In vitro systematic drug testing reveals carboplatin, paclitaxel, and alpelisib as a potential novel combination treatment for adult granulosa cell tumors

Joline Roze, Elena Sendino Garví, Ellen Stelloo, Christina Stangl, Ferdinando Sereno, Karen Duran, Jolijn Groeneweg, Sterre Paijens, Hans Nijman, Hannah van Meurs, Luc van Lonkhuijzen, Jurgen Piek, Christianne Lok, Geertruida Jonges, Petronella Witteveen, René Verheijen, Gijs van Haaften, Ronald Zweemer, Glen Monroe

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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.

Original languageEnglish
Article number368
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume13
Issue number3
DOIs
Publication statusPublished - 1 Feb 2021

Keywords

  • Alpelisib
  • Drug screens
  • Granulosa cell tumors
  • Ovarian cancer
  • Targeted treatment

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