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

一种新型 Hsp90 抑制剂作为成人胶质母细胞瘤的化疗和放射增敏剂

• 批准号: 10480888
• 负责人: VINAY K PUDUVALLI
• 金额: $ 57.05万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480888
• 关键词: Address; Adjuvant; Adult; Affect; Aftercare; Alkylating Agents; Animal Model; Animals; Blood - brain barrier anatomy; Brain Neoplasms; Bypass; CRISPR/Cas technology; Cancer Center; Cell Line; Cell Survival; Cells; Chemotherapy and/or radiation; Client; Clinical; Clinical Trials; Complex; Correlative Study; DNA; DNA Repair; DNA Repair Gene; Data; Defense Mechanisms; Development; Development Plans; Drug Kinetics; Epidermal Growth Factor Receptor; Evolution; Funding; Future; Generations; Glioblastoma; Glioma; Grant; Growth; HSP 90 inhibition; Heat shock proteins; Heat-Shock Proteins 90; Heat-Shock Response; Heterogeneity; Human; In Vitro; Individual; Institution; MGMT gene; Malignant Neoplasms; Malignant neoplasm of brain; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Methylation; Microdialysis; Mismatch Repair; Modeling; Molecular Chaperones; Mus; Newly Diagnosed; Normal Cell; Oncogenic; Oncology; Oncoproteins; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Plasma; Positioning Attribute; Primary Brain Neoplasms; Process; Protein Family; Proteins; Radiation therapy; Radiation-Sensitizing Agents; Randomized; Recurrence; Recurrent tumor; Resistance; Role; Sampling; Schedule; Serum; Signal Transduction; Slice; Specimen; Stress; Tissues; Toxic effect; Treatment Failure; Tumor Tissue; Up-Regulation; Ursidae Family; Zebrafish; aggressive therapy; angiogenesis; antitumor effect; base; cancer cell; chemoradiation; chemotherapy; co-clinical trial; conventional therapy; cytotoxic; ds-DNA; efficacy trial; epidermal growth factor receptor VIII; glioma cell line; improved; improved outcome; in vivo; inhibitor; insight; knock-down; member; migration; mouse model; neoplastic cell; novel; novel therapeutics; patient subsets; pharmacokinetics and pharmacodynamics; phase 2 study; phase I trial; phase II trial; pre-clinical; protein complex; radiation effect; resistance mechanism; response; stem cells; temozolomide; therapy resistant; transcriptome; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor heterogeneity

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.

项目概要 胶质母细胞瘤是一种致命的原发性脑肿瘤，治疗选择有限。目前的标准疗法是 联合放化疗 (chemoRT) 与烷化剂替莫唑胺 (TMZ) 的中位治疗效果 生存期仅有16-18个月。迫切需要新的疗法，特别是那些能够克服 对化疗的耐药性。癌细胞会形成复杂的抵抗机制，使它们能够在 常规疗法的效果。一种这样的进化保守机制是热休克反应 （HSR），它可以在不利的环境条件下部署多种不同的防御过程。 HSR 由热休克蛋白 (HSP) 介导，热休克蛋白是一类分子伴侣，可以穿梭和 将客户端癌蛋白配置为适当的功能状态。在初步研究中，我们表明 onalespib 是一种 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， 阻断神经胶质瘤中的肿瘤生长、侵袭和血管生成，表明强大的独立疗法的潜力 抗肿瘤作用。与该提案相关的是，onalespib 使患者来源的神经胶质瘤细胞对 TMZ 和 RT 敏感。 (PDX) 细胞系以及斑马鱼和小鼠颅内神经胶质瘤动物模型。根据这些数据，在本次 在提交拨款申请后，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 onalespib 与 chemoRT 联合治疗新发成人患者的最大耐受剂量 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 onalespib 联合化疗和替莫唑胺佐剂的 MTD 并将确定 onalespib 是否可以穿过血脑屏障并在体内达到足够的浓度 与血浆水平相比，增强和非增强神经胶质瘤组织。目标 2 将确定 通过评估 onalespib 是否可以抑制其靶标 Hsp90 在人体中的药效学作用 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 修复和细胞存活相关的抵抗 RT 和 TMZ 影响的研究。在目标 3 中，我们将 使用 PDX 颅内神经胶质瘤模型和器官型人类神经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机制，以提供有助于帮助的见解 修改后续的II期试验。这是 Hsp90 抑制剂治疗脑肿瘤的首次人体试验 第一个将 Hsp90 抑制剂与针对 GBM 的化疗和放疗结合起来。顺利完成 该试验将使我们能够进行 II 期疗效试验（经 NRG 肿瘤学批准），并将提供 全面的 PK 和 PD 数据可帮助 onalespib 和 Hsp90 抑制剂在其他领域的开发 恶性肿瘤。