In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors
by
, , , , ,
Joline Roze
1,†
,
Elena Sendino Garví
2,†,
Ellen Stelloo
2,
Christina Stangl
2,
Ferdinando Sereno
2,
Karen Duran
2,
Jolijn Groeneweg
1,
Sterre Paijens
3,
Hans Nijman
3,
Hannah van Meurs
4,
Luc van Lonkhuijzen
4,
Jurgen Piek
5
,
Christianne Lok
6,
Geertruida Jonges
7,
Petronella Witteveen
8,
René Verheijen
1,
Gijs van Haaften
2,
Ronald Zweemer
1,* and
Glen Monroe
1 1
Department of Gynaecological Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
2
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Oncode Institute, Utrecht University, 3584 CX Utrecht, The Netherlands
3
Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
4
Department of Gynecological Oncology, Centre for Gynaecological Oncology Amsterdam, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
5
Department of Obstetrics and Gynaecology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
6
Department of Gynaecological Oncology, Centre for Gynaecological Oncology Amsterdam, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands
7
Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
8
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
†
These authors contributed equally.
Cancers 2021, 13(3), 368; https://doi.org/10.3390/cancers13030368
Submission received: 20 November 2020
/
Revised: 15 January 2021
/
Accepted: 18 January 2021
/
Published: 20 January 2021
Simple Summary
Granulosa cell tumor treatment is challenging as there are few effective options besides surgery. In this study, we obtained tumor tissue from patients at surgery and cultured tumor cells in the laboratory. After sufficient expansion, we tested the effects of current treatments, such as chemotherapy and anti-hormonal treatment, and novel anti-cancer treatment options on cell survival. Results were generated within three weeks after tissue collection. We found that all drugs were ineffective when used as single treatments; however, some combinations were very effective. The PI3K protein inhibitor alpelisib was effective in combination with chemotherapy and achieved 50% cell death at assumed tolerable patient plasma concentrations. In conclusion, this study shows an approach to rapidly establish patient-derived cell lines for drug screens. The effectiveness of combined treatment with alpelisib and chemotherapy in granulosa cell tumors should be further investigated and may be a promising novel treatment option in patients with a granulosa cell tumor.
Abstract
Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.
