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Selective Estrogen Receptor β Agonist LY500307 as a Novel Therapeutic Agent for Glioblastoma
Gangadhara R Sareddy1, Xiaonan Li1, Jinyou Liu1
1The Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio TX 78229, USA.
Abstract:
Glioblastomas (GBM), deadly brain tumors, have greater incidence in males than females. Epidemiological evidence supports a tumor suppressive role of estrogen; however, estrogen as a potential therapy for GBM is limited due to safety concerns. Since GBM express ERβ, a second receptor for estrogen, targeting ERβ with a selective agonist may be a potential novel GBM therapy. In the present study, we examined the therapeutic effect of the selective synthetic ERβ agonist LY500307 using in vitro and in vivo GBM models. Treatment with LY500307 significantly reduced the proliferation of GBM cells with no activity on normal astrocytes in vitro. ERβ agonists promoted apoptosis of GBM cells, and mechanistic studies using RNA sequencing revealed that 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. Our results demonstrate that LY500307 has potential as a therapeutic agent for GBM.
Insights
Selective estrogen receptor beta (ERβ) agonist LY500307 shows therapeutic potential for glioblastoma (GBM). This novel agent reduced GBM cell proliferation and tumor growth while enhancing chemotherapy effectiveness and improving survival in preclinical models.
Area of Science:
- Neuro-oncology
- Endocrinology
- Pharmacology
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with a higher incidence in males.
- Estrogen's tumor-suppressive role is recognized, but systemic estrogen therapy for GBM is limited by safety concerns.
- Estrogen receptor beta (ERβ), expressed in GBM, presents a potential therapeutic target.
Purpose of the Study:
- To investigate the therapeutic efficacy of LY500307, a selective ERβ agonist, in preclinical glioblastoma models.
- To evaluate the effects of LY500307 on GBM cell proliferation, apoptosis, and chemosensitization.
- To assess the in vivo anti-tumor activity and survival benefits of LY500307 in glioblastoma models.
Main Methods:
- In vitro studies using GBM cell lines and normal astrocytes.
- In vivo studies utilizing orthotopic and syngeneic glioma models in mice.
- RNA sequencing to elucidate molecular mechanisms of action.
- Assessment of cell proliferation, apoptosis, tumor growth, and overall survival.
Main Results:
- LY500307 significantly reduced GBM cell proliferation in vitro without affecting normal astrocytes.
- Treatment with LY500307 induced apoptosis in GBM cells and modulated key cellular pathways.
- LY500307 sensitized GBM cells to standard chemotherapeutic agents (cisplatin, lomustine, temozolomide).
- In vivo, LY500307 inhibited tumor growth, promoted apoptosis, and improved survival in GBM models.
Conclusions:
- Selective ERβ agonism with LY500307 demonstrates significant therapeutic potential for glioblastoma.
- LY500307 offers a targeted approach to GBM treatment, potentially overcoming limitations of systemic estrogen therapy.
- Further investigation of LY500307 as a novel GBM therapeutic agent is warranted.
