Engineering Knotted Peptide Therapeutics for Pediatric Brain Tumor Patients

针对小儿脑肿瘤患者的工程打结肽治疗

基本信息

批准号：
10531428
负责人：
JAMES M OLSON
金额：
$ 64.47万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531428
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

项目摘要

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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A potent peptide-steroid conjugate accumulates in cartilage and reverses arthritis without evidence of systemic corticosteroid exposure.

一种有效的肽-类固醇缀合物在软骨中积聚并逆转关节炎，而无需全身皮质类固醇暴露的证据。

DOI：
发表时间：
2020
期刊：
影响因子：
17.1
作者：
Cook Sangar, Michelle L;Girard, Emily J;Hopping, Gene;Yin, Chunfeng;Pakiam, Fiona;Brusniak, Mi;Nguyen, Elizabeth;Ruff, Raymond;Gewe, Mesfin M;Byrnes;Nairn, Natalie W;Miller, Dennis M;Mehlin, Christopher;Strand, Andrew D;Mhy
通讯作者：
Mhy

A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.

TfR 结合胱氨酸致密肽促进生物活性分子穿透血脑屏障。

DOI：
发表时间：
2020-06-26
期刊：
影响因子：
5.6
作者：
Crook ZR;Girard E;Sevilla GP;Merrill M;Friend D;Rupert PB;Pakiam F;Nguyen E;Yin C;Ruff RO;Hopping G;Strand AD;Finton KAK;Coxon M;Mhyre AJ;Strong RK;Olson JM
通讯作者：
Olson JM

Miniproteins as a Powerful Modality in Drug Development.

微蛋白作为药物开发的强大方式。

DOI：
10.1016/j.tibs.2019.12.008
发表时间：
2020-01-31
期刊：
Trends in biochemical sciences
影响因子：
13.8
作者：
Zachary R. Crook;Natalie W. Nairn;J. Olson
通讯作者：
J. Olson

Publisher Correction: Mammalian display screening of diverse cystine-dense peptides for difficult to drug targets.

出版商更正：哺乳动物展示筛选多种胱氨酸致密肽，以寻找难以用药的靶点。

DOI：
发表时间：
2018
期刊：
影响因子：
16.6
作者：
Crook, Zachary R;Sevilla, Gregory P;Friend, Della;Brusniak, Mi;Bandaranayake, Ashok D;Clarke, Midori;Gewe, Mesfin;Mhyre, Andrew J;Baker, David;Strong, Roland K;Bradley, Philip;Olson, James M
通讯作者：
Olson, James M