Surrogate imaging biomarkers for tracking anti-stromal therapy

用于追踪抗基质治疗的替代成像生物标志物

• 批准号: 9551768
• 负责人: Marvin M Doyley
• 金额: $ 44万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2019-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9551768
• 关键词: Ablation; Animal Model; Animals; Biology; Biopsy; Blood Pressure; Blood Vessels; Blood capillaries; Cancer Cell Growth; Cancer Model; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Data; Disease; Drug Delivery Systems; Drug Kinetics; Effectiveness; Enzymes; Extracellular Matrix; Fluorescence; Frequencies; Geometry; Growth; Histology; Human; Hyaluronic Acid; Hyaluronidase; Hybrids; Hypoxia; Image; Imaging Device; Imaging Techniques; Imaging technology; Immunotherapy; Institutional Review Boards; Intercellular Fluid; Investigational New Drug Application; Lateral; Left; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Methods; Modeling; Modulus; Molecular; Monitor; Mus; Oncologist; Operative Surgical Procedures; Optics; Oryctolagus cuniculus; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Performance; Perfusion; Pharmaceutical Preparations; Phase; Radiation therapy; Research; Research Personnel; Safety; Small Animal Imaging Systems; Solid; Sonic Hedgehog Pathway; Stress; Surrogate Markers; Survival Rate; System; Technology; Testing; Therapeutic; Time; Tissues; Tracer; Transgenic Organisms; Translating; Translational Research; Ultrasonic Transducer; Ultrasonic wave; Ultrasonography; United States; United States Food and Drug Administration; Vascular Permeabilities; Work; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; anticancer research; cancer cell; cell stroma; chemotherapy; contrast enhanced; cost; density; design; efficacy evaluation; efficacy study; elastography; imaging biomarker; improved; in vivo; interstitial; mechanical properties; molecular phenotype; mouse model; novel strategies; novel therapeutics; outcome forecast; pancreas xenograft; pancreatic neoplasm; pre-clinical; pressure; prevent; prototype; subcutaneous; targeted treatment; temporal measurement; therapy development; tomography; tool; tumor; tumor microenvironment; tumor progression; tumor xenograft

Pancreatic ductal adenocarcinoma (PDA) is a common and lethal disease, with a 5-year survival rate of less than 6%. The unique tumor microenvironment prevents the disease from being eradicated, even when surgery is combined with chemotherapy. Specifically, the absence of a functional vasculature and the build-up of dense stromal regions impede drug delivery. Consequently, several researchers are actively developing therapies to improve drug delivery. Besides improving drug delivery, we should also track cancer cell growth and other features of the tumor microenvironment. We hypothesize that information about changes in stromal stiffness, cancer cell growth, and drug delivery will help clinical researchers evaluate novel therapies that improves drug delivery, such as radiotherapy and immunotherapy or hyaluronic acid ablation. Since vascular imaging techniques (e.g., MRI and CT) cannot provide this data, we will develop an integrated system of shear wave ultrasound elastography (USE) and optical fluorescence tomography (OFT). We will conduct this work in two phases. In the first phase, we will develop the integrated USE/OFT system (Aim 1). This hybrid system will provide co-registered images of shear modulus, which is related to total tissue pressure and drug delivery. We will use three models (an orthotopic pancreas xenograft model, a transgenic spontaneous tumor model, and a murine pancreatic cancer model) to characterize and optimize the system's performance in vivo. The xenograft AsPC-1 model is well-controlled with 5-25% stromal content and low vascular space (< 0.5%) when grown in the pancreas. We will also use the transgenic murine model, which more closely recapitulates the molecular phenotype of human PDA to validate performance (Aim 2). The murine pancreatic model will be used to study the efficacy of different therapeutic approaches for improving drug delivery. In these studies, we will assess the sensitivity of the proposed system to changes in mechanical properties and vascular permeability during the growth phase of PDA, as well as during hyaluronidase enzymatic treatment of the extracellular matrix and combinational therapy (immuno-enhanced radiotherapy). In the second phase (Aim 3), we will (a) translate the USE and OFT technology to an endoscopic platform; and (b) conduct preliminary safety and efficacy evaluation in a rabbit model of pancreatic cancer to prepare for human use. This last aim will provide data required to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA), and for human use with the local Institutional Review Board (IRB) to monitor changes in tumor microenvironment during combinational therapies as assessed here pre-clinically. The proposed team includes expertise in elastography, ultrasound transducer design, OFT, PDA models, and human pancreatic cancer. Together this is an ideal group to translate the technology through the research phase and into an alpha commercial prototype for clinical trials.

胰腺导管腺癌（PDA）是一种常见的致死性疾病，5年生存率低于 超过6%。独特的肿瘤微环境阻止疾病被根除，即使手术 与化疗相结合。具体来说，功能性脉管系统的缺乏和致密血管的积聚 基质区阻碍药物递送。因此，一些研究人员正在积极开发治疗方法， 改善药物输送。除了改善药物输送，我们还应该跟踪癌细胞的生长和其他 肿瘤微环境的特征。我们假设基质硬度变化的信息， 癌细胞生长和药物输送将有助于临床研究人员评估新的治疗方法，改善药物 递送，如放射治疗和免疫治疗或透明质酸消融。自从血管成像 技术（例如，MRI和CT）不能提供这些数据，我们将开发一个集成的横波系统 超声弹性成像（USE）和光学荧光断层成像（OFT）。我们将分两个阶段进行这项工作 阶段。在第一阶段，我们将开发综合USE/OFT系统（目标1）。该混合动力系统将 提供剪切模量的共配准图像，其与总组织压力和药物递送相关。我们 将使用三种模型（原位胰腺异种移植模型、转基因自发肿瘤模型和 鼠胰腺癌模型）来表征和优化系统的体内性能。异种移植 AsPC-1模型控制良好，当生长在 胰腺我们还将使用转基因小鼠模型，它更接近地概括了分子生物学。 人PDA的表型，以验证性能（目的2）。小鼠胰腺模型将用于研究 不同治疗方法改善药物输送的功效。在这些研究中，我们将评估 所提出的系统对机械性能和血管渗透性变化的敏感性 PDA的生长期，以及在透明质酸酶酶处理细胞外基质期间， 联合治疗（免疫增强放射治疗）。在第二阶段（目标3），我们将（a） 将USE和OFT技术应用于内窥镜平台;以及（B）进行初步安全性和有效性研究 在胰腺癌的兔模型中进行评估以准备用于人。最后一个目标将提供数据 需要向美国食品药品监督管理局（FDA）提交研究性新药（IND）申请， 和供人使用，由当地机构审查委员会（IRB）监测肿瘤的变化 如本文临床前评估的，在组合治疗期间的微环境。拟议的小组包括 在弹性成像、超声换能器设计、OFT、PDA模型和人类胰腺癌方面的专业知识。 这是一个理想的团队，可以通过研究阶段将技术转化为alpha 用于临床试验的商业原型。

项目成果

Parallel Receive Beamforming Improves the Performance of Focused Transmit-Based Single-Track Location Shear Wave Elastography.

并行接收光束形成可改善集中的基于发射的单轨位置剪切波弹性弹力的性能。

• DOI: 10.1109/tuffc.2020.2998979
• 发表时间: 2020-10
• 期刊: IEEE transactions on ultrasonics, ferroelectrics, and frequency control
• 作者: Ahmed R;Doyley MM
• 通讯作者: Doyley MM

Shear Wave Elastography Can Differentiate between Radiation-Responsive and Non-responsive Pancreatic Tumors: An ex Vivo Study with Murine Models.

剪切波弹性成像可以区分辐射响应性和非响应性胰腺肿瘤：小鼠模型的离体研究。

• DOI: 10.1016/j.ultrasmedbio.2019.10.005
• 发表时间: 2020
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Wang,Hexuan;Mills,Bradley;Mislati,Reem;Ahmed,Rifat;Gerber,ScottA;Linehan,David;Doyley,MarvinM
• 通讯作者: Doyley,MarvinM