Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma
Abstract Background Serous endometrial cancer (SEC) is a genomically and morphologically distinct endometrial cancer (EC) subtype with a poor progression-free and overall survival. The development of novel therapies is needed to improve outcomes. Methods We used serous and serous-like EC patient-der...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-05-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-025-03406-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850269089955577856 |
|---|---|
| author | Xiaonan Hou Valentina Zanfagnin Conway Xu Erik Jessen Yuanhang Liu Chen Wang Yajue Huang Shaun D. Fontaine Daniel V. Santi Gerardo Colon-Otero Sarah E. Gill Gretchen E. Glaser Kristina A. Butler Jamie N. Bakkum-Gamez Sean C. Dowdy Ann L. Oberg Melissa C. Larson Hunter J. Atkinson Laura N. Duffield Kevin L. Peterson Scott H. Kaufmann S. John Weroha |
| author_facet | Xiaonan Hou Valentina Zanfagnin Conway Xu Erik Jessen Yuanhang Liu Chen Wang Yajue Huang Shaun D. Fontaine Daniel V. Santi Gerardo Colon-Otero Sarah E. Gill Gretchen E. Glaser Kristina A. Butler Jamie N. Bakkum-Gamez Sean C. Dowdy Ann L. Oberg Melissa C. Larson Hunter J. Atkinson Laura N. Duffield Kevin L. Peterson Scott H. Kaufmann S. John Weroha |
| author_sort | Xiaonan Hou |
| collection | DOAJ |
| description | Abstract Background Serous endometrial cancer (SEC) is a genomically and morphologically distinct endometrial cancer (EC) subtype with a poor progression-free and overall survival. The development of novel therapies is needed to improve outcomes. Methods We used serous and serous-like EC patient-derived xenografts (PDXs) to test a novel drug combination in vitro and in vivo: rucaparib and pegylated SN-38 (PLX038A). Sensitivity to treatment was correlated with indicators of homologous recombination (HR) deficiency. Efficacy in fresh primary patient tumors was also tested ex vivo. Results Five of eight PDXs had genomic instability scores ≥ 42, but only one of these five had evidence of HR deficiency in assays of irradiation-induced RAD51 foci formation. Moreover, PARP inhibitor (PARPi) monotherapy failed to induce regressions in any of the five SEC models treated with rucaparib in vivo, suggesting limited clinical activity of PARPi in SEC. In further studies, we assessed the response of these models to the sustained release topoisomerase 1 inhibitor, PLX038A, as monotherapy and in combination with rucaparib ex vivo and in vivo. Results of these studies showed that PLX038A had limited monotherapy activity, but combination therapy induced significant regressions in two of five SEC PDXs and markedly slowed tumor growth in the other three regardless of underlying homologous recombination repair deficiency. In addition, 11 of 20 (55%) primary tumors showed synergy with rucaparib + SN-38. Conclusions Collectively, these studies identify a set of genomically characterized PDX models for preclinical testing of potential SEC therapies and a therapeutic combination that warrants further preclinical investigation. |
| format | Article |
| id | doaj-art-75c2bc90f8a74285aca0fad21b6005ac |
| institution | OA Journals |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-75c2bc90f8a74285aca0fad21b6005ac2025-08-20T01:53:15ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-05-0144111510.1186/s13046-025-03406-7Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinomaXiaonan Hou0Valentina Zanfagnin1Conway Xu2Erik Jessen3Yuanhang Liu4Chen Wang5Yajue Huang6Shaun D. Fontaine7Daniel V. Santi8Gerardo Colon-Otero9Sarah E. Gill10Gretchen E. Glaser11Kristina A. Butler12Jamie N. Bakkum-Gamez13Sean C. Dowdy14Ann L. Oberg15Melissa C. Larson16Hunter J. Atkinson17Laura N. Duffield18Kevin L. Peterson19Scott H. Kaufmann20S. John Weroha21Division of Medical Oncology, Mayo ClinicDivision of Medical Oncology, Mayo ClinicDivision of Medical Oncology, Mayo ClinicDepartment of Health Sciences Research, Mayo ClinicDepartment of Health Sciences Research, Mayo ClinicDepartment of Health Sciences Research, Mayo ClinicDivision of Anatomic Pathology, Mayo ClinicProLynx LLCProLynx LLCHematology/Oncology, Mayo Clinic FloridaDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mayo ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mayo ClinicMedical & Surgical Gynecology Department, Mayo ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mayo ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Mayo ClinicDepartment of Quantitative Health Sciences, Division of Computational Biology, Mayo ClinicDepartment of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo ClinicDepartment of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo ClinicDivision of Oncology Research, Mayo ClinicDivision of Oncology Research, Mayo ClinicDivision of Oncology Research, Mayo ClinicDivision of Medical Oncology, Mayo ClinicAbstract Background Serous endometrial cancer (SEC) is a genomically and morphologically distinct endometrial cancer (EC) subtype with a poor progression-free and overall survival. The development of novel therapies is needed to improve outcomes. Methods We used serous and serous-like EC patient-derived xenografts (PDXs) to test a novel drug combination in vitro and in vivo: rucaparib and pegylated SN-38 (PLX038A). Sensitivity to treatment was correlated with indicators of homologous recombination (HR) deficiency. Efficacy in fresh primary patient tumors was also tested ex vivo. Results Five of eight PDXs had genomic instability scores ≥ 42, but only one of these five had evidence of HR deficiency in assays of irradiation-induced RAD51 foci formation. Moreover, PARP inhibitor (PARPi) monotherapy failed to induce regressions in any of the five SEC models treated with rucaparib in vivo, suggesting limited clinical activity of PARPi in SEC. In further studies, we assessed the response of these models to the sustained release topoisomerase 1 inhibitor, PLX038A, as monotherapy and in combination with rucaparib ex vivo and in vivo. Results of these studies showed that PLX038A had limited monotherapy activity, but combination therapy induced significant regressions in two of five SEC PDXs and markedly slowed tumor growth in the other three regardless of underlying homologous recombination repair deficiency. In addition, 11 of 20 (55%) primary tumors showed synergy with rucaparib + SN-38. Conclusions Collectively, these studies identify a set of genomically characterized PDX models for preclinical testing of potential SEC therapies and a therapeutic combination that warrants further preclinical investigation.https://doi.org/10.1186/s13046-025-03406-7Endometrial cancerXenograftsPARP inhibitorRucaparibHomologous recombinationDNA repair |
| spellingShingle | Xiaonan Hou Valentina Zanfagnin Conway Xu Erik Jessen Yuanhang Liu Chen Wang Yajue Huang Shaun D. Fontaine Daniel V. Santi Gerardo Colon-Otero Sarah E. Gill Gretchen E. Glaser Kristina A. Butler Jamie N. Bakkum-Gamez Sean C. Dowdy Ann L. Oberg Melissa C. Larson Hunter J. Atkinson Laura N. Duffield Kevin L. Peterson Scott H. Kaufmann S. John Weroha Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma Journal of Experimental & Clinical Cancer Research Endometrial cancer Xenografts PARP inhibitor Rucaparib Homologous recombination DNA repair |
| title | Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma |
| title_full | Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma |
| title_fullStr | Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma |
| title_full_unstemmed | Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma |
| title_short | Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma |
| title_sort | antitumor activity of rucaparib plus plx038a in serous endometrial carcinoma |
| topic | Endometrial cancer Xenografts PARP inhibitor Rucaparib Homologous recombination DNA repair |
| url | https://doi.org/10.1186/s13046-025-03406-7 |
| work_keys_str_mv | AT xiaonanhou antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT valentinazanfagnin antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT conwayxu antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT erikjessen antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT yuanhangliu antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT chenwang antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT yajuehuang antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT shaundfontaine antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT danielvsanti antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT gerardocolonotero antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT sarahegill antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT gretcheneglaser antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT kristinaabutler antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT jamienbakkumgamez antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT seancdowdy antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT annloberg antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT melissaclarson antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT hunterjatkinson antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT lauranduffield antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT kevinlpeterson antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT scotthkaufmann antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma AT sjohnweroha antitumoractivityofrucaparibplusplx038ainserousendometrialcarcinoma |