Development of Potent Estrogen Receptor Beta Agonists for Treating Glioblastoma
NIH
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Glioblastoma (GBM) is the most common primary malignant brain tumor with a survival time of approximately 19 months and the 5-year survival rate is ~10%. Standard treatment for GBM consists of surgical resection, external beam radiation therapy (XRT), and adjuvant chemotherapy with temozolomide; however, resistance to XRT and chemotherapy is a major clinical problem. Recent studies suggest female sex hormones play a protective role in GBM progression. However, the utility of using estrogen as a treatment for GBM is limited due to its associated toxicity and risks of developing new cancers. Estrogen functions are mediated by two estrogen receptor (ER)- subtypes: ERα that functions as a tumor promoter and ERβ that functions as a tumor suppressor. Recent studies using CRISPR KO in human GBM models have confirmed that ERβ functions as a tumor suppressor in GBM. Nonetheless, the therapeutic potential of ERβ have not been extensively exploited. Currently available synthetic ERβ agonists (LY and ERB041) are proven to be safe for human use; however, these are no longer in clinical development by industry due to failure to meet clinical endpoints in non-oncological clinical studies. Low efficacy of synthetic ERβ agonists is ascribed in part to requiring high concentrations (10-100 µM) resulting in their cross reactivity with ERα. Therefore, the development of novel selective ERβ agonists, with higher selectivity and high potency is needed for clinical translation. In collaboration with the Center for Innovative Drug Discovery (CIDD) at UTSA, we have developed lead ERβ agonists that deliver higher potency and specificity to ERβ, which we have branded as CIDD-ERβ agonists. The objective of this proposal to translate the functional role of ERβ as a tumor suppressor into a clinical strategy utilizing novel CIDD-ERβ agonists as a new therapeutic agent. The hypothesis is that potent ERβ specific agonists block GBM progression by promoting growth inhibitory pathways and sensitizes them to radiation and chemotherapy. We will test this hypothesis using three aims. In Aim 1, we will further optimize the translatability of CIDD-ERβ agonist leads by using its structure- based design, medicinal chemistry approaches and develop CIDD-ERβ agonists with higher specificity, potency and central nervous system (CNS) ADME properties. Further, we will determine maximum tolerated dose, toxicology and establish PK, PD. In Aim2, we will confirm the specificity of interaction of CIDD-ERβ agonists with ERβ using biophysical methods and confirm the effect of CIDD-ERβ agonists on ERβ genomic, non-genomic and DNA damage response functions. In Aim3, we will test the efficacy of optimized CIDD-ERβ agonists on glioma stem cells (GSCs), test their efficacy on tumor progression and survival using patient xenograft GBM models and also test the efficacy in conjunction with radiation and chemotherapies. This proposal is clinically significant as successful testing of these hypotheses will result in the development of novel ERβ agonists that promote tumor suppression, which can be readily translated into clinical use simultaneously with current chemo and radiation therapies, providing an additional tool for enhancing survival in GBM patients. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with poor survival. This research proposal is based on strong preliminary data showing that Estrogen Receptor beta (ERβ) exerts tumor suppressive functions in GBM. This proposal is will develop novel ERβ agonists that promote tumor suppression leading to a new therapeutic modality to treat GBM. Identification of CIDD-ERβ agonists as a therapeutic agent can be readily translated into clinical use with current chemo and radiation therapies, providing an additional tool for enhancing survival in GBM patients.
Non-SBIR/STTR