Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation

Abstract

Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…Widespread DCE investigations were used in the development of the combretastatins (CA4P and CA1P) as well as DMXAA and ZD6126) [ 5 , 27 , 37 , 96 , 97 , 100 , 102 , 103 , 104 , 106 , 117 , 124 , 125 , 126 , 127 , 128 , 131 , 132 , 135 , 136 , 137 , 138 , 219 , 220 , 221 ] and continue to be popular in pre-clinical development ( Table 3 ), since they may also be implemented readily in clinical trials ( Table 1 ). Examples of parametric images derived from DCE-MRI are presented in Figure 7 , where tumor heterogeneity is apparent at baseline, as well as in response to the novel vascular disrupting agent OXi6197, the phosphate prodrug of OXi6196 ( Figure 2 A) a dihydronaphthalene analog of combretastatin.…”

“…Acute vascular shutdown is the most obvious early effect revealed by MRI. Later effects may also be examined such as using diffusion-weighted imaging (DWI) to observe changes in cell structure, whereby diffusion is restricted in well-structured tissue, but becomes more mobile with necrosis, which occurs extensively within 24 h after VDA [ 98 , 102 , 104 , 117 , 219 , 222 ]. MR Elastography indicated reduction in tumor viscoelasticity 24 h after ZD6126 at which time no significant change in tumor apparent diffusion coefficient (ADC) was observed [ 228 ].…”

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…Acute vascular shutdown is the most obvious early effect revealed by MRI. Later effects may also be examined such as using diffusion-weighted imaging (DWI) to observe changes in cell structure, whereby diffusion is restricted in well-structured tissue, but becomes more mobile with necrosis, which occurs extensively within 24 hrs after VDA [98,102,104,116,211,214]. MR Elastography indicated reduction in tumor viscoelasticity 24 hrs after ZD6126 at which time no significant change in tumor apparent diffusion coefficient (ADC) was observed [220].…”

New Heterocyclic Combretastatin A-4 Analogs: Synthesis and Biological Activity of Styryl-2(3H)-benzothiazolones

“…Originally isolated from the bark of the South African willow tree Combretum caffrum [6], CA-4 is one of the most potent inhibitors of tubulin polymerization, which interferes with microtubule dynamics and perturbs the mitotic cycle [7,8]. CA-4 selectively inhibits tumor neovascularization, causing rapid vascular shutdown and tumor necrosis [9,10]. When administered in vivo, CA-4 causes disruption and collapse of tumor blood vessels and subsequent necrotic cell death of tumor cells due to the lack of oxygen and nutrients [11][12][13].…”