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

基本信息

批准号：
10687871
负责人：
VINAY K PUDUVALLI
金额：
$ 56.84万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10687871
关键词：
Address Adjuvant Adult Affect Aftercare Alkylating Agents Animal Model Animals Brain Neoplasms Bypass CRISPR/Cas technology Cancer Center Cell Line Cell Survival Cells Chemotherapy and/or radiation Client Clinical Clinical Trials Combination Drug Therapy 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 Invaded MGMT gene Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Mediating Mediator 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 Zebrafish aggressive therapy angiogenesis antitumor effect blood-brain barrier crossing cancer cell chemoradiation chemotherapy co-clinical trial conventional therapy cytotoxic ds-DNA efficacy evaluation 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 therapeutic intervention novel therapeutics overexpression 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 outcome therapy resistant transcriptome transcriptome sequencing trial planning tumor tumor growth tumor heterogeneity

项目摘要

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。当前的标准疗法与与替莫唑胺（TMZ）联合化学放疗疗法（化学），烷基化剂具有中位数仅16-18个月的生存。迫切需要新颖的疗法，尤其是那些可以克服的疗法对化学的抗性。癌细胞发展了复杂的抗性机制，使它们能够生存常规疗法的影响。这种进化保守的机制是热休克响应（HSR）可以在不利的环境条件下部署几种不同的防御过程。 HSR是由热激蛋白（HSP）介导的，这是一类穿梭和将客户量癌蛋白配置为适当的功能状态。在初步研究中，我们表明Onalespib，一个新型长作用抑制剂的热休克蛋白90（HSP90），癌细胞中HSR的关键介体，胶质瘤中肿瘤的生长，侵袭和血管生成阻塞，表明具有强大独立的潜力抗肿瘤效应。与该提案相关，OnaLESPIB在患者衍生的患者衍生（PDX）细胞系以及斑马鱼和颅内神经胶质瘤动物模型。基于这些数据，在此基础上授予提交，我们通过NCI资助的成人脑肿瘤财团提出了I期临床试验确定新成年人的最大耐受剂量诊断为GBM。我们还建议通过以下具体目的：AIM 1将识别Chemort和Temozolomide辅助的组合中ONALESPIB的MTD 并将确定OnaLESPIB是否可以越过血脑屏障并获得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。 AIM 2将确定通过评估ONALESPIB是否可以抑制人类的HSP90，ONALESPIB的药效动力学作用在此试验中获得的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与DNA修复和细胞存活相关的那些与RT和TMZ的作用相关的。在AIM 3中，我们将使用PDX颅内神经胶质瘤模型和器官型人神经胶质瘤切片进行共同临床试验确定灵敏度和对OnAlespib效应的抗性的机制，以提供可以帮助的见解修改随后的II期试验。这是HSP90抑制剂在脑肿瘤和首先将HSP90抑制剂与针对GBM的化学和放射疗法相结合。成功完成该试验将使我们能够进行II阶段效力试验（由NRG肿瘤学批准），并将提供综合的PK和PD数据可以帮助其他在其他中开发OnaLESPIB和HSP90抑制剂恶性肿瘤。