Toward Changing Glioblastoma Outcomes: Targeted drug delivery of an inhibitory biopolymer in conjunction with systemic chemotherapy

改变胶质母细胞瘤的结果：抑制性生物聚合物的靶向药物输送与全身化疗相结合

• 批准号: 9808689
• 负责人: DRAZEN RAUCHER
• 金额: $ 20.78万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808689
• 关键词: Address; Animal Cancer Model; Biodistribution; Biopolymers; Blood - brain barrier anatomy; Body Weight Changes; Brain; Brain Neoplasms; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Trials; Code; Combined Modality Therapy; Data; Diagnosis; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Elastin; Engineering; Excision; Exposure to; Face; Fluorescence; Foundations; Genetic Transcription; Glioblastoma; Glioma; Goals; Heart; Helix-Turn-Helix Motifs; Human; Hyperthermia; Image; Imaging technology; Implant; Intravenous; Label; Laboratories; Local Hyperthermia; Luciferases; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Methods; Modeling; Mus; Neutropenia; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phase Transition; Physiological; Plasma; Radiation; Radiation therapy; Radio; Rattus; Regimen; Resistance; Safety; Signal Transduction; Site; Solid; Source; Specificity; Subfamily lentivirinae; System; Systemic Therapy; Technology; Temperature; Testing; Therapeutic; Tissues; Toxic effect; Treatment Effectiveness; Treatment Efficacy; Tumor-Derived; Xenograft Model; anti-cancer therapeutic; base; brain tissue; c-myc Genes; cellular transduction; chemotherapy; clinically relevant; comparative efficacy; design; implementation strategy; improved; in vivo; in vivo imaging system; innovation; neoplastic cell; novel strategies; outcome forecast; peptide drug; polypeptide; response; side effect; small molecule; standard care; standard of care; systemic toxicity; temozolomide; transcytosis; treatment effect; treatment optimization; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor xenograft

Abstract: Toward Changing Glioblastoma Outcomes: Targeted drug delivery of an inhibitory biopolymer in conjunction with systemic chemotherapy Glioblastoma (GBM), the most common and aggressive brain tumor, ranks among the least curable cancers owing to its strong tendency for intracranial dissemination, high proliferation potential, and inherent tumor resistance to radiation and chemotherapy. Current GBM treatment strategies are hampered by a further critical challenge: adverse, nonspecific treatment effects in normal tissue and the inability of potentially effective drugs to penetrate the blood brain barrier (BBB) and reach the tumor microenvironment. We have developed an externally triggered drug delivery system to selectively deliver c-Myc transcriptional pathway inhibitory peptides (CPP-ELP-H1) to GBM tumors. This carrier, based on a thermally responsive biopolymer elastin-like polypeptide (ELP), is soluble at physiological temperatures, but undergoes a phase transition and accumulates at tumor sites when exposed to an externally applied, mild (40-41°C) hyperthermia. Conjugating this ELP with a cell-penetrating peptide (CPP) facilitates transcytosis through the BBB and tumor cell entry. The system’s anti-cancer therapeutic, an H1 peptide, antagonizes c-Myc signaling and disrupts cell proliferation. Our preliminary data show that, in a rat glioma model, CPP-ELP-H1 accumulates with the application of a mild hyperthermia in these tumors, inhibits rat glioma cells, and achieves effective tumor reduction. We thus propose here to explore and extend this novel approach in a clinically relevant, primary human GBM xenograft model in mice. We will test our system’s innovative approach to GBM treatment by assessing the effectiveness of c-Myc inhibitory polypeptide delivery to and accumulation at tumor sites. In Aim 1 we will identify polypeptide tissue and tumor concentrations, assess BBB penetration, and evaluate the capacity of an external, focused hyperthermia to further increase polypeptide levels at tumor sites. Aim 2 will demonstrate whether our engineered polypeptides can be safely administered to mice at doses required for therapeutic efficacy. We will evaluate safety profiles for our biopolymer delivery construct, conjugated with H1, when applied (1) in isolation and (2) in combination with temozolomide and radiation therapy. In Aim 3 we seek to significantly improve tumor cell responsiveness to the currently approved radiation and systemic temozolomide therapy, counter temozolomide resistant tumor xenografts, and increase GBM treatment effectiveness by applying this ‘standard-of-care’ therapy in combination with our delivery system’s GBM-targeted c-Myc transcription inhibitory peptide so as to advance our understanding of and eventual clinical armamentarium against GBM. Our goal is to contribute an effective, function-sparing therapy for patients with GBM. The proposed studies will show whether this innovative, much less toxic, targeted technology significantly lowers systemic therapy doses, effectively inhibits tumor growth, and reduces overall systemic toxicity. If successful, we will advance our construct to clinical trials toward achieving a powerful addition to treatments available for patients and clinicians who daily encounter and must counter the daunting challenges posed by glioblastomas.

摘要：为改变胶质母细胞瘤的预后：靶向给药抑制物 生物聚合物与全身化疗 胶质母细胞瘤(GBM)是最常见和最具侵袭性的脑肿瘤，是最难治愈的癌症之一。 由于它有强烈的颅内扩散倾向，高增殖潜能和固有的肿瘤 对放射和化疗的抵抗力。目前的GBM治疗策略受到另一个关键问题的阻碍 挑战：正常组织中的不良、非特异性治疗效果以及潜在有效药物的无能为力 穿透血脑屏障(BBB)，到达肿瘤微环境。我们已经开发出一种 体外触发药物递送系统选择性递送c-Myc转录途径抑制肽 (CPP-ELP-H1)对基底膜肿瘤的抑制作用。这种载体基于一种类似弹性蛋白的热响应性生物聚合物 多肽(ELP)，在生理温度下可溶，但经历相变并积累 当暴露在外部施加的温和(40-41°C)热疗时，肿瘤部位的温度会降低。将此ELP与 细胞穿透肽(CPP)通过血脑屏障和肿瘤细胞进入促进细胞穿透。该系统的 抗癌治疗是一种H1肽，可以拮抗c-Myc信号并扰乱细胞增殖。我们的 初步数据显示，在大鼠脑胶质瘤模型中，CPP-ELP-H1在应用温和的 热疗在这些肿瘤中，抑制大鼠胶质瘤细胞，实现有效的肿瘤减瘤。因此，我们 建议在临床相关的原发人类基底膜异种移植中探索和推广这一新方法。 以小鼠为模型。我们将通过评估疗效来测试我们系统对GBM治疗的创新方法 C-Myc抑制多肽递送到肿瘤部位并在肿瘤部位积聚。在目标1中，我们将鉴定多肽 组织和肿瘤浓度，评估血脑屏障穿透，并评估外部，聚焦的能力 热疗可进一步提高肿瘤部位的多肽水平。目标2将证明我们的 工程多肽可以安全地按治疗效果所需的剂量给小鼠服用。我们会 评估我们与H1结合的生物聚合物递送构建物在隔离应用(1)时的安全性 联合替莫唑胺和放射治疗。在目标3中，我们寻求显著改进 肿瘤细胞对目前批准的放疗和全身替莫唑胺治疗的反应性 替莫唑胺耐药的肿瘤移植瘤，并通过应用该方法提高GBM的治疗效果 结合我们的递送系统的GBM靶向c-Myc转录的“标准护理”疗法 抑制肽，以促进我们的认识，并最终临床武器抗基底膜。 我们的目标是为GBM患者提供一种有效的、节省功能的治疗方法。拟议的研究将 展示这种创新的、毒性小得多的靶向技术是否显著降低了系统治疗 剂量，有效地抑制肿瘤生长，并降低整体全身毒性。如果成功，我们将晋级 我们对临床试验的构建，旨在实现对患者和 临床医生每天都会遇到并必须应对胶质母细胞瘤带来的艰巨挑战。