Cancer metastases have caused the major mortality rate for cancer patients, with limited options of treatment and unsatisfactory therapeutic efficacy. Estrogen and the estrogen receptors (ERs) are closely related to breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Unlike the tumor-promoting role of estrogen receptor ERα, ERβ has shown potent antitumor effects in many cancers. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.

Erteberel (LY500307) is a synthetic, nonsteroidal estrogen which acts as a selective ERβ agonist and is under development by Eli Lilly for the treatment of schizophrenia. Zhao L, et al, examined whether Erteberel could suppress lung metastasis of triple-negative breast cancer and melanoma. LY500307 potently induced cell death of cancer cells metastasized to lung in vivo. However, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. LY500307 generated a potent neutrophil-mediated antitumor innate immune response in the metastatic niche. This lead to metastasis suppression in both the 4T1 and B16 murine models.

In another study, treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes. LY500307 modulated several pathways related to apoptosis, cell cycle, and DNA damage response. Further, LY500307 sensitized GBM cells to several FDA-approved chemotherapeutic drugs including cisplatin, lomustine and temozolomide. LY500307 treatment significantly reduced the in vivo tumor growth and promoted apoptosis of GBM tumors in an orthotopic model and improved the overall survival of tumor-bearing mice in the GL26 syngeneic glioma model. Results demonstrate that LY500307 has potential as a therapeutic agent for GBM.