Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma
Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generat...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558620301342 |
| _version_ | 1818042306467463168 |
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| author | Christopher S. Koivisto Melodie Parrish Santosh B. Bonala Soo Ngoi Adrian Torres James Gallagher Rebekah Sanchez-Hodge Victor Zeinner Georges J. Nahhas Bei Liu David E. Cohn Floor J. Backes Paul J. Goodfellow Helen M. Chamberlin Gustavo Leone |
| author_facet | Christopher S. Koivisto Melodie Parrish Santosh B. Bonala Soo Ngoi Adrian Torres James Gallagher Rebekah Sanchez-Hodge Victor Zeinner Georges J. Nahhas Bei Liu David E. Cohn Floor J. Backes Paul J. Goodfellow Helen M. Chamberlin Gustavo Leone |
| author_sort | Christopher S. Koivisto |
| collection | DOAJ |
| description | Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response. |
| first_indexed | 2024-12-10T08:44:13Z |
| format | Article |
| id | doaj.art-912673eee79c4ad5a5854b02212df2e6 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-10T08:44:13Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-912673eee79c4ad5a5854b02212df2e62022-12-22T01:55:46ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862020-10-012210484496Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinomaChristopher S. Koivisto0Melodie Parrish1Santosh B. Bonala2Soo Ngoi3Adrian Torres4James Gallagher5Rebekah Sanchez-Hodge6Victor Zeinner7Georges J. Nahhas8Bei Liu9David E. Cohn10Floor J. Backes11Paul J. Goodfellow12Helen M. Chamberlin13Gustavo Leone14Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Molecular Genetics, The Ohio State University, Columbus, OH, USADepartment of Molecular Genetics, The Ohio State University, Columbus, OH, USADepartment of Molecular Genetics, The Ohio State University, Columbus, OH, USA; Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, OH, USADepartment of Molecular Genetics, The Ohio State University, Columbus, OH, USADepartment of Psychiatry and Behavioral Sciences, College of Medicine, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADivision of Gynecologic Oncology, College of Medicine, The Ohio State University, Columbus, OH, USADivision of Gynecologic Oncology, College of Medicine, The Ohio State University, Columbus, OH, USADepartment of Obstetrics and Gynecology, College of Medicine, The Ohio State University, Columbus, OH, USADepartment of Molecular Genetics, The Ohio State University, Columbus, OH, USADepartment of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Corresponding author at: Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.http://www.sciencedirect.com/science/article/pii/S1476558620301342PTENAndrogen receptor antagonistEnzalutamideEndometrial carcinomaPreclinical drug evaluationMouse model of endometrial cancer |
| spellingShingle | Christopher S. Koivisto Melodie Parrish Santosh B. Bonala Soo Ngoi Adrian Torres James Gallagher Rebekah Sanchez-Hodge Victor Zeinner Georges J. Nahhas Bei Liu David E. Cohn Floor J. Backes Paul J. Goodfellow Helen M. Chamberlin Gustavo Leone Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma Neoplasia: An International Journal for Oncology Research PTEN Androgen receptor antagonist Enzalutamide Endometrial carcinoma Preclinical drug evaluation Mouse model of endometrial cancer |
| title | Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma |
| title_full | Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma |
| title_fullStr | Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma |
| title_full_unstemmed | Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma |
| title_short | Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma |
| title_sort | evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type i endometrial carcinoma |
| topic | PTEN Androgen receptor antagonist Enzalutamide Endometrial carcinoma Preclinical drug evaluation Mouse model of endometrial cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558620301342 |
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