Novel Small Molecule Hsp90 Therapeutics to Treat Glioma

治疗神经胶质瘤的新型小分子 Hsp90 疗法

• 批准号: 7746573
• 负责人: RUIHONG CHEN
• 金额: $ 11.75万
• 依托单位: NEXGENIX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746573
• 关键词: ATP phosphohydrolase; Ansamycin Antineoplastic Antibiotic; Biological Assay; Biological Factors; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cell Cycle Progression; Cell Proliferation; Cells; Characteristics; Client; Clinical; Clinical Trials; Development; Dose; Drug Formulations; Drug Kinetics; Epidermal Growth Factor Receptor; Exhibits; Gelatinase A; Geldanamycin; Geldanamycin Analogue; Glioma; Goals; Growth; HSP 90 inhibition; Heat-Shock Proteins 90; Hepatotoxicity; Histopathology; Human; In Vitro; Inhibition of Cancer Cell Growth; Life; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Modeling; Molecular Chaperones; Molecular Conformation; Mus; Nature; Oncogene Proteins; Outcome; Patients; Penetration; Pharmacologic Substance; Phase; Phase I Clinical Trials; Process; Proteins; Publishing; Relative (related person); Reporting; Research; Resistance; Series; Small Business Innovation Research Grant; Solid Neoplasm; Stress; Therapeutic; Therapeutic Uses; Time; Treatment Efficacy; Tumor Volume; Validation; Xenograft Model; angiogenesis; base; cancer therapy; cell growth; cell motility; clinical care; commercialization; design; effective therapy; efficacy testing; glioma cell line; in vivo; inhibitor/antagonist; malignant breast neoplasm; meetings; migration; monorden; mortality; neoplastic cell; novel; pre-clinical; preclinical efficacy; preclinical study; prototype; public health relevance; response; small molecule; therapeutic target; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): Despite improvements in clinical care for patients, mortality rates for primary brain cancer remain high. Patients with glioma have a median survival of 1 year with poor responses to current therapies, likely due to the highly angiogenic and invasive nature of these tumors. Therapies effective for a variety of solid tumors are ineffective for gliomas. Thus, there is a critical need for novel therapies targeting these tumors. Heat shock protein 90 (Hsp90) functions to maintain the conformation and activity of many oncoproteins, and has thus become an attractive target for cancer therapy. Inhibitors of Hsp90 have demonstrated inhibition of cancer cell growth in various tumor models and the first inhibitor in clinical development, 17-AAG, is in Phase II/III development for cancer. Indeed, 17-AAG has already shown preclinical efficacy in GL261 cells and GL261 gliomas. Because 17-AAG and most other Hsp90 inhibitors in development cross the blood brain barrier (BBB) poorly, their potential efficacy for treatment of gliomas is limited. NexGenix Pharmaceuticals is currently developing a novel radicicol-based series of Hsp90 inhibitors. These compounds, for which the prototype is NXD30001, inhibit Hsp90 more potently than 17-AAG and have a more favorable pharmacokinetic profile. NXD30001 efficiently depletes Hsp90 client oncoproteins, inhibits tumor cell growth in vitro and in vivo, readily crosses the BBB and accumulates in the brain. Taken together, these characteristics make NXD30001 an attractive therapeutic candidate for gliomas. Objective: The goal of this Phase I SBIR project is to establish proof-of-principle for the development of NXD30001 as a therapeutic for glioma. A successful outcome from this Phase I study will be followed by preclinical development and clinical validation supporting subsequent development and commercialization of NXD30001 for glioma treatment. Specific Aim 1: Anti-tumor effect of NXD30001 on glioma cells in vitro. We hypothesize that NXD30001, given its increased potency relative to 17-AAG, will exhibit greater anti-tumor efficacy in cell based assays with murine (GL261) and human (U87MG, U251MG, LN443, T98G) glioma cells. A dose- and time-dependent effect of NXD30001 treatment on GL261 cell proliferation, cell cycle progression, client protein depletion, cell migration, MMP-2 secretion will be analyzed. In addition, NXD30001 and 17-AAG will be compared in a proliferation assay and Hsp90 client protein depletion assay using a panel of human glioma cell lines. Specific Aim 2: Anti-tumor effect of NXD30001 on GL261 gliomas in vivo. We hypothesize that NXD30001, given its increased BBB penetration relative to 17-AAG, will exhibit greater anti-tumor efficacy in the GL261 in vivo brain tumor model. We will test the efficacy of different doses of NXD30001 on tumor volume, in vivo Hsp90 client protein depletion, histopathology, angiogenesis and invasive potential. PUBLIC HEALTH RELEVANCE: Malignant gliomas are highly aggressive tumors with a high mortality rate that claim up to 10,000 lives each year in the US. Current therapies that are effective for other solid tumors are ineffective in controlling the growth of these inevitably fatal tumors. The proposed research is designed to establish proof-of-principle evidence for the novel heat shock protein 90 (Hsp90) inhibitor, NXD30001, in a glioma model, that will likely support its development as a potential treatment for malignant glioma.

描述（由申请人提供）：尽管患者的临床护理有所改善，但原发性脑癌的死亡率仍然很高。神经胶质瘤患者的中位生存期为 1 年，对当前治疗的反应较差，这可能是由于这些肿瘤的高度血管生成和侵袭性所致。对多种实体瘤有效的疗法对神经胶质瘤无效。因此，迫切需要针对这些肿瘤的新疗法。热休克蛋白 90 (Hsp90) 的作用是维持许多癌蛋白的构象和活性，因此已成为癌症治疗的一个有吸引力的靶点。 Hsp90 抑制剂已在各种肿瘤模型中显示出对癌细胞生长的抑制作用，第一个临床开发抑制剂 17-AAG 正处于癌症的 II/III 期开发阶段。事实上，17-AAG 已在 GL261 细胞和 GL261 神经胶质瘤中显示出临床前功效。由于 17-AAG 和大多数其他正在开发的 Hsp90 抑制剂穿过血脑屏障 (BBB) 的能力较差，因此它们治疗神经胶质瘤的潜在疗效有限。 NexGenix Pharmaceuticals 目前正在开发一种新型的基于 radicicol 的 Hsp90 抑制剂系列。这些化合物的原型为 NXD30001，比 17-AAG 更有效地抑制 Hsp90，并且具有更有利的药代动力学特征。 NXD30001 可有效消耗 Hsp90 客户癌蛋白，在体外和体内抑制肿瘤细胞生长，轻松穿过血脑屏障并在大脑中积聚。综上所述，这些特性使 NXD30001 成为一种有吸引力的神经胶质瘤治疗候选药物。目的：该 I 期 SBIR 项目的目标是为 NXD30001 作为神经胶质瘤治疗药物的开发建立原理验证。该一期研究取得成功后，将进行临床前开发和临床验证，以支持 NXD30001 用于神经胶质瘤治疗的后续开发和商业化。具体目标1：NXD30001对胶质瘤细胞的体外抗肿瘤作用。我们假设 NXD30001 相对于 17-AAG 具有更高的效力，因此在小鼠 (GL261) 和人类 (U87MG、U251MG、LN443、T98G) 神经胶质瘤细胞的细胞检测中将表现出更大的抗肿瘤功效。将分析 NXD30001 治疗对 GL261 细胞增殖、细胞周期进展、客户蛋白消耗、细胞迁移、MMP-2 分泌的剂量和时间依赖性影响。此外，还将使用一组人胶质瘤细胞系在增殖测定和 Hsp90 客户蛋白消耗测定中对 NXD30001 和 17-AAG 进行比较。具体目标2：NXD30001对GL261胶质瘤的体内抗肿瘤作用。我们假设，鉴于 NXD30001 相对于 17-AAG 具有更高的 BBB 渗透性，它将在 GL261 体内脑肿瘤模型中表现出更大的抗肿瘤功效。我们将测试不同剂量的 NXD30001 对肿瘤体积、体内 Hsp90 客户蛋白消耗、组织病理学、血管生成和侵袭潜力的功效。公共卫生相关性：恶性神经胶质瘤是一种高度侵袭性的肿瘤，死亡率很高，在美国每年夺走多达 10,000 人的生命。目前对其他实体瘤有效的疗法无法有效控制这些不可避免的致命肿瘤的生长。拟议的研究旨在为神经胶质瘤模型中的新型热休克蛋白 90 (Hsp90) 抑制剂 NXD30001 建立原理验证证据，这可能会支持其开发为恶性神经胶质瘤的潜在治疗方法。