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: ERa that functions as a tumor promoter and ERß that functions as a tumor suppressor. Recent studies
using CRISPR KO in human GBM models have confirmed that ERß functions as a tumor suppressor in GBM.
Nonetheless, the therapeutic potential of ERß have not been extensively exploited. Currently available
synthetic ERß 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 ERß agonists is ascribed in part to requiring high concentrations (10-100 µM) resulting in
their cross reactivity with ERa. Therefore, the development of novel selective ERß 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 ERß agonists that deliver higher potency and specificity
to ERß, which we have branded as CIDD-ERß agonists. The objective of this proposal to translate the
functional role of ERß as a tumor suppressor into a clinical strategy utilizing novel CIDD-ERß agonists as a new
therapeutic agent. The hypothesis is that potent ERß 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-ERß agonist leads by using its structure-
based design, medicinal chemistry approaches and develop CIDD-ERß 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-ERß agonists
with ERß using biophysical methods and confirm the effect of CIDD-ERß agonists on ERß genomic, non-genomic
and DNA damage response functions. In Aim3, we will test the efficacy of optimized CIDD-ERß 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 ERß 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.