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

摘要 本项目的目的是开发一种新的图像引导方法来调节肿瘤。 机械治疗药物(MechTx)联合超声空化对肝细胞癌微环境的影响 治疗(USCTx)，并评价其疗效。我们计划实施USCTx和目标和 在临床扫描仪上监测联合(与MechTx)治疗，以使其广泛适用于 未来的临床前和临床研究。肝细胞癌是与癌症相关的第三大病因。 据估计，全球每年新增病例约为75万例。大多数不是候选人的肝细胞癌患者 对于外科手术切除或消融，采用经动脉化疗栓塞术或全身化疗 化疗。然而，这些治疗只能有限地改善患者的存活率，而代价是 相当大的毒性。我们的主要假设是联合使用USCTx和MechTx会导致肿瘤 压力、僵硬和血管改变促进局部肿瘤全身或经动脉摄取增加 化疗药物，并将导致更好的治疗结果。虽然新的化疗药物的发现 药剂和介入程序将继续发展，我们的方法来调节TME与联合 MechTx和USCTx的目标是大幅改善现有和未来的化疗结果 化疗药物。一支强大的跨学科团队(生物工程师、科学家、临床医生)来自学术界和 业界将在以下目标方面进行合作：(目标1)评估MechTx调节肿瘤的能力 (目的2)评价USCTx对肿瘤的调节能力 微环境和加强药物传递；(目标3)评价联合使用MechTx和USCTx的能力 调节肿瘤微环境和加强药物输送；以及(目标4)展示临床前 化疗药物联合MechTx和USCTx在两种活体生存研究中的疗效 肝细胞癌模型。该项目的创新之处在于：(A)使用MechTx作为一种新的治疗策略 调节肿瘤压力、微血管流量和TME的硬度；(B)实施图像引导的USCTx 关于临床超声扫描仪，导致可翻译的肝细胞癌精确药物；(C)利用 MechTx和USCTx作为调节TME以最大化化疗的新颖和创新方法 结果；和(D)结合超分辨率和非线性多普勒处理在空间和临时 超分辨肿瘤的血管系统正在接受靶向TME的治疗。拟议的项目将 利用MechTx和USCTx不同而又协同的机制作为一种新的 TME对化疗药物的敏感性，导致更好的治疗结果和总存活率 最初是肝癌患者，将来是其他恶性肿瘤和疾病的患者。

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.