Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma

Abstract

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;Pten fl/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.

Myeloid-Derived Suppressor Cells as Key Players and Promising Therapy Targets in Prostate Cancer

“…As mentioned, chemokines and their receptors are pivotal for the recruitment of MDSCs and the rapid progression of PC ( 36 , 37 ); therefore, targeting the chemokine receptors or the use of chemokine inhibitors seems to be a promising form of immunotherapy in PC ( 74 ). One of the ongoing clinical trials (NCT03177187) seems to verify this hypothesis by using the CXCR2 antagonist AZD5069 in combination with enzalutamide—the androgen receptor’s antagonist in patients with mCRPC ( 75 ). An important additional factor associated with MDSCs expansion is VEGF ( 26 ); thus, administration of cabozantinib (a small-molecule inhibitor of tyrosine kinase receptor, including the VEFG pathway) followed by radical prostatectomy vs. prostatectomy alone (NCT03964337) is being tested in men with high-risk PC.…”