Exploring LY500307: A Promising Therapeutic Approach for Glioblastoma Treatment

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor, typically with a grim prognosis, and it shows a gender bias with a higher incidence in males. Research has pointed to estrogen's potential as a tumor suppressor for brain tumors, but its use in therapy is limited due to safety concerns. Therefore, there is interest in agents that can mimic estrogen's effects without its risks.

A synthetic compound, LY500307, has been identified as a selective estrogen receptor β (ERβ) agonist. ERβ acts as a tissue-specific tumor suppressor, and LY500307 has shown promise in preclinical trials for other conditions and is currently in clinical trials for schizophrenia. Given that ERβ is the predominant ER subtype in GBM, the study aimed to evaluate LY500307's therapeutic impact on GBM using in vitro and orthotopic models.

The research demonstrated that LY500307 treatment significantly curtailed the proliferation of GBM cells without affecting normal astrocytes, indicating its tumor-specific action. ERβ overexpression reduced GBM cell proliferation, and LY500307's therapeutic effect was compromised with ERβ knockdown, highlighting the compound's specificity.

RNA sequencing analysis revealed that LY500307 modulates various pathways associated with apoptosis, cell cycle, stem cells, and differentiation. The compound induced apoptosis in GBM cells through both ERβ-classical and AP1-mediated non-classical pathways, as well as the p38MAPK and JNK pathways. Additionally, LY500307 was found to inhibit the proliferation and self-renewal of glioma stem cells (GSCs), contributing to the loss of stemness and promoting differentiation and apoptosis.

In vivo studies using orthotopic GBM models showed that LY500307 treatment significantly reduced tumor growth and enhanced tumor apoptosis. The compound's good blood-brain barrier permeability and low neuronal toxicity suggest that it could be integrated into clinical use alongside current radiation and chemotherapy treatments, potentially offering a new strategy to improve survival rates in GBM patients.