Engineering knotted peptide therapeutics for pediatric brain tumor patients

为儿童脑肿瘤患者设计打结肽疗法

基本信息

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
项目类别：
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

项目摘要

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.