Targeting Androgen Receptor-HSP27 Signaling in Glioblastoma

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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. 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 is an anti- apoptotic chaperone overexpressed in GBM. HSP27 promote the biological activity of AR, which contributes to GBM progression. We hypothesize that HSP27-AR 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 HSP27 inhibitor to induce AR degradation in GBM, which is a new approach for the treatment of GBM. We have identified a small molecule HSP27 inhibitor, and it greatly induced AR degradation and selectively inhibited AR overexpressed GBM cell growth. Furthermore, we have a preliminary structure activity relationship summarized for the designing of next generation of derivatives to optimize the lead compound. We have also demonstrated that targeting HSP27-AR is selective to AR overexpressed GBM cells. We propose to systematically investigate the in vivo activity of the drug candidate and its combination with TMZ in GBM models, and further structurally optimize the lead compound. Aim 1. Lead optimization of HSP27 inhibitors as AR abolisher in GBM. We will lead optimize the structure of lead compound, by a mix of rationale design, synthesis and screening. We will then: a) Examine the growth of GBM cells in the presence of these derivatives to summarize a structure activity relationship (SAR) for growth inhibition. We will also exclude toxic compounds by testing with non-malignant cells. b) Determine the HSP27 targeting effect of top derivatives with in vitro assays including HSP27 chaperone assay, surface plasmon resonance (SPR) HSP27 assay and cellular AR protein level determination. c) Test the LogP value of the compounds, and determine the blood brain barrier passing effect of the compounds with LC-MS/MS method. Aim 2. In vivo investigation of the drug candidates with GBM patient derived xenograft (PDX) tumor models. We will test the lead compound and newly identified ones with in vivo GBM PDX model, including subcutaneous PDX and intracranial PDX GBM models, and the AR level in the tumor as a therapeutic biomarker will be examined. TMZ will be the positive control and vehicle as the negative control. Another experiment will be the drug candidate combination with TMZ.