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

项目摘要 胶质母细胞瘤是一种致命的原发性脑肿瘤，治疗选择有限。目前的标准疗法， 联合放化疗（chemoRT）与替莫唑胺（TMZ），一种烷化剂， 生存期仅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抵抗机制，使它们能够在 传统疗法的效果。其中一个进化上保守的机制是热休克反应 (HSR)其可以在不利的环境条件下部署几种不同的防御过程。 HSR由热休克蛋白（HSP）介导，热休克蛋白是一类穿梭并 将客户癌蛋白配置为适当的功能状态。在初步研究中，我们表明，onalb，a 热休克蛋白90（Hsp90）的新型长效抑制剂，热休克蛋白90是癌细胞中HSR的关键介质， 在胶质瘤中阻断肿瘤生长、侵袭和血管生成，这表明在胶质瘤中具有强大的独立的 抗肿瘤作用与此相关的是，onalb使胶质瘤细胞对TMZ和RT在患者源性肿瘤中敏感。 (PDX)细胞系以及在斑马鱼和小鼠颅内胶质瘤动物模型中。根据这些数据，在 我们建议通过NCI资助的成人脑肿瘤联盟进行I期临床试验， 确定在成人新感染者中onalb与chemoRT联合治疗的最大耐受剂量 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onalbib联合化疗RT和辅助替莫唑胺的MTD 并将确定onalb是否可以穿过血脑屏障，并达到足够的浓度， 增强和非增强胶质瘤组织与血浆水平相比。目标2将决定 通过评估onalb是否可以抑制其在人体中的靶点Hsp90，来评估onalb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 特别是那些与DNA修复和细胞存活对抗RT和TMZ作用相关的。在目标3中，我们 使用PDX颅内胶质瘤模型和器官型人胶质瘤切片进行联合临床试验， 确定onalb效应的敏感性和抗性机制，以提供有助于 修改后续的II期试验。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的化学和放射疗法联合收割机。成功完成 这项试验将使我们能够进行II期疗效试验（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onalb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.