Jolijn W Groeneweg1, Tracilyn R Hall2, Ling Zhang3, Minji Kim3, Virginia F Byron3, Rosemary Tambouret4, Sriram Sathayanrayanan5, Rosemary Foster2, Bo R Rueda2, Whitfield B Growdon6. 1. Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. 2. Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. 3. Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. 4. Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. 5. Merck Oncology, Boston, MA, USA. 6. Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: wgrowdon@partners.org.
Abstract
OBJECTIVE: Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity. METHODS: Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan-Meier methods. RESULTS: High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts. CONCLUSIONS: Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.
OBJECTIVE: Uterine serous carcinoma (USC) represents an aggressive subtype of endometrial cancer. We sought to understand Notch pathway activity in USC and determine if pathway inhibition has anti-tumor activity. METHODS:Patient USC tissue blocks were obtained and used to correlate clinical outcomes with Notch1 expression. Three established USC cell lines were treated with gamma-secretase inhibitor (GSI) in vitro. Mice harboring cell line derived or patient derived USC xenografts (PDXs) were treated with vehicle, GSI, paclitaxel and carboplatin (P/C), or combination GSI and P/C. Levels of cleaved Notch1 protein and Hes1 mRNA were determined in GSI treated samples. Statistical analysis was performed using the Wilcoxon rank sum and Kaplan-Meier methods. RESULTS: High nuclear Notch1 protein expression was observed in 58% of USC samples with no correlation with overall survival. GSI induced dose-dependent reductions in cell number and decreased levels of cleaved Notch1 protein and Hes1 mRNA in vitro. Treatment of mice with GSI led to decreased Hes1 mRNA expression in USC xenografts. In addition, GSI impeded tumor growth of cell line xenografts as well as UT1 USC PDXs. When GSI and P/C were combined, synergistic anti-tumor activity was observed in UT1 xenografts. CONCLUSIONS:Notch1 is expressed in a large subset of USC. GSI-mediated Notch pathway inhibition led to both reduced cell numbers in vitro and decreased tumor growth of USC some xenograft models. When combined with conventional chemotherapy, GSI augmented anti-tumor activity in one USC PDX line suggesting that targeting of the Notch signaling pathway is a potential therapeutic strategy for future investigation.
Authors: Jolijn W Groeneweg; Silvia F Hernandez; Virginia F Byron; Celeste M DiGloria; Hector Lopez; Vanessa Scialabba; Minji Kim; Ling Zhang; Darrell R Borger; Rosemary Tambouret; Rosemary Foster; Bo R Rueda; Whitfield B Growdon Journal: Clin Cancer Res Date: 2014-10-07 Impact factor: 12.531
Authors: Rosalia C M Simmen; Melissa E Heard; Angela M Simmen; Maria Theresa M Montales; Meera Marji; Samantha Scanlon; John Mark P Pabona Journal: J Mol Endocrinol Date: 2015-02-05 Impact factor: 5.098
Authors: Dustin M Brown; Hsiu-Chi Lee; Shi Liu; Charles M Quick; Lorenzo M Fernandes; Frank A Simmen; Shaw-Jenq Tsai; Rosalia C M Simmen Journal: J Endocr Soc Date: 2018-05-25
Authors: Cristian P Moiola; Carlos Lopez-Gil; Silvia Cabrera; Angel Garcia; Tom Van Nyen; Daniela Annibali; Tina Fonnes; August Vidal; Alberto Villanueva; Xavier Matias-Guiu; Camilla Krakstad; Frédéric Amant; Antonio Gil-Moreno; Eva Colas Journal: Int J Mol Sci Date: 2018-08-17 Impact factor: 5.923