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调节肿瘤的新型图像引导方法 HCC的微环境（TME），具有合并的机械疗法药物（MECHTX）和超声气蚀 治疗（USCTX），并评估其治疗功效。我们计划实施USCTX和目标 在临床扫描仪上监测合并的（使用机甲）治疗，以使其广泛使用 未来的临床前和临床研究。肝细胞癌（HCC）是与癌症有关的第三主要原因 全球死亡人数估计每年有75万例新病例。大多数不是候选人的HCC患者 为了手术去除或消融，用跨性化学栓塞或全身治疗 化学疗法。然而，这些治疗只会导致患者生存的改善有限 相当大的毒性。我们的主要假设是联合USCTX和MECHTX会导致肿瘤 压力，刚度和血管变化会促进全身或跨性别的局部肿瘤吸收增加 化学治疗药，并将带来更好的治疗结果。而发现新的化学治疗性 代理和介入程序将继续发展，我们通过合并调节TME的方法 MECHTX和USCTX旨在与现有和未来的化疗结果显着改善化学疗法 化学疗法剂。来自学术界的强大跨学科团队（生物工程师，科学家，临床医生） 行业将在以下目的中进行合作：（目标1）评估机器人调节肿瘤的能力 微环境并增强药物输送； （AIM 2）评估USCTX调节肿瘤的能力 微环境并增强药物输送； （AIM 3）评估合并MECHTX和USCTX的能力 调节肿瘤微环境并增强药物输送； （目标4）演示临床前 化学治疗剂与MechTX和USCTX在生存研究中使用两个体内的疗效 HCC的模型。该项目的创新是：（a）将MECHTX用作一种新型的治疗策略 调节TME的肿瘤压力，微血管流量和刚度； （b）实施图像引导的USCTX 在临床超声扫描仪上，可为HCC提供可翻译的精度药物； （c）利用 MechTX和USCTX是一种调节TME以最大化化学疗法的新颖而创新的方法 结果； （d）将超级分辨率和非线性多普勒处理结合到空间和临时 超级溶解靶向TME的治疗的肿瘤的脉管系统。拟议的项目将 利用MechTX和USCTX的独特但协同的机制作为一种新颖的范式 TME对化学疗法的敏化，从而提供更好的治疗结果和整体生存率 HCC患者最初是其他恶性肿瘤和疾病的患者。