ENHANCEMENT OF BBB CROSSING OF AR DEGRADERS IN GBM

Cleveland State University, Cleveland OH

Investigators

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Abstract

Abstract Glioblastoma (GBM) is the most malignant brain tumor with poor prognosis. Very few patients could survive more than a year after the diagnosis even with the development of new surgical techniques, which is primarily due to the highly infiltrative/invasive behavior of these tumors. GBM commonly has de novo or acquired resistance to Temozolomide (TMZ), a DNA-alkylating reagent that is the only chemotherapy for GBM due to the excellent blood-brain barrier (BBB) penetration efficiency of 20%. GBM has a higher rate in men than women. Androgen Receptor (AR) overexpressing contributes to this sex difference of GBM. AR is a client protein of the 27 kDa Heat Shock Protein (HSP27) that plays a key role of AR stability and translocation into cell nucleus. We hypothesize that AR-HSP27 axis is a critical driving force to tumor growth in GBM, particularly for the male GBM patients. The proposed studies arise from our efforts to develop small molecule AR degraders in GBM, which is a new approach for the treatment of GBM. We have identified a small molecule AR degrader with an excellent BBB penetration efficiency of 30% that is better than TMZ. It also selectively inhibited AR overexpressed GBM cell growth. We propose to systematically investigate the in vivo activity of the drug candidate and its combination with TMZ in GBM models including cells from patients, and further structurally optimize the lead compound. Aim 1: Structurally optimize AR degrader and evaluate the in vitro biological activity with GBM cells. We will: a) Synthesize new analogs; evaluate the compounds for the growth inhibition to AR overexpressed GBM cells; b) Determine the activity of top derivatives on cellular AR protein degradation through western blotting assays; examine the HSP27 targeting effects using the HSP27 chaperone and surface plasmon resonance (SPR) assays. c) Measure the Log P value of the new analogs to identify candidates with better BBB penetration. Aim 2: Determine the pharmacokinetic (PK) profile, examine the in vivo activity of the drug candidates with mice GBM models. We will: a) Determine the PK profiles of the new lead compound and TMZ for their co-administration to mice. Examine the in vivo anti-tumor activity of the combination with patient derived xenograft (PDX) GBM models including subcutaneous and intracranial tumor. b) Determine the PK profile and in vivo activity of the new candidates identified in Aim1 and their combination with TMZ.