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)是恶性程度最高的脑肿瘤，预后不良。很少有病人可以 即使开发了新的手术技术，也能在诊断后存活一年以上， 主要是由于这些肿瘤的高度浸润性/侵袭性行为。GBM通常有从头开始或 对替莫唑胺(TMZ)的获得性耐药性，TMZ是一种DNA烷化试剂，是唯一的化疗药物 GBM。男性的GBM患病率高于女性。雄激素受体(AR)的过度表达有助于 这种基底膜的性别差异。AR是27 kDa热休克蛋白(HSP27)的客户蛋白，HSP27是一种抗 凋亡伴侣蛋白在GBM中高表达。HSP27促进AR的生物活性，从而有助于 为了GBM的进步。我们假设HSP27-AR轴是GBM肿瘤生长的关键驱动力， 尤其是对男性基底膜患者。拟议的研究源于我们努力开发小型 HSP27分子抑制剂诱导肾小球系膜AR降解是治疗骨肉瘤的新途径 GBM。我们已经鉴定出一种小分子HSP27抑制剂，它能极大地诱导AR降解和 选择性抑制AR过表达的GBM细胞生长。此外，我们有一个初步的结构 总结出用于设计下一代衍生产品的活性关系，以优化引线 化合物。我们还证明了靶向HSP27-AR对AR过度表达的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。 在GBM模型中加入TMZ，并进一步从结构上优化先导化合物。 目的1.热休克蛋白27(HSP27)抑制剂在肾小管上皮细胞中作为AR解除剂的先导优化。 我们将通过合理的设计、合成和优化来优化先导化合物的结构 放映。然后我们将：a)研究在这些衍生物存在的情况下GBM细胞的生长情况 总结了抑制生长的构效关系(SAR)。我们还将排除有毒物质 通过测试非恶性细胞来合成化合物。B)确定TOP衍生物的HSP27靶向效应 体外检测包括HSP27伴侣检测、表面等离子体共振(SPR)检测 以及细胞AR蛋白水平的测定。C)测试化合物的LogP值，并确定 LC-MS/MS法研究化合物的血脑屏障通透性。 目的2.体内实验研究GBM患者来源的异种移植瘤(PDX)模型中的候选药物。 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AR水平的治疗作用 生物标记物将被检测。TMZ将作为积极对照，车辆将作为负面对照。另一个 实验将TMZ作为候选药物联合应用。