Novel Small Molecule Hsp90 Therapeutics to Treat Glioma

描述(申请人提供)：尽管患者的临床护理有所改善，但原发脑癌的死亡率仍然很高。胶质瘤患者的中位生存期为1年，对目前的治疗反应不佳，这可能是由于这些肿瘤的高度血管生成和侵袭性所致。对各种实体瘤有效的治疗方法对胶质瘤无效。因此，迫切需要针对这些肿瘤的新疗法。热休克蛋白90(Hsp90)具有维持多种癌蛋白构象和活性的功能，已成为肿瘤治疗的靶点。Hsp90的抑制剂已经在各种肿瘤模型中显示出对癌细胞生长的抑制作用，临床开发的第一个抑制剂17-AAG正处于癌症的II/III期开发中。事实上，17-AAG已经在GL261细胞和GL261胶质瘤中显示出临床前的疗效。由于17-AAG和大多数其他正在开发的Hsp90抑制剂很难通过血脑屏障(BBB)，它们治疗胶质瘤的潜在疗效有限。NexGenix制药公司目前正在开发一种新型的基于自由基的Hsp90抑制剂系列。这些化合物的原型是NXD30001，它们比17-AAG更有效地抑制Hsp90，并具有更有利的药代动力学特征。NXD30001有效地消耗Hsp90客户癌蛋白，抑制肿瘤细胞的体外和体内生长，很容易跨越血脑屏障并在脑内蓄积。综上所述，这些特点使NXD30001成为治疗胶质瘤的有吸引力的候选药物。目的：该第一阶段SBIR项目的目标是为NXD30001作为治疗胶质瘤的药物的开发建立原则证明。在这项第一阶段研究取得成功结果之后，将进行临床前开发和临床验证，以支持NXD30001用于治疗胶质瘤的后续开发和商业化。具体目的1：NXD30001对胶质瘤细胞的体外抗肿瘤作用。我们推测，鉴于NXD30001相对于17-AAG的增强效力，在以小鼠(GL261)和人(U87 MG、U251 MG、LN443、T98G)胶质瘤细胞为基础的细胞检测中，NXD30001将显示出更好的抗肿瘤效果。将分析NXD30001处理对GL261细胞增殖、细胞周期进程、客户蛋白耗竭、细胞迁移、基质金属蛋白酶-2分泌的剂量和时间依赖性的影响。此外，NXD30001和17-AAG将在一组人脑胶质瘤细胞系的增殖试验和Hsp90客户蛋白消耗试验中进行比较。特异性目的2：NXD30001对GL261胶质瘤的体内抗肿瘤作用我们推测，由于NXD30001相对于17-AAG具有更高的血脑屏障渗透率，因此在GL261体内脑瘤模型中将显示出更好的抗肿瘤效果。我们将测试不同剂量的NXD30001对肿瘤体积、体内Hsp90客户蛋白耗竭、组织病理学、血管生成和侵袭潜能的影响。与公共卫生相关：恶性胶质瘤是一种高度侵袭性的肿瘤，死亡率高，每年在美国夺走多达10,000人的生命。目前对其他实体肿瘤有效的治疗方法在控制这些不可避免的致命肿瘤的生长方面无效。这项拟议的研究旨在为新型热休克蛋白90(Hsp90)抑制剂NXD30001在胶质瘤模型中建立原理证据，这可能支持其作为恶性胶质瘤的潜在治疗方法。

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.