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

摘要 该项目的目的是开发一种新的图像引导的方法来调节肿瘤 联合机械治疗药物（MechTx）和超声空化对HCC微环境（TME）的影响 治疗（USCTx），并评估其治疗效果。我们计划实施USCTx和目标定位， 在临床扫描仪上监测（与MechTx）联合治疗，以便广泛用于 未来的临床前和临床研究。肝细胞癌（HCC）是癌症相关的第三大原因。 全世界每年估计有750，000例新病例。大多数非候选人的HCC患者 对于手术切除或消融，采用经动脉化疗栓塞或全身化疗栓塞治疗 化疗然而，这些治疗仅在患者生存方面产生有限的改善， 相当大的毒性。我们的主要假设是USCTx和MechTx的组合将导致肿瘤 压力、僵硬度和血管变化，促进全身或经动脉局部肿瘤摄取增加 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 药物和介入手术将继续发展，我们调节TME的方法与联合 MechTx和USCTx旨在通过现有和未来的化疗来显著改善化疗结果 化疗药物。一个强大的跨学科团队（生物工程师，科学家，临床医生）来自学术界和 业界将在以下目标上进行合作：（目标1）评估MechTx调节肿瘤的能力 （2）评价USCTx调节肿瘤的能力 （目的3）评估组合的MechTx和USCTx的能力， 调节肿瘤微环境并增强药物递送;以及（目的4）证明临床前 在使用两种体内试验的生存研究中，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 在临床超声扫描仪上，导致HCC的可平移精确医学;（c）利用以下方面的协同作用： MechTx和USCTx是一种新型的创新方法，用于调节TME以最大限度地提高化疗效果 （d）结合超分辨率和非线性多普勒处理， 超分辨正在接受靶向TME的治疗的肿瘤的脉管系统。拟议项目将 利用MechTx和USCTx的独特但协同的机制作为一种新的范例， TME对化疗药物的敏感性，导致更好的治疗结果和总生存期， 最初是肝癌患者，将来是其他恶性肿瘤和疾病患者。

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.