TY - JOUR
T1 - In vitro systematic drug testing reveals carboplatin, paclitaxel, and alpelisib as a potential novel combination treatment for adult granulosa cell tumors
AU - Roze, Joline
AU - Garví, Elena Sendino
AU - Stelloo, Ellen
AU - Stangl, Christina
AU - Sereno, Ferdinando
AU - Duran, Karen
AU - Groeneweg, Jolijn
AU - Paijens, Sterre
AU - Nijman, Hans
AU - van Meurs, Hannah
AU - van Lonkhuijzen, Luc
AU - Piek, Jurgen
AU - Lok, Christianne
AU - Jonges, Geertruida
AU - Witteveen, Petronella
AU - Verheijen, René
AU - van Haaften, Gijs
AU - Zweemer, Ronald
AU - Monroe, Glen
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - Alpelisib
KW - Drug screens
KW - Granulosa cell tumors
KW - Ovarian cancer
KW - Targeted treatment
UR - http://www.scopus.com/inward/record.url?scp=85099700262&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers13030368
DO - https://doi.org/10.3390/cancers13030368
M3 - Article
C2 - 33498451
SN - 2072-6694
VL - 13
SP - 1
EP - 18
JO - Cancers
JF - Cancers
IS - 3
M1 - 368
ER -