Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Abstract

Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulindestabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI‐microangiography‐histopathology in rats

“…Detecting early and transient tumor vascular changes upon VDA treatment, which occurs prior to later reduction in tumor size, requires functional imaging techniques. Multiparametric MRI can afford imaging biomarkers for clinical determination of therapeutic efficacies of antivascular therapies . Notably, both DWI and DCE‐MRI have been increasingly applied in clinical trials of CA4P to compare dynamic changes in tumor blood perfusion and permeability before and several hours after CA4P administration .…”

“…Multiparametric MRI can afford imaging biomarkers for clinical determination of therapeutic efficacies of antivascular therapies. 17 Notably, both DWI and DCE-MRI have been increasingly applied in clinical trials of CA4P to compare dynamic changes in tumor blood perfusion and permeability before and several hours after CA4P administration. [35][36][37][38][39] By the highly reproducible measurements such as ADC, K trans , IAUGC 90 , K ep and V e in multi-center trial setting, outcomes of CA4P therapy could be early predicted in patients.…”

“…In addition, as a noninvasive imaging technique, MRI enables monitoring therapeutic effects at different time points as frequently as every several minutes, hours or days. Moreover, MRI can also provide multiparametric functional information . For instance, by using the contrast agent gadoterate dimeglumine (Gd‐DOTA), dynamic contrast enhanced (DCE)‐MRI can help evaluate tumor vascular properties including blood flow, blood volume, vascular permeability and extravascular extracellular space; while apparent diffusion coefficients (ADCs) derived from diffusion‐weighted imaging (DWI) can help to distinguish VDA‐induced cytolytic necrosis from the residual viable tumor by changes in fluid diffusion and blood perfusion …”

“…Moreover, MRI can also provide multiparametric functional information. 17 For instance, by using the contrast agent gadoterate dimeglumine (Gd-DOTA), dynamic contrast enhanced (DCE)-MRI can help evaluate tumor vascular properties including blood flow, blood volume, vascular permeability and extravascular extracellular space; [18][19][20] while apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging (DWI) can help to distinguish VDA-induced cytolytic necrosis from the residual viable tumor by changes in fluid diffusion and blood perfusion. [21][22][23][24] In our study, we first hypothesized that good therapeutic responses of CA4P may occur in primary HCCs, since they are generally hypervascular, which may form ideal targets for CA4P to cause massive tumor necrosis.…”

Small Molecule Sequential Dual-Targeting Theragnostic Strategy (SMSDTTS): from Preclinical Experiments towards Possible Clinical Anticancer Applications

“…Following CA4P injection, the endothelium of tumoral capillary vessels is selectively targeted, which subsequently causes collapse and shutdown of tumor vasculature. Thereafter, tumor cells are deprived from major blood and oxygen supply, and hemorrhagic necrosis happens inside the tumor within minutes to hours after injection 14,17,85,86. However, few layers of viable tumor cells at the periphery always survive CA4P treatment, and eventually lead to tumor relapse.…”