A novel paradigm of sensitization of the tumor microenvironment with image-guided ultrasound cavitation and mechanotherapeutics for targeted HCC treatment

通过图像引导超声空化和机械治疗对肿瘤微环境进行敏化的新范例，用于靶向 HCC 治疗

• 批准号: 10683239
• 负责人: MICHALAKIS AVERKIOU
• 金额: $ 61.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683239
• 关键词: Ablation; Academia; Acute; Angiotensin Receptor; Animals; Antihypertensive Agents; BAY 54-9085; Biological Availability; Biomedical Engineering; Biophysical Process; Blood Vessels; Cancer Etiology; Cessation of life; Chemoembolization; Clinical; Clinical Research; Clinical Trials; Collaborations; Development; Diagnosis; Discipline; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Targeting; Effectiveness; Eligibility Determination; Excision; Future; Genetic Engineering; Goals; Hepatotoxicity; Industry; Knockout Mice; Liver; Losartan; Malignant Neoplasms; Mechanics; Mediating; Microbubbles; Modeling; Monitor; Nature; Oncology; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Primary carcinoma of the liver cells; Procedures; Property; Public Health; Research; Research Personnel; Resistance; Risk; Scientist; Systemic Therapy; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Transplantation; Treatment Efficacy; Treatment outcome; Work; advanced disease; cancer cell; cancer type; chemotherapeutic agent; chemotherapy; curative treatments; human model; image guided; improved; in vivo Model; innovation; interest; liver cancer model; mechanical properties; mouse model; novel; novel therapeutic intervention; precision medicine; preclinical efficacy; preclinical study; pressure; response; subcutaneous; synergism; systemic toxicity; therapy outcome; tumor; tumor microenvironment; ultra high resolution; ultrasound; uptake

ABSTRACT The purpose of this project is to develop a novel image-guided approach for modulating the tumor microenvironment (TME) of HCC with combined mechanotherapeutic drugs (MechTx) and ultrasound cavitation treatment (USCTx), and evaluate its therapeutic efficacy. We plan to implement USCTx and the targeting and monitoring of the combined (with MechTx) treatment on a clinical scanner in order to make it widely available for future preclinical and clinical studies. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide with an estimated 750,000 new cases per year. Most patients with HCC who are not candidates for surgical removal or ablation are treated with either transarterial chemoembolization or systemic chemotherapy. Yet these treatments result in only limited improvements in patient survival at the expense of considerable toxicities. Our main hypothesis is that the combined USCTx and MechTx will lead to tumor pressure, stiffness and vascular changes that promote increased local tumor uptake of systemic or transarterial chemotherapeutics, and will result in better therapy outcomes. While the discovery of new chemotherapeutic agents and interventional procedures will continue to evolve, our approach to modulate the TME with combined MechTx and USCTx aims to dramatically improve chemotherapy outcomes with both the existing and future chemotherapy agents. A strong interdisciplinary team (bioengineers, scientists, clinicians) from academia and industry will collaborate in the following aims: (Aim 1) Evaluate the ability of MechTx to modulate the tumor microenvironment and enhance drug delivery; (Aim 2) Evaluate the ability of USCTx to modulate the tumor microenvironment and enhance drug delivery; (Aim 3) Evaluate the ability of combined MechTx and USCTx to modulate the tumor microenvironment and enhance drug delivery; and (Aim 4) Demonstrate the preclinical efficacy of chemotherapeutics when combined with MechTx and USCTx in survival studies using two in vivo models of HCC. The innovation of the project is in: (a) the use of MechTx as a novel therapeutic strategy to modulate tumor pressure, microvascular flow, and stiffness of the TME; (b) implementing image-guided USCTx on a clinical ultrasound scanner leading to translatable precision medicine for HCC; (c) utilizing the synergy of MechTx and USCTx as a novel and innovative approach for modulating the TME to maximize chemotherapy outcomes; and (d) combining super resolution and nonlinear Doppler processing to spatially and temporarily super-resolve the vasculature of tumors undergoing treatments that target the TME. The proposed project will take advantage of the distinct, yet synergistic mechanisms of MechTx and USCTx as a novel paradigm of sensitization of the TME to chemotherapeutics, leading to better treatment outcomes and overall survival for HCC patients initially and patients of other malignancies and diseases in the future.

抽象的 该项目的目的是开发一种新颖的图像引导方法来调节肿瘤 联合机械治疗药物 (MechTx) 和超声空化作用的 HCC 微环境 (TME) 治疗（USCTx），并评估其治疗效果。我们计划实施 USCTx 以及目标和 在临床扫描仪上监测联合（与 MechTx）治疗，以使其广泛用于 未来的临床前和临床研究。肝细胞癌 (HCC) 是导致癌症相关疾病的第三大原因 全球每年估计有 750,000 例新病例死亡。大多数 HCC 患者不属于候选者 对于手术切除或消融，可采用经动脉化疗栓塞或全身治疗 化疗。然而，这些治疗只能有限地提高患者的生存率，但代价是 相当大的毒性。我们的主要假设是 USCTx 和 MechTx 相结合会导致肿瘤 压力、硬度和血管变化促进局部肿瘤对全身或经动脉的摄取增加 化疗，将带来更好的治疗效果。在发现新的化疗药物的同时 药剂和介入程序将继续发展，我们的方法结合组合来调节 TME MechTx 和 USCTx 旨在显着改善现有和未来的化疗结果 化疗药物。来自学术界和学术界的强大跨学科团队（生物工程师、科学家、临床医生） 业界将在以下目标上进行合作：（目标1）评估MechTx调节肿瘤的能力 微环境和增强药物输送； （目标2）评估USCTx调节肿瘤的能力 微环境和增强药物输送； （目标 3）评估 MechTx 和 USCTx 组合的能力 调节肿瘤微环境并增强药物输送； （目标 4）展示临床前 在使用两种体内药物的生存研究中，化疗药物与 MechTx 和 USCTx 联合使用时的疗效 HCC 模型。该项目的创新点在于：（a）使用MechTx作为一种新颖的治疗策略 调节肿瘤压力、微血管血流和 TME 的硬度； (b) 实施图像引导 USCTx 临床超声扫描仪为 HCC 提供可转化的精准医疗； (c) 利用协同作用 MechTx 和 USCTx 作为调节 TME 以最大化化疗的新颖和创新方法 结果； (d) 将超分辨率和非线性多普勒处理结合到空间和临时 超解析正在接受针对 TME 治疗的肿瘤的脉管系统。拟议的项目将 利用 MechTx 和 USCTx 独特但协同的机制作为一种新颖的范式 TME 对化疗药物的敏感性，从而带来更好的治疗结果和总体生存率 最初是肝癌患者，将来是其他恶性肿瘤和疾病的患者。