256506368 |
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| author | Strobl, MAR Martin, AL West, J Gallaher, J Robertson-Tessi, M Gatenby, R Wenham, R Maini, PK Damaghi, M Anderson, ARA |
| author_facet | Strobl, MAR Martin, AL West, J Gallaher, J Robertson-Tessi, M Gatenby, R Wenham, R Maini, PK Damaghi, M Anderson, ARA |
| author_sort | Strobl, MAR |
| collection | OXFORD |
| description | Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules. Our model indicates that adjusting the dosage, rather than skipping treatments, is more effective at reducing drug use while maintaining efficacy due to a delay in cell kill and a diminishing dose-response relationship. In vivo pilot experiments confirm this conclusion. Although our focus is toxicity mitigation, reducing drug use may also delay resistance. This study enhances our understanding of PARPi treatment scheduling and illustrates the first steps in developing adaptive therapies for new treatment settings. A record of this paper's transparent peer review process is included in the supplemental information. |
| first_indexed | 2024-09-25T04:09:32Z |
| format | Journal article |
| id | oxford-uuid:d30a7924-b445-4f5b-bb31-399b797bbbce |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:09:32Z |
| publishDate | 2024 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:d30a7924-b445-4f5b-bb31-399b797bbbce2024-06-07T14:34:04ZTo modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d30a7924-b445-4f5b-bb31-399b797bbbceEnglishSymplectic ElementsCell Press2024Strobl, MARMartin, ALWest, JGallaher, JRobertson-Tessi, MGatenby, RWenham, RMaini, PKDamaghi, MAnderson, ARAToxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules. Our model indicates that adjusting the dosage, rather than skipping treatments, is more effective at reducing drug use while maintaining efficacy due to a delay in cell kill and a diminishing dose-response relationship. In vivo pilot experiments confirm this conclusion. Although our focus is toxicity mitigation, reducing drug use may also delay resistance. This study enhances our understanding of PARPi treatment scheduling and illustrates the first steps in developing adaptive therapies for new treatment settings. A record of this paper's transparent peer review process is included in the supplemental information. |
| spellingShingle | Strobl, MAR Martin, AL West, J Gallaher, J Robertson-Tessi, M Gatenby, R Wenham, R Maini, PK Damaghi, M Anderson, ARA To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
| title | To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
| title_full | To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
| title_fullStr | To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
| title_full_unstemmed | To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
| title_short | To modulate or to skip: de-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
| title_sort | to modulate or to skip de escalating parp inhibitor maintenance therapy in ovarian cancer using adaptive therapy |
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