Combined therapy targeting AR and EZH2 curbs castration-resistant prostate cancer enhancing anti-tumor T-cell response.
Epigenomics
; 2024 Mar 26.
Article
em En
| MEDLINE
| ID: mdl-38530086
ABSTRACT
Aim:
Castration-resistant prostate cancer (CRPC) eventually becomes resistant to androgen receptor pathway inhibitors like enzalutamide. Immunotherapy also fails in CRPC. We propose a new approach to simultaneously revert enzalutamide resistance and rewire anti-tumor immunity.Methods:
We investigated in vitro and in subcutaneous and spontaneous mouse models the effects of combining enzalutamide and GSK-126, a drug inhibiting the epigenetic modulator EZH2.Results:
Enzalutamide and GSK-126 synergized to reduce CRPC growth, also restraining tumor neuroendocrine differentiation. The anti-tumor activity was lost in immunodeficient mice. Indeed, the combination treatment awoke cytotoxic activity and IFN-γ production of tumor-specific CD8+ T lymphocytes.Conclusion:
These results promote the combination of enzalutamide and GSK-126 in CRPC, also offering new avenues for immunotherapy in prostate cancer.
Prostate cancer depends on hormones called androgens for its growth. Therefore, hormonal therapies are commonly used. However, the tumor often does not respond to these treatments and new therapeutic approaches are needed. Here, using cell and mouse models, we have tested a new combination between hormone therapy and a drug that restrains an enzyme regulating gene expression. Our results have shown that this combination therapy not only reduces the growth of the tumor but also stops it from becoming more aggressive. This is really important because aggressive prostate cancer is much harder to treat. We have also found that this approach helps the immune system recognizing and attacking cancer cells. More research is needed to identify the mechanism of action of this treatment. However, our findings suggest that this approach could pave the way for new therapeutic strategies, including using immunotherapy, typically unsuccessful in treating prostate cancer.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article