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: 10083110
• 负责人: JAMES M OLSON
• 金额: $ 79万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-12 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083110
• 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; Prognosis; 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; blood-brain barrier penetration; brain parenchyma; brain tumor imaging; cancer cell; chemotherapy; childhood cancer mortality; clinical candidate; clinical development; design; drug candidate; drug development; drug discovery; drug efficacy; fluorophore; improved; irradiation; medulloblastoma; neoplastic cell; novel; peptide drug; pharmacophore; prevent; programs; protein protein interaction; side effect; small molecule therapeutics; success; therapeutic candidate; tumor

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.

脑肿瘤导致的儿童死亡人数比任何其他形式的癌症都要多。大多数儿童脑肿瘤患者 接受手术和放射作为治疗的关键要素。帮助外科医生最大限度地、安全地切除 脑肿瘤，我们之前发现并开发了肿瘤涂料，它可以向大脑传递荧光信号 儿科临床试验中的肿瘤细胞。氯毒素 (CTX) 是一种源自蝎子的肿瘤靶向肽，可与 血脑屏障（BBB）并与癌细胞特异性结合。因为氯毒素可以发出荧光 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 出色地。当我们专注于开发使用 CTX 或 CTX 药效团的治疗候选药物时，它就变成了 了解 BBB 穿透机制至关重要。 除了致力于基于 CTX 的脑肿瘤疗法（例如，向患者提供化疗或免疫疗法） 脑肿瘤），我们在候选药物方面取得了重大进展，可能会帮助每个孩子 接受脑肿瘤放射治疗的人。因为脑部照射会造成严重且不可逆转的 儿童神经认知损伤，我们渴望设计一种治疗剂来阻止有毒呼吸道疾病 辐射后正常大脑中小胶质细胞的爆发。阻断小胶质细胞上的 Kv1.3 钾离子通道 已被证明可以阻止对小鼠正常大脑的辐射损伤。我们设计了一个 optide（优化 肽）特异性阻断 Kv1.3，但不幸的是，以其目前的形式无法穿过 BBB。 我们打算解决的知识差距是 CTX 和其他一些选择的机制 穿透 BBB 未知。因为 CTX 的 Lys27 面受到荧光团的空间位阻 肿瘤油漆跨越儿童血脑屏障的临床候选药物，我们假设药效团 负责 BBB 渗透的面与包含 Lys27 的面不同。 阻碍 Kv1.3 缓解辐射诱导的 optide 临床开发的关键障碍 脑损伤是它无法穿过血脑屏障，因此无法到达目标。我们假设我们 可以以促进 BBB 渗透的方式设计候选 Kv1.3 阻断剂。 我们的具体目标是： 目标 1：确定负责血脑屏障渗透的氯毒素药效团 目标 2：确定负责选择性渗透 BBB 的转运蛋白 目标 3：创建一种具有治疗药效团和 BBB 穿透药效团的 optide 这项工作的意义在于我们将产生一种临床开发候选药物，可以缓解 儿童受到辐射造成的严重脑损伤。基础知识可以应用到新的领域 产生治疗许多脑部疾病的药物。