Thermally Targeted Delivery of c-Myc Inhibitory Polypeptides to Malignant Gliomas

c-Myc 抑制性多肽热靶向递送至恶性神经胶质瘤

• 批准号: 7990812
• 负责人: DRAZEN RAUCHER
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990812
• 关键词: Address; Adjuvant Chemotherapy; Adverse effects; Amino Acid Sequence; Animal Model; Antineoplastic Agents; Biodistribution; Biopolymers; Blood - brain barrier anatomy; Blood Circulation; Body Temperature; Brain; Brain Neoplasms; Cell Proliferation; Cells; Clinical Trials; Combined Modality Therapy; Coupled; Data; Diagnosis; Drug Kinetics; Effectiveness; Elastin; Engineering; Excision; Fever; Glioblastoma; Glioma; Goals; Growth; Heating; Helix-Loop-Helix Motifs; Helix-Turn-Helix Motifs; Human; Injection of therapeutic agent; Intracranial Neoplasms; Intravenous; Kinetics; Lead; Local Hyperthermia; MRI Scans; Malignant Glioma; Measures; Mediating; Methods; Modeling; Monitor; Normal tissue morphology; Oncogenes; Operative Surgical Procedures; Outcome; Penetration; Peptides; Physiological; Plasma; Play; Primary Brain Neoplasms; Quantitative Autoradiography; Radiation; Radiation therapy; Radiolabeled; Rattus; Research; Resistance; Role; Site; Solutions; Specificity; Technology; Temperature; Testing; Therapeutic; Tissues; Toxic effect; Toxicity due to chemotherapy; Transcriptional Activation; Treatment Efficacy; Treatment Protocols; Tumor Volume; Work; aqueous; bactenecin; base; c-myc Genes; c-myc Proto-Oncogenes; cancer cell; carcinogenesis; cell growth regulation; chemotherapeutic agent; chemotherapy; conventional therapy; cytotoxicity; design; endozepine-like peptide ELP; in vivo; inhibitor/antagonist; intraperitoneal; neoplastic; outcome forecast; overexpression; polypeptide; protein aminoacid sequence; public health relevance; radiotracer; targeted delivery; therapeutic target; transcription factor; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): Malignant gliomas represent the largest group of glial tumors, and they have a poor prognosis because of their high proliferation potential, strong tendency for intracranial dissemination, and the severe adverse effects of conventional therapies. Although surgical resection with adjuvant chemotherapy and/or radiotherapy is used to treat malignant gliomas, inherent tumor resistance to radiation or chemotherapy and toxicity from systemic administration of antineoplastic agents often hinders a successful outcome. Therefore, motivated by the limitations of current therapeutic approaches for gliomas, our long term goal is to develop a targeted therapeutic approach for localized tumors that increases the specificity and efficacy of the therapy and reduces the cytotoxicity in normal tissues. We have developed a thermally responsive polypeptide (CPP-ELP-H1) that inhibits c-Myc transcriptional activity and malignant glioma cell proliferation. The objective of the proposed research is to demonstrate that after systemic administration in vivo, these genetically engineered polypeptides can be targeted to the brain tumor site by applying local hyperthermia and inhibit tumor growth. The amino acid sequence of the thermally responsive polypeptides is based on the elastin-like (ELP) biopolymer, which is soluble in aqueous solution below physiological temperature (37 0C), but aggregates when the temperature is raised above 41 0C. A cell-penetrating peptide (CPP), Bactenecin (Bac) or Tat, is conjugated to the ELP to enhance delivery of the polypeptide across the blood brain barrier and to facilitate cell entry. To the CPP-ELP is added a peptide derived from helix 1 (H1) of the helix-loop-helix domain of c-Myc, which inhibits transcriptional activation by c-Myc and consequently inhibits cancer cell proliferation. Our hypothesis is that intravenously delivered thermally responsive c-Myc inhibitory polypeptides are likely to be cleared under physiological conditions (37 0C). However, they will accumulate in gliomas grown in rat brains, where externally induced local heat (40-42 0C) will be applied. The accumulated polypeptides will block c-Myc activity and consequently inhibit proliferation of the cancer cells. In order to address this hypothesis, the following specific aims will be addressed: (1) measure the plasma kinetics and in vivo distribution of CPP-ELP-H1 in normal and neoplastic tissue and (2) evaluate the therapeutic efficacy of CPP-ELP-H1 in the treatment of neoplastic brain tumors in rats through repeated administration of the agent coupled with and without local hyperthermia. Successful completion of the proposed study will provide the first evidence that ELP can deliver a therapeutic molecule and reduce brain tumor size in a thermally targeted manner, and this work will obtain the necessary toxicity, pharmacokinetic, biodistribution, and efficacy data necessary to advance this technology toward the ultimate goal of human therapeutics. Therefore, proposed research may have a significant impact, leading this technology into clinical trials, and it may provide a powerful technology to treat and manage brain tumors. PUBLIC HEALTH RELEVANCE: Glioblastoma is the most common and most aggressive of the primary brain tumors. Despite advances in combined treatment regimens including surgery, radio- and chemotherapy, the prognosis of a glioblastoma diagnosis is still bleak due to poor blood- brain barrier penetration of therapeutics, resistance to chemotherapeutic agents and nonspecific cytotoxicity in normal tissues. Motivated by the limitations of current therapeutic approaches for treatment of glioblastoma, the objective of the proposed research is to develop a thermally responsive therapeutic polypeptide which can be targeted to the brain tumor site by applying local hyperthermia and inhibit its growth.

描述（由申请人提供）：恶性神经胶质瘤是最大的神经胶质肿瘤，由于其高增殖潜力，强烈的颅内传播趋势以及常规疗法的严重不良影响，它们的预后较差。尽管使用辅助化疗和/或放射疗法的手术切除术可用于治疗恶性神经胶质瘤，但固有的肿瘤对放射或化学疗法的抵抗力以及抗肿瘤剂的全身施用抗肿瘤的毒性通常会阻碍成功的结果。因此，由于当前的胶质瘤治疗方法的局限性，我们的长期目标是开发针对局部肿瘤的靶向治疗方法，以提高治疗的特异性和功效，并降低正常组织中的细胞毒性。我们已经开发了一种热响应的多肽（CPP-ELP-H1），该多肽抑制了C-MYC转录活性和恶性神经胶质瘤细胞增殖。拟议的研究的目的是证明，在体内进行全身给药后，这些基因工程的多肽可以通过应用局部高温并抑制肿瘤生长来靶向脑肿瘤部位。热响应性多肽的氨基酸序列基于弹性（ELP）生物聚合物，该生物聚合物可溶于生理温度以下的水溶液（37 0c），但是当温度升高时，凝聚在41 0c以上时聚集。将细胞穿透肽（CPP），bactenecin（BAC）或TAT偶联到ELP中，以增强多肽在血液脑屏障中的递送并促进细胞进入。向CPP-ELP添加了c-Myc的螺旋 - 环螺旋结构域的螺旋1（H1）的肽，该肽抑制C-MYC的转录激活，从而抑制癌细胞增殖。我们的假设是，在生理条件下（37 0c），静脉内传递的热响应性C-MYC抑制性多肽可能会被清除。但是，它们将积聚在大鼠大脑中生长的胶质瘤中，在那里将应用外部诱导的局部热量（40-42 0c）。累积的多肽将阻断C-MYC活性，从而抑制癌细胞的增殖。为了解决这一假设，将解决以下具体目的：（1）测量正常和肿瘤组织中CPP-ELP-H1的血浆动力学和体内分布，以及（2）（2）评估CPP-H1的治疗性在CPP-H1通过重复施用的大鼠治疗中CPP-ELP-H1在治疗中的肿瘤肿瘤的治疗方法，并评估COYPLIA局部COUPLIA的疗效。拟议研究的成功完成将提供第一个证据，表明ELP可以以热靶向方式提供治疗性分子并减少脑肿瘤大小，并且这项工作将获得必要的毒性，药代动力学，生物分布和功效，以将这种技术朝着人类治疗疗法的最终目标推进这项技术。因此，拟议的研究可能会产生重大影响，将这项技术带入临床试验，并可能提供一种强大的技术来治疗和管理脑肿瘤。 公共卫生相关性：胶质母细胞瘤是原发性脑肿瘤中最常见和最具侵略性的。尽管在包括手术，放射性和化学疗法在内的联合治疗方案方面取得了进步，但由于治疗剂的血液屏障渗透不良，对化学治疗剂的耐药性和非特异性细胞毒性在正常组织中，胶质母细胞瘤诊断的预后仍然黯淡。拟议研究的目的是受到当前治疗方法治疗胶质母细胞瘤的局限性的动机，是开发一种热反应式响应的治疗性多肽，可以通过应用局部高热并抑制其生长来针对脑肿瘤部位。