Engineering knotted peptide therapeutics for pediatric brain tumor patients

为儿童脑肿瘤患者设计打结肽疗法

• 批准号: 9897193
• 负责人: JAMES M OLSON
• 金额: $ 6.57万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897193
• 关键词: Address; Adult; Animals; Antibodies; Base of the Brain; Binding; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain Injuries; Brain Neoplasms; Cancer Etiology; Cancer Patient; Cancer Survivor; Cell membrane; Cells; Cessation of life; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Chlorotoxin; Clinical; Clinical Trials; Cranial Irradiation; Cysteine; Cytoplasm; Data; Disease; Elements; Engineering; Excision; Face; Fluorescent Dyes; Fostering; Foundations; Generations; Glioblastoma; Goals; Homing; Human; Image; Immunotherapy; Inflammatory; Ion Channel; Knowledge; Magnetic Resonance Imaging; Malignant Neoplasms; Medical; Medicine; Membrane Proteins; Mental Health; Microglia; Molecular; Mus; Nerve Degeneration; Neurocognitive; Neurofibromatosis 2; Oncogenic; Operative Surgical Procedures; Paint; Patients; Pediatric Neoplasm; Penetration; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Plants; Potassium Channel; Production; Property; Proteins; Radiation; Radiation induced damage; Radiation therapy; Research; Respiratory Burst; Scorpions; Signal Transduction; Specificity; Surgeon; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Tumor-Derived; Variant; Work; brain parenchyma; cancer cell; cancer imaging; chemotherapy; childhood cancer mortality; clinical candidate; clinical development; design; drug candidate; drug development; drug discovery; drug efficacy; fluorophore; improved; irradiation; medulloblastoma; neoplastic cell; novel; outcome forecast; peptide drug; pharmacophore; prevent; programs; protein protein interaction; side effect; small molecule therapeutics; success; therapeutic candidate; tumor

PROJECT ABSTRACT/SUMMARY Brain tumors cause more deaths in children than any other form of cancer. Most pediatric brain tumor patients receive surgery and radiation as key elements of treatment. To help surgeons maximally and safely remove brain tumors, we previously discovered and developed Tumor Paint, which delivers fluorescent signal to brain tumor cells in pediatric clinical trials. Chlorotoxin (CTX), the scorpion-derived tumor targeting peptide, crosses the blood brain barrier (BBB) and specifically binds to cancer cells. Because chlorotoxin can deliver fluorescent molecules to the cytoplasm of brain tumor cells, we hypothesized that it could carry therapeutic molecules as well. As we focus on developing therapeutic candidates that use CTX or CTX pharmacophores, it becomes essential to understand the mechanism of BBB penetration. In addition to work on CTX-based brain tumor therapies (e.g., delivery of chemotherapy or immunotherapy to brain tumors), we have made significant progress on a candidate drug that could potentially help every child who undergoes radiation therapy for brain tumors. Because brain irradiation causes severe and irreversible neurocognitive damage in children, we aspire to engineer a therapeutic agent that blocks the toxic respiratory burst of microglia in normal brain following radiation. Blockade of the Kv1.3 potassium ion channel on microglia has been shown to block radiation damage to normal brain in mice. We have engineered an optide (optimized peptide) that specifically blocks Kv1.3 but unfortunately does not, in its current form, cross the BBB. The gap in knowledge that we intend to address is that the mechanism by which CTX and some other optides penetrate the BBB is unknown. Because the Lys27 face of CTX is sterically hindered by a fluorophore in the Tumor Paint clinical candidate that crosses the BBB in children, we hypothesize that the pharmacophore responsible for BBB penetration lies on a different face than the face that contains Lys27. The key hurdle that prevents clinical development of an optide that blocks Kv1.3 to alleviate radiation-induced brain damage is that it does not cross the BBB and therefore fails to reach its target. We hypothesize that we can engineer the candidate Kv1.3 blocker in a manner that fosters BBB penetration. Our Specific Aims are: Aim 1: To identify the pharmacophore of chlorotoxin responsible for BBB penetration Aim 2: To identify the transporter responsible for optide penetration of the BBB Aim 3: To create an optide that has a therapeutic pharmacophore and a BBB-penetrating pharmacophore The significance of this work is that we will produce a clinical development candidate that could alleviate severe brain damage caused by irradiation in children. The foundational knowledge could be applied to a new generation of drugs for many brain disorders.

项目摘要/摘要 脑肿瘤在儿童中造成的死亡比任何其他形式的癌症都要多。大多数小儿脑肿瘤患者 接受手术和辐射作为治疗的关键要素。帮助外科医生最大，安全地去除 脑肿瘤，我们以前发现并开发了肿瘤油漆，该油漆向大脑传递荧光信号 小儿临床试验中的肿瘤细胞。藻毒素（CTX）是蝎子靶向肽的斑点肿瘤 血脑屏障（BBB）并专门与癌细胞结合。因为氯毒素可以输送荧光 分子到脑肿瘤细胞的细胞质，我们假设它可以携带治疗分子为 出色地。当我们专注于开发使用CTX或CTX药剂团的治疗候选者时，它变成了 了解BBB渗透的机制至关重要。 除了从事基于CTX的脑肿瘤疗法（例如，化学疗法或免疫疗法递送至 脑肿瘤），我们在候选药物上取得了重大进展，该药物有可能帮助每个孩子 他接受脑肿瘤的放射治疗。因为大脑照射会导致严重和不可逆 儿童的神经认知损害​​，我们渴望设计一种阻塞有毒呼吸系统的治疗剂 辐射后正常大脑中的小胶质细胞爆发。小胶质细胞上的KV1.3钾离子通道的封锁 已证明可以阻止小鼠正常脑的辐射损害。我们已经设计了一个Optide（优化 特异性阻断KV1.3但不幸的是，以其当前形式并没有穿越BBB。 我们打算解决的知识差距是CTX和其他一些OPTIDE的机制 穿透BBB是未知的。因为CTX的Lys27面在空间上被荧光团阻碍 肿瘤油漆临床候选者，跨越儿童BBB，我们假设药理 负责BBB穿透性的负责人与包含Lys27的面部不同。 阻止OPTIDE的临床开发的关键障碍，该OPTIDE阻止KV1.3减轻辐射诱导的 脑损伤是它不会越过BBB，因此无法达到其目标。我们假设我们 可以以促进BBB渗透的方式来设计候选KV1.3阻滞剂。 我们的具体目的是： 目标1：确定负责BBB穿透的氯毒素的药效算机 目标2：确定负责Optide渗透BBB的运输蛋白 AIM 3：创建具有治疗性药剂团和BBB渗透药效团的OPTIDE 这项工作的意义在于，我们将生产一个可以减轻的临床发展候选人 儿童辐照引起的严重脑损伤。基本知识可以应用于新的 许多脑部疾病的药物产生。