Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context
Summary: Background: Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence. Methods: In a circadian sub-s...
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Elsevier
2025-07-01
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| author | Deeksha Malhan Janina Hesse Nina Nelson Kay Stankov Jessica Nguyen Ouda Aboumanify Josefin Garmshausen Gunther Rogmans Bastian Czogalla Jens Gerber Martin Koch Tomáš Kupec Oliver Tomé Ralf Witteler Mustafa Deryal Michael Eichbaum Jalid Sehouli Elena Ioana Braicu Angela Relógio |
| author_facet | Deeksha Malhan Janina Hesse Nina Nelson Kay Stankov Jessica Nguyen Ouda Aboumanify Josefin Garmshausen Gunther Rogmans Bastian Czogalla Jens Gerber Martin Koch Tomáš Kupec Oliver Tomé Ralf Witteler Mustafa Deryal Michael Eichbaum Jalid Sehouli Elena Ioana Braicu Angela Relógio |
| author_sort | Deeksha Malhan |
| collection | DOAJ |
| description | Summary: Background: Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence. Methods: In a circadian sub-study of the MAMOC trial—a double-blind, phase III study—42 patients (FIGO stage IIIA-IV) were randomised in a 2:1 ratio to receive rucaparib or placebo. In a subset of these patients, we performed differential gene expression and rhythmicity analysis on up to 800 genes, including clock and clock-controlled genes. Machine learning algorithms and mathematical modelling were employed to simulate patient-specific toxicity profiles and to explore correlations between gene expression patterns and treatment-related side effects. Findings: Our analysis revealed significant disruptions in circadian rhythms, specifically in the expression of the core clock genes BMAL1 and PER2, following treatment. These disruptions strongly correlated with the severity and frequency of side effects, including nausea and fatigue, displaying opposite trends between the placebo and rucaparib-treated groups. K-means clustering successfully distinguished rucaparib-treated patients from those receiving placebo based on BMAL1 phase and gene expression profiles. In addition, rucaparib therapy also altered the expression of several clock-controlled genes, including SIRT1, BRCA1, BRCA2, and TP53. Notably, our data suggest that individual differences in circadian rhythms may lead to distinct 24-h toxicity profiles among patients. Interpretation: These findings suggest that circadian rhythm dysregulation may contribute to the toxicity of PARPi therapy. Aligning treatment timing with circadian rhythms could mitigate these adverse effects, and improve patient outcomes. Funding: This study was funded by the Dr. Rolf Schwiete Stiftung and the MSH Medical School Hamburg, Germany. The MAMOC trial (ClinicalTrials.gov: NCT04227522) was funded by Clovis Oncology, United States. |
| format | Article |
| id | doaj-art-345afcaef83545eaad2150ca7e62730e |
| institution | DOAJ |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj-art-345afcaef83545eaad2150ca7e62730e2025-08-20T03:10:24ZengElsevierEBioMedicine2352-39642025-07-0111710576410.1016/j.ebiom.2025.105764Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in contextDeeksha Malhan0Janina Hesse1Nina Nelson2Kay Stankov3Jessica Nguyen4Ouda Aboumanify5Josefin Garmshausen6Gunther Rogmans7Bastian Czogalla8Jens Gerber9Martin Koch10Tomáš Kupec11Oliver Tomé12Ralf Witteler13Mustafa Deryal14Michael Eichbaum15Jalid Sehouli16Elena Ioana Braicu17Angela Relógio18Institute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, GermanyInstitute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany; Leibniz-Institute for Resilience Research (LIR), Mainz, Germany; Johannes Gutenberg University Medical Center Mainz, Mainz, Germany; Institute for Quantitative and Computational Biosciences (IQCB), Johannes-Gutenberg University, Mainz, GermanyInstitute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, GermanyStat4med (Ainovate GmbH), Frankfurt, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, GermanyInstitute for Theoretical Biology (ITB), Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyInstitute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany; Institute for Theoretical Biology (ITB), Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; ZAGO- Zentrum für ambulante gynäkologische Onkologie, Krefeld, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Department of Obstetrics and Gynecology, LMU University Hospital, LMU Munich, Munich, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Städtisches Klinikum Dessau, Frauenheilkunde und Geburtshilfe, Dessau, GermanyDepartment of Gynecology and Obstetrics, Hospital Anregiomed Ansbach, Ansbach, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Department of Obstetrics and Gynecology, University Hospital Aachen, Aachen, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; ViDia Christliche Kliniken Karlsruhe, Department of Gynecology and Obstetrics, Karlsruhe, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Universitätsklinikum Münster, Klinik für Frauenheilkunde und Geburtshilfe, Münster, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Center for Gynecology, Caritas Klinikum St. Theresia-Saarbruecken, Saarbruecken, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Helios Dr. Horst Schmidt Kliniken Wiesbaden, Department of Gynecology and Obstetrics, Wiesbaden, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Department of Gynecology with Center for Oncological Surgery, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, GermanyNorth-Eastern German Society of Gynecological Oncology (NOGGO e.V.), Berlin, Germany; Department of Gynecology with Center for Oncological Surgery, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany; Tumorbank Ovarian Cancer Network, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Corresponding author. Tumorbank Ovarian Cancer Network, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.Institute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany; Institute for Theoretical Biology (ITB), Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; TimeTeller GmbH, Hamburg, Germany; Corresponding author. Institute for Systems Medicine and Faculty of Human Medicine, MSH Medical School Hamburg, Hamburg, Germany.Summary: Background: Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence. Methods: In a circadian sub-study of the MAMOC trial—a double-blind, phase III study—42 patients (FIGO stage IIIA-IV) were randomised in a 2:1 ratio to receive rucaparib or placebo. In a subset of these patients, we performed differential gene expression and rhythmicity analysis on up to 800 genes, including clock and clock-controlled genes. Machine learning algorithms and mathematical modelling were employed to simulate patient-specific toxicity profiles and to explore correlations between gene expression patterns and treatment-related side effects. Findings: Our analysis revealed significant disruptions in circadian rhythms, specifically in the expression of the core clock genes BMAL1 and PER2, following treatment. These disruptions strongly correlated with the severity and frequency of side effects, including nausea and fatigue, displaying opposite trends between the placebo and rucaparib-treated groups. K-means clustering successfully distinguished rucaparib-treated patients from those receiving placebo based on BMAL1 phase and gene expression profiles. In addition, rucaparib therapy also altered the expression of several clock-controlled genes, including SIRT1, BRCA1, BRCA2, and TP53. Notably, our data suggest that individual differences in circadian rhythms may lead to distinct 24-h toxicity profiles among patients. Interpretation: These findings suggest that circadian rhythm dysregulation may contribute to the toxicity of PARPi therapy. Aligning treatment timing with circadian rhythms could mitigate these adverse effects, and improve patient outcomes. Funding: This study was funded by the Dr. Rolf Schwiete Stiftung and the MSH Medical School Hamburg, Germany. The MAMOC trial (ClinicalTrials.gov: NCT04227522) was funded by Clovis Oncology, United States.http://www.sciencedirect.com/science/article/pii/S2352396425002087Circadian rhythmsOvarian cancerCircadian profilesChronotherapyAdverse eventsMathematical modelling |
| spellingShingle | Deeksha Malhan Janina Hesse Nina Nelson Kay Stankov Jessica Nguyen Ouda Aboumanify Josefin Garmshausen Gunther Rogmans Bastian Czogalla Jens Gerber Martin Koch Tomáš Kupec Oliver Tomé Ralf Witteler Mustafa Deryal Michael Eichbaum Jalid Sehouli Elena Ioana Braicu Angela Relógio Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context EBioMedicine Circadian rhythms Ovarian cancer Circadian profiles Chronotherapy Adverse events Mathematical modelling |
| title | Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context |
| title_full | Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context |
| title_fullStr | Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context |
| title_full_unstemmed | Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context |
| title_short | Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsResearch in context |
| title_sort | circadian rhythm disruption by parp inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effectsresearch in context |
| topic | Circadian rhythms Ovarian cancer Circadian profiles Chronotherapy Adverse events Mathematical modelling |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425002087 |
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