Targeting Androgen Receptor-HSP27 Signaling in Glioblastoma

胶质母细胞瘤中靶向雄激素受体 HSP27 信号传导

• 批准号: 10201212
• 负责人: Bin Su
• 金额: $ 44.55万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201212
• 关键词: Adult; Aftercare; Androgen Receptor; Apoptotic; Biological; Biological Assay; Biological Process; Blood; Blood - brain barrier anatomy; Brain; Cells; Characteristics; Chemotherapy and/or radiation; Client; Clinic; Clinical; Collaborations; DNA; Development; Diagnosis; Drug Kinetics; Environment; Foundations; Future; Glioblastoma; Growth; HSPB1 gene; Heat shock proteins; In Vitro; Institutes; Investigational Drugs; Lead; Malignant neoplasm of brain; Methods; Modeling; Molecular Chaperones; Mus; Mutate; Mutation; Non-Malignant; Operative Surgical Procedures; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Poison; Prognosis; Proteins; Reagent; Receptor Signaling; Research; Resistance; Scientist; Sex Differences; Signal Transduction; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Techniques; Testing; Therapeutic; Toxic effect; Training; Universities; Western Blotting; Woman; base; cell growth; chemotherapy; design; driving force; drug candidate; experimental study; improved; in vitro Assay; in vivo; inhibitor/antagonist; lead optimization; male; men; mouse model; next generation; novel; novel strategies; novel therapeutics; overexpression; patient derived xenograft model; protein degradation; public health relevance; receptor; screening; small molecule; small molecule inhibitor; subcutaneous; success; temozolomide; therapeutic biomarker; translational scientist; tumor; tumor behavior; tumor growth; tumor progression; tumor xenograft; undergraduate student

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.

摘要 胶质母细胞瘤（GBM）是脑内最恶性的肿瘤，预后差。很少有病人能 即使随着新的外科技术的发展， 主要是由于这些肿瘤的高度浸润性/侵袭性行为。GBM通常具有新发或 对替莫唑胺（TMZ）的获得性耐药，这是一种DNA烷基化试剂，是唯一的化疗药物， GBM。男性GBM的发病率高于女性。雄激素受体（AR）过表达有助于 GBM的性别差异AR是27 kDa热休克蛋白（HSP 27）的客户蛋白，HSP 27是抗- GBM中凋亡分子伴侣过度表达。HSP 27促进AR的生物学活性，这有助于 GBM进展。我们假设HSP 27-AR轴是GBM中肿瘤生长的关键驱动力， 特别是对于男性GBM患者。建议的研究产生于我们的努力， HSP 27分子抑制剂诱导GBM中AR降解，这为治疗GBM中AR的治疗提供了新的途径。 GBM。我们已经鉴定了一种小分子HSP 27抑制剂，它极大地诱导AR降解， 选择性抑制AR过表达的GBM细胞生长。此外，我们还有一个初步结构 活性关系总结，用于设计下一代衍生物，以优化先导化合物 化合物.我们还证明了靶向HSP 27-AR对AR过表达的GBM具有选择性， 细胞我们建议系统地研究候选药物及其组合的体内活性 与TMZ在GBM模型中，并进一步优化先导化合物的结构。 目标1.引导优化HSP 27抑制剂作为GBM中的AR消除剂。 我们将通过合理的设计、合成和优化， 筛选a）在这些衍生物存在下检查GBM细胞的生长， 总结了生长抑制构效关系。我们还将排除有毒物质 用非恶性细胞测试化合物。B）确定顶级衍生物的HSP 27靶向作用 用体外试验，包括HSP 27伴侣试验、表面等离子体共振（SPR）HSP 27试验 和细胞AR蛋白水平测定。c）测试化合物的LogP值，并确定化合物的浓度。 用LC-MS/MS法测定化合物的血脑屏障通过作用。 目标2.用GBM患者来源的异种移植（PDX）肿瘤模型对候选药物进行体内研究。 我们将用体内GBM PDX模型测试先导化合物和新鉴定的化合物，包括 皮下PDX和颅内PDX GBM模型，以及肿瘤中的AR水平作为治疗 将检查生物标志物。TMZ为阳性对照，溶剂为阴性对照。另一 实验将是候选药物与TMZ的组合。