Bench to bedside: non-invasive treatment of tumors in children

从实验室到床边：儿童肿瘤的无创治疗

基本信息

批准号：
10221626
负责人：
AeRang Kim
金额：
$ 3.2万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221626
关键词：
Acute Address Adolescent and Young Adult Aftercare Age Animals Antitumor Response Area Benign Blood Cancer Patient Child Childhood Solid Neoplasm Clinical Clinical Protocols Clinical Trials Combined Modality Therapy Comparative Study DNA Repair Inhibition Deposition Devices Disease Dose Doxorubicin Drug Delivery Systems Drug Exposure Drug Extravasation Enrollment Evaluation Exposure to Extramural Activities Femoral vein Focused Ultrasound Therapy Formulation Future Goals Heat shock proteins Heating High temperature of physical object Hour Hyperthermia Immune Immune response Immunization Immunologic Markers Infusion procedures Injury Intervention Late Effects Limb structure Liposomal Doxorubicin Magnetic Resonance Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Measures Methods Microsomes Modality Modeling Morbidity - disease rate Mus Neoplasm Metastasis Nerve Nerve Tissue Neural Conduction Oncology Operative Surgical Procedures Oryctolagus cuniculus Patient-Focused Outcomes Patients Pediatric Neoplasm Pediatric Oncology Perfusion Permeability Pharmaceutical Preparations Phase I Clinical Trials Phase II Clinical Trials Physiologic pulse Pre-Clinical Model Precision therapeutics Prognosis Property Quality of life Radiation Randomized Recurrence Refractory Relapse Research Research Institute Resources Risk Rodent Safety Site Solid Neoplasm Structure System Systemic disease Technology Temperature Testing Time Tissues Toxic effect Tumor-Derived Ultrasonography United States National Institutes of Health Work antitumor effect base bench to bedside chemotherapy clinical application clinical center clinically relevant cold temperature cytotoxic design drug distribution femoral artery flexibility image guided immunogenic improved innovation local drug delivery mathematical model neurovascular pediatric patients phase I trial phase II trial pre-clinical preclinical study prevent response sciatic nerve screening side effect success treatment effect treatment optimization treatment trial tumor tumor growth tumor heterogeneity young adult

项目摘要

ABSTRACT Prognosis for children and young adults with metastatic, relapsed, or refractory solid tumors remains unacceptably poor and has not improved significantly over the past three decades despite multimodality treatment including surgery, radiation, and chemotherapy. Current approaches have reached the limits of maximal dose intensification, and the acute and late effects of combination therapy are substantial. The goal of this proposal is to improve the cure rate and quality of life in pediatric cancer patients through approaches that maximize effects of current therapy while minimizing associated complications. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) provides controlled delivery of heat through precise image guidance, real-time temperature mapping, and spatially well-defined deposition of energy using an external applicator that is completely non-invasive and non-ionizing. Lyso-thermosensitive liposomal doxorubicin (LTLD) is a heat-activated formulation of liposomal doxorubicin with the unique property of heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The flexibility and control over low temperature local heating induced by MR-HIFU provides an ideal system to be used in conjunction with LTLD. Mathematical modeling and studies in rodents demonstrated that overall exposure of targeted tissue to drug can be significantly enhanced by pulse of higher temperature heating (++) following drug release from LTLD triggered by MR-HIFU mild hyperthermia (40 – 45 °C, HT++). The heating pulse is thought to not only prevent drug washout, but also to target those parts of the tumor that may not be exposed to a sufficient quantity of drug. The synergistic effects of this therapy are manifold and include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high concentrations of doxorubicin in the targeted tumor, the expression of heat shock proteins, inhibition of DNA repair, and stimulation of immune responses. We propose to address the clinical challenges posed by advanced local disease through a robust bench to bedside proposal that combines the strengths of both the intramural and extramural teams. We will first evaluate the relative ability of this combination to improve the homogeneity and overall levels of drug delivery in preclinical rabbit Vx2 tumor model that is large enough to allow for precise spatial control of heating with MR-HIFU. We will evaluate the impact of LTLD combined with MR-HIFU mild hyperthermia and heating pulse on vasculature and nerve tissue function, its influence on host immune response and its impact on tumor growth delay and metastasis outside of treatment field in the same pre-clinical model. Following a comparative study of effects in the pre-clinical model, we will evaluate the safety and clinical benefit of LTLD-HT++ in Phase II clinical trial enrolling children and young adults with refractory solid tumors.

抽象的患有转移性、复发性或难治性实体瘤的儿童和年轻人的预后仍然存在尽管采用了多模态，但在过去的三十年里，情况仍差得令人无法接受，并且没有显着改善。治疗包括手术、放射和化疗。目前的方法已经达到了极限最大剂量强化以及联合治疗的急性和迟发效应是显着的。该提案旨在通过以下方法提高儿科癌症患者的治愈率和生活质量：最大限度地提高当前治疗的效果，同时最大限度地减少相关并发症。磁共振引导高强度聚焦超声 (MR-HIFU) 提供受控输送通过精确的图像引导、实时温度测绘和空间明确的沉积来加热使用完全非侵入性且非电离热敏的外部涂抹器提供能量。脂质体阿霉素（LTLD）是脂质体阿霉素的热激活制剂，具有独特的性质阿霉素的热激活释放，阿霉素是大多数儿科实体瘤的活性剂。对 MR-HIFU 引起的低温局部加热的控制提供了一个理想的系统，可用于与 LTLD 结合。数学建模和啮齿动物研究表明，总体暴露通过更高温度加热脉冲 (++) 可以显着增强靶向组织对药物的作用 MR-HIFU 温和热疗（40 – 45 °C，HT++）触发 LTLD 的药物释放加热脉冲为。人们认为不仅可以防止药物流失，还可以针对肿瘤中可能未暴露的部分这种疗法的协同作用是多方面的，包括增强。肿瘤脉管系统的渗透性、药物外渗增强以及随后的高浓度阿霉素在靶肿瘤中的作用、热休克蛋白的表达、DNA修复的抑制以及刺激免疫反应。我们建议通过一个强大的平台来解决晚期局部疾病带来的临床挑战我们将首先结合校内和校外团队的优势提出床边提案。评估该组合提高药物输送均匀性和整体水平的相对能力在临床前兔 Vx2 肿瘤模型中，该模型足够大，可以精确地空间控制加热我们将评估 LTLD 与 MR-HIFU 轻度热疗和加热脉冲相结合的影响。对脉管系统和神经组织功能、对宿主免疫反应的影响及其对肿瘤的影响相同临床前模型中的生长延迟和治疗范围外的转移。通过临床前模型的效果研究，我们将在阶段性评估 LTLD-HT++ 的安全性和临床效益 II 临床试验招募患有难治性实体瘤的儿童和年轻成人。

项目成果

期刊论文数量（2）

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 collaborative computer aided diagnosis (C-CAD) system with eye-tracking, sparse attentional model, and deep learning.

DOI：
10.1016/j.media.2018.10.010
发表时间：
2019-01
期刊：
Medical image analysis
影响因子：
10.9
作者：
Khosravan N;Celik H;Turkbey B;Jones EC;Wood B;Bagci U
通讯作者：
Bagci U

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

DOI：
10.1158/1078-0432.ccr-19-1604
发表时间：
2020-03-01
期刊：
CLINICAL CANCER RESEARCH
影响因子：
11.5
作者：
Eranki, Avinash;Srinivasan, Priya;Ries, Mario;Kim, AeRang;Lazarski, Christopher A.;Rossi, Christopher T.;Khokhlova, Tatiana D.;Wilson, Emmanuel;Knoblach, Susan M.;Sharma, Karun, V;Wood, Bradford J.;Moonen, Chrit;Sandler, Anthony D.;Kim, Peter C. W.
通讯作者：
Kim, Peter C. W.