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/总结 脑肿瘤导致儿童死亡的人数比任何其他形式的癌症都多。大多数小儿脑肿瘤患者 接受手术和放疗作为治疗的关键要素。为了帮助外科医生最大限度地安全切除 脑肿瘤，我们以前发现并开发了肿瘤涂料，它提供荧光信号到大脑 肿瘤细胞在儿科临床试验中。蝎源性肿瘤靶向肽氯毒素（CTX） 血脑屏障（BBB），并特异性结合癌细胞。因为氯毒素可以释放荧光 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， 好.当我们专注于开发使用CTX或CTX药效团的治疗候选药物时， 这对于理解BBB穿透的机制至关重要。 除了研究基于CTX的脑肿瘤疗法（例如，化疗或免疫疗法的递送， 脑肿瘤），我们在一种可能帮助每一个孩子的候选药物上取得了重大进展 他因脑肿瘤接受放射治疗。因为脑部放射会导致严重的不可逆的 儿童神经认知损伤，我们渴望设计一种治疗剂， 辐射后正常大脑中的小胶质细胞爆发。小胶质细胞Kv1.3钾离子通道的阻断 已经被证明可以阻止辐射对小鼠正常大脑的损伤。我们设计了一个优化（优化 肽），其特异性阻断Kv1.3，但不幸的是，其目前的形式不能穿过BBB。 我们打算解决的知识上的差距是，CTX和其他一些优选药物 穿透血脑屏障是未知的。由于CTX的Lys 27面在空间上受到荧光团的阻碍， Tumor Paint临床候选药物，在儿童中穿过BBB，我们假设药效团 负责BBB渗透的蛋白位于与含有Lys 27的表面不同的表面上。 阻止阻断Kv1.3以减轻辐射诱导的放射性损伤的optide的临床开发的关键障碍 脑损伤的另一个重要原因是它不能穿过BBB，因此无法到达其目标。我们假设 可以以促进BBB渗透的方式设计候选Kv1.3阻滞剂。 我们的具体目标是： 目的1：确定负责BBB渗透的氯毒素药效团 目的2：确定负责optide穿透血脑屏障的转运蛋白 目的3：创建具有治疗药效团和BBB穿透药效团的肽 这项工作的意义在于，我们将产生一种临床开发候选药物， 儿童因辐射而造成的严重脑损伤。基础知识可以应用于一个新的 治疗许多脑部疾病的药物。