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

• 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
• 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

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.

文摘

项目成果

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.