Ulla-Maija Haltia1, Noora Andersson2, Bhagwan Yadav3, Anniina Färkkilä4, Evgeny Kulesskiy3, Matti Kankainen3, Jing Tang3, Ralf Bützow5, Annika Riska6, Arto Leminen6, Markku Heikinheimo7, Olli Kallioniemi3, Leila Unkila-Kallio6, Krister Wennerberg3, Tero Aittokallio8, Mikko Anttonen9. 1. Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland. 2. Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland. 3. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland. 4. Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland. Electronic address: anniina.farkkila@helsinki.fi. 5. Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290 Helsinki, Finland. 6. Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, PO Box 140, 00290 Helsinki, Finland. 7. Children's Hospital, University of Helsinki and Helsinki University Hospital, PO Box 20, 00014 University of Helsinki, Finland; Department of Pediatrics, Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO 63110, USA. 8. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO Box 20, 00014 Helsinki, Finland; Department of Mathematics and Statistics, University of Turku, 20014 Turku, Finland. 9. Clinical Chemistry and Hematology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290 Helsinki, Finland.
Abstract
OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells. RESULTS: Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression. CONCLUSIONS: We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options. Copyright Â
OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancerpatients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells. RESULTS:Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression. CONCLUSIONS: We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options. Copyright Â
Authors: Powel Crosley; Anniina Farkkila; Adrianne L Jenner; Chloé Burlot; Olivia Cardinal; Kyle G Potts; Kate Agopsowicz; Marjut Pihlajoki; Markku Heikinheimo; Morgan Craig; Yangxin Fu; Mary M Hitt Journal: Int J Mol Sci Date: 2021-04-29 Impact factor: 5.923
Authors: Ulla-Maija Haltia; Marjut Pihlajoki; Noora Andersson; Lotta Mäkinen; Johanna Tapper; Alejandra Cervera; Hugo M Horlings; Ursula Turpeinen; Mikko Anttonen; Ralf Bützow; Leila Unkila-Kallio; Olli Carpén; David B Wilson; Markku Heikinheimo; Anniina Färkkilä Journal: J Endocr Soc Date: 2020-03-16
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