A Novel Hsp90 Inhibitor as a Chemo and Radiosensitizer in Adults with Glioblastoma

项目总结 胶质母细胞瘤是一种致命的原发脑瘤，治疗选择有限。目前的标准治疗方法是 联合放化疗与替莫唑胺(TMZ)，一种烷化剂提供了 存活时间只有16-18个月。迫切需要新的治疗方法，特别是那些可以克服 对化疗耐药。癌细胞发展出复杂的耐药机制，使它们能够在 传统疗法的效果。其中一种进化上保守的机制是热休克反应 (高铁)，可以在不利的环境条件下部署几个不同的防御过程。 HSR是由热休克蛋白(HSP)介导的，HSP是一类分子伴侣，穿梭于 将客户癌蛋白配置为正确的功能状态。在初步研究中，我们发现onalespib，a 一种新型长效热休克蛋白90抑制物(Hsp90)，它是癌细胞中HSR的关键介质， 抑制胶质瘤的生长、侵袭和血管生成提示有很强的独立性 抗肿瘤作用。与这一建议相关的是，onalespib使胶质瘤细胞对患者来源的TMZ和RT敏感 (PDX)细胞系，并在斑马鱼和小鼠脑内胶质瘤动物模型。根据这些数据，在这个 我们建议通过NCI资助的成人脑瘤财团进行一项I期临床试验 确定奥那司匹布联合化疗在成人新发肿瘤中的最大耐受量 诊断为GBM。我们还建议通过以下方式进行关键的相关组织和血浆研究 具体目标：目标1将确定奥那司匹布联合化疗和替莫唑胺的MTD 并将确定onalespib是否能通过血脑屏障并在体内达到足够的浓度 增强和非增强的胶质瘤组织与血浆水平比较。目标2将决定 评价奥那司匹布是否能抑制其靶标Hsp90的药效学作用 本试验中获得的GBM组织以及这种抑制是否会影响其伴侣癌蛋白客户 尤其是那些与DNA修复和细胞存活有关的基因，对抗RT和TMZ的影响。在《目标3》中，我们将 使用PDX颅内胶质瘤模型和器官型人脑胶质瘤切片进行联合临床试验 确定对onalespib效应的敏感性和抵抗力的机制，以提供有助于 修改后续的第二阶段试验。这是Hsp90抑制剂在脑肿瘤中的首次人体试验， 第一个将Hsp90抑制剂与针对GBM的化疗和放射治疗相结合。成功完成 这项试验将使我们能够进入第二阶段疗效试验(由NRG肿瘤学批准)，并将提供 全面的PK和PD数据，可以帮助开发其他药物中的onalespib和Hsp90抑制剂 恶性肿瘤。

PROJECT SUMMARY Glioblastoma is a lethal primary brain tumor with limited treatment options. The current standard therapy with combined chemoradiation therapy (chemoRT) with temozolomide (TMZ), an alkylating agent offers a median survival of only 16-18 months. There is an urgent need for novel therapies especially those that can overcome resistance to chemoRT. Cancer cells develop complex resistance mechanisms that enable them to survive the effects of conventional therapies. One such evolutionally conserved mechanism is the heat shock response (HSR) which can deploy several diverse defense processes in the setting of adverse environmental conditions. The HSR is mediated by heat shock proteins (HSP), a class of molecular chaperones that shuttle and configure client oncoproteins into proper functional states. In preliminary studies, we show that onalespib, a novel long acting inhibitor of heat shock protein 90 (Hsp90), a critical mediator of the HSR in cancer cells, blocked tumor growth, invasion and angiogenesis in gliomas suggesting the potential for a strong independent antitumor effect. Relevant to this proposal, onalespib sensitizes glioma cells to TMZ and RT in patient-derived (PDX) cell lines and in a zebrafish and mouse intracranial glioma animal models. Based on these data, in this grant submission, we propose a phase I clinical trial through the NCI-funded Adult Brain Tumor Consortium to identify the maximum tolerated dose of the combination of onalespib with chemoRT in adults with newly diagnosed GBM. We also propose to conduct key correlative tissue and plasma studies through the following specific aims: Aim 1 will identify the MTD of onalespib in combination of chemoRT and adjuvant temozolomide and will determine whether onalespib can cross the blood brain barrier and achieve sufficient concentrations in enhancing and non-enhancing glioma tissue compared with plasma levels. Aim 2 will determine the pharmacodynamic effects of onalespib by assessing whether onalespib can inhibit Hsp90, its target, in human GBM tissue obtained in this trial and whether this inhibition can affect its chaperone oncoprotein clients particularly those relevant to DNA repair and cell survival against the effects of RT and TMZ. In Aim 3, we will conduct co-clinical trials using PDX intracranial glioma models and organotypic human glioma slices to determine the mechanisms of sensitivity and resistance to onalespib effects to provide insights that can help modify the subsequent phase II trial. This is the first human trial of an Hsp90 inhibitor in brain tumors and the first to combine an Hsp90 inhibitor with chemo- and radiation therapy against GBM. Successful completion of this trial will enable us to proceed to a Phase II efficacy trial (approved by NRG oncology) and will provide comprehensive PK and PD data that can help the development of onalespib and Hsp90 inhibitors in other malignancies.