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Updated: May 7, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival
Andressa Ardiani1, Benedetto Farsaci, Connie J Rogers
1Authors' Affiliations: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; Medivation Inc., San Francisco, California; and GlobeImmune Inc., Louisville, Colorado.
Purpose:
Enzalutamide, a second-generation androgen antagonist, was approved by the U.S. Food and Drug Administration (FDA) for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study was performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment.
Experimental Design:
Male C57BL/6 or TRAMP (transgenic adenocarcinoma of the mouse prostate) prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiologic and immunologic effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was assessed. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated.
Results:
Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4(+) T-cell proliferation and regulatory T cell (Treg) functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the ability of Twist-vaccine to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP mice by immunohistochemistry. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared with other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors.
Conclusions:
These data support the combination of enzalutamide and immunotherapy as a promising treatment strategy for CRPC. Clin Cancer Res; 19(22); 6205-18. ©2013 AACR.
Insights
Combining enzalutamide and immunotherapy significantly improves survival in castration-resistant prostate cancer (CRPC) models. This combination therapy shows promise, especially in advanced stages of prostate cancer.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Enzalutamide is FDA-approved for castration-resistant prostate cancer (CRPC).
- Immunotherapy presents a promising strategy for prostate cancer treatment.
- Investigating combination therapies is crucial for advancing CRPC treatment options.
Purpose of the Study:
- To evaluate the potential of combining enzalutamide with immunotherapy for CRPC.
- To assess the immunologic effects of enzalutamide in prostate cancer models.
- To determine if combination therapy enhances survival in prostate cancer.
Main Methods:
- Utilized male C57BL/6 and TRAMP mice models for prostate cancer.
- Administered enzalutamide and a therapeutic vaccine targeting the Twist antigen.
- Characterized enzalutamide's physiologic and immunologic effects.
- Assessed Twist-specific immunity and evaluated combination therapy's impact on survival.
Main Results:
- Enzalutamide demonstrated immunogenic modulation and altered immune parameters but was deemed immune inert.
- The Twist vaccine effectively generated Twist-specific immunity.
- Combination therapy significantly increased overall survival in TRAMP mice (27.5 vs. 10.3 weeks).
- Therapeutic benefit was more pronounced in advanced-stage prostate tumors.
Conclusions:
- Data support enzalutamide and immunotherapy combination as a promising strategy for CRPC.
- The combination therapy's efficacy increases with disease stage.
- Further clinical investigation is warranted for CRPC treatment.
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