Theranostics for Pediatric Brain Cancer

小儿脑癌的治疗诊断学

基本信息

批准号：
10095690
负责人：
Heike Elizabeth Daldrup-Link
金额：
$ 67.68万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10095690
关键词：
Adult Affect Animals Apoptosis Binding Sites Biosensor Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Cell Death Cells Child Childhood Childhood Malignant Brain Tumor Cleaved cell Colchicine Data Development Diagnosis Diagnostic Disease Disease remission Dose Dose-Limiting Drug Delivery Systems Drug Monitoring Endothelial Cells Endothelium Enzymes FDA approved Fluorescein-5-isothiocyanate Fluorescence Microscopy Formulation Generations Glioblastoma Glioma Goals High Prevalence Horseradish Peroxidase Intravenous Label Lead Link Location MMP14 gene Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Mean Survival Times Measures Mediating Microtubules Mitosis Modeling Mus Nature Nutritional Organ Outcome Pediatric Neoplasm Peptide Hydrolases Perivascular Neoplasm Permeability Pharmaceutical Preparations Pharmacotherapy Placebos Positioning Attribute Problem Solving Prodrugs Prognosis Proteins Radiation Rattus Recurrence Research Site Starvation System Therapeutic Therapeutic Agents Therapeutic Effect Toxic effect Treatment Efficacy Tubulin Tumor Suppression Tumor Tissue Visceral antiangiogenesis therapy antitumor effect base cancer therapy cell killing clinical translation clinically translatable conventional therapy curative treatments cytotoxic density design improved improved outcome in vivo interest intravital microscopy iron oxide nanoparticle macromolecule nanocarrier nanoparticle neoplastic cell neuro-oncology novel novel drug class novel strategies novel therapeutics overexpression real time monitoring side effect success theranostics therapy resistant tumor tumor growth

项目摘要

THERANOSTICS FOR PEDIATRIC BRAIN CANCER Glioblastoma (GBM) is the most frequently diagnosed primary malignant brain tumor in children with median survival of less than one year. Disease recurrence is common and is caused by the presence of glioma-initiating cells (GICs) that are unreceptive to conventional therapies, underscoring the urgent need for new therapeutic options. We aim to develop a novel strategy to specifically disrupt the lifeline of GICs, without causing toxic effects to the normal brain. The highly vascularized nature of GBMs and the critical function of the perivascular niche for nutritional supply of GICs have spurred much interest in novel vascular-disruptive agents (VDAs). Intravenously administered VDAs easily reach GBM vessels and do not rely on the enhanced permeability and retention effect, which can limit the delivery of macromolecules to the tumor tissue. VDA-mediated blood vessel disruption causes efficient drug delivery to the GIC niche and starvation of many tumor cells. In contrast to classical anti-angiogenesis drugs, VDAs not only disrupt the tumor vasculature, but also cause significant GIC apoptosis through direct cytotoxic effects. While being highly effective for cancer treatment, initial VDA formulations also caused significant toxicity to the normal brain. This is particularly concerning for children, as the developing brain is more vulnerable to toxic side effects compared to the adult brain. To solve this problem, we developed novel VDA-loaded theranostic (combined therapeutic and diagnostic) nanoparticles, which are specifically activated in brain tumors by matrix metalloproteinases 14 (MMP-14). The normal brain does not express MMP-14 and therefore, does not activate the theranostic drug, thereby creating highly effective cancer therapy without side effects. The major goal of our project is to develop MMP-14-activatable theranostic nanoparticles (TNPs) for curative treatment of GBM, without causing toxicity to the normal brain. The approach relies on the high prevalence of MMP-14 in GBM, a proven MMP-14-activatable prodrug strategy, and a nanocarrier platform based on FDA-approved iron oxide nanoparticles. We hypothesize that our TNPs will be converted to an active therapeutic agent only within MMP-14-expressing tumors, releasing the therapeutic drug azademethylcolchicine and causing significant antitumor effects. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with magnetic resonance imaging (MRI). In aim 1, we will evaluate whether TNP dose and VDA payload affect VDA mediated vascular disruption, blood brain barrier (BBB) breakdown and cancer-specific toxicity. In aim 2, we will investigate the link between VDA-mediated tumor microvessel disruption, microvascular endothelial cell death and GIC death. TNPs hold the potential to substantially improving therapeutic efficacy whilst simultaneously reducing dose-limiting toxicities. Realizing our goal will uncover new targets and mechanisms for successful GBM therapy, eliminate or substantially reduce off-target toxicities and provide children with brain cancers with a much needed new treatment option.

小儿脑癌的治疗学胶质母细胞瘤（GBM）是儿童中最常诊断的原发性恶性脑肿瘤。生存期不足一年。疾病复发很常见，是由神经胶质瘤引发的存在引起的不接受传统疗法的细胞（GIC），强调了对新疗法的迫切需要选项。我们的目标是开发一种新颖的策略来专门破坏 GIC 的生命线，而不造成有毒物质对正常大脑的影响。 GBM 的高度血管化性质和血管周围的关键功能 GIC 的营养供应利基激发了人们对新型血管破坏剂 (VDA) 的浓厚兴趣。静脉注射 VDA 很容易到达 GBM 血管，并且不依赖于增强的渗透性和滞留效应，可以限制大分子向肿瘤组织的输送。 VDA介导的血管破坏导致药物有效输送到 GIC 生态位并导致许多肿瘤细胞饥饿。相比之下作为经典的抗血管生成药物，VDA 不仅会破坏肿瘤血管系统，还会引起显着的 GIC 通过直接的细胞毒作用而导致细胞凋亡。虽然初始 VDA 对癌症治疗非常有效，制剂还对正常大脑造成显着毒性。这对于儿童来说尤其令人担忧，因为与成人大脑相比，发育中的大脑更容易受到毒副作用的影响。为了解决这个问题，我们开发了新型负载 VDA 的治疗诊断（治疗和诊断相结合）纳米粒子，它们是在脑肿瘤中被基质金属蛋白酶 14 (MMP-14) 特异性激活。正常的大脑不会表达 MMP-14，因此不会激活治疗诊断药物，从而产生高效的癌症治疗无副作用。我们项目的主要目标是开发 MMP-14 可激活的治疗诊断剂纳米颗粒（TNP）用于治疗 GBM，不会对正常大脑造成毒性。这该方法依赖于 GBM 中 MMP-14 的高患病率，这是一种经过验证的 MMP-14 可激活前药策略，并且基于 FDA 批准的氧化铁纳米颗粒的纳米载体平台。我们假设我们的 TNP 将是仅在表达 MMP-14 的肿瘤内转化为活性治疗剂，释放治疗药物氮杂甲基秋水仙碱并引起显着的抗肿瘤作用。此外，我们假设氧化铁纳米颗粒部分将允许通过磁性实时监测肿瘤中的药物积累和定位磁共振成像（MRI）。在目标 1 中，我们将评估 TNP 剂量和 VDA 有效负载是否影响 VDA 介导的血管破坏、血脑屏障 (BBB) 破坏和癌症特异性毒性。在目标 2 中，我们将调查 VDA介导的肿瘤微血管破坏、微血管内皮细胞死亡和GIC之间的联系死亡。 TNPs 有潜力显着提高治疗效果，同时减少剂量限制性毒性。实现我们的目标将发现成功 GBM 治疗的新靶点和机制，消除或大幅减少脱靶毒性，并为患有脑癌的儿童提供急需的药物新的治疗选择。