Preclinical Activity of the Vascular Disrupting Agent OXi4503 against Head and Neck Cancer

Abstract

Vascular disrupting agents (VDAs) represent a relatively distinct class of agents that target established blood vessels in tumors. In this study, we examined the preclinical activity of the second-generation VDA OXi4503 against human head and neck squamous cell carcinoma (HNSCC). Studies were performed in subcutaneous and orthotopic FaDu-luc HNSCC xenografts established in immunodeficient mice. In the subcutaneous model, bioluminescence imaging (BLI) along with tumor growth measurements was performed to assess tumor response to therapy. In mice bearing orthotopic tumors, a dual modality imaging approach based on BLI and magnetic resonance imaging (MRI) was utilized. Correlative histologic assessment of tumors was performed to validate imaging data. Dynamic BLI revealed a marked reduction in radiance within a few hours of OXi4503 administration compared to baseline levels. However, this reduction was transient with vascular recovery observed at 24 h post treatment. A single injection of OXi4503 (40 mg/kg) resulted in a significant (p < 0.01) tumor growth inhibition of subcutaneous FaDu-luc xenografts. MRI revealed a significant reduction (p < 0.05) in volume of orthotopic tumors at 10 days post two doses of OXi4503 treatment. Corresponding histologic (H&E) sections of Oxi4503 treated tumors showed extensive areas of necrosis and hemorrhaging compared to untreated controls. To the best of our knowledge, this is the first report, on the activity of Oxi4503 against HNSCC. These results demonstrate the potential of tumor-VDAs in head and neck cancer. Further examination of the antivascular and antitumor activity of Oxi4503 against HNSCC alone and in combination with chemotherapy and radiation is warranted.

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

“…Optical techniques are subject to attenuation at depth due to absorption and scattering of light, and thus superficial tumors are most easily detected, specifically subcutaneous, or at disease sites near the surface such as mammary fat pad ( Figure 3 ). However, light can penetrate several millimeters and effective signal is observed by BLI in deeper tissues such as the lungs [ 187 , 193 , 194 , 195 ], prostate [ 196 , 197 , 198 ], brain [ 199 , 200 ], pancreas [ 201 , 202 ], liver [ 203 , 204 ], head and neck [ 114 ], bone [ 205 , 206 ] and kidney [ 138 , 207 ] in mice. The most common implementation of BLI in oncology is simply to relate signal intensity to tumor burden and indeed several studies have shown that there is a strong correlation for untreated control tumors up to about 2 cm 3 [ 89 , 208 ].…”

“…Some primary tumors effectively yield spontaneous metastases, which are readily observed, although the primary tumor may need to be masked for effective imaging due to relative signal intensities ( Figure 4 c,d). Dynamic BLI was initially applied to known VDAs to establish the technique, e.g., CA4P [ 209 ] ( Figure 3 and Figure 4 ), CA1P [ 114 ], DMXAA [ 134 , 210 ], BPR0L075 [ 129 ], and ATO [ 161 ]. It has also been validated by comparing changes in BLI signal against alternative technologies such as MRI [ 209 ], ultrasound [ 161 ], photoacoustics [ 92 ] and histology ( Figure 3 ), each of which has shown effectively correlated data.…”

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

“…Optical techniques are subject to attenuation at depth due to absorption and scattering of light, and thus superficial tumors are most easily detected, specifically subcutaneous, or at disease sites near the surface such as mammary fat pad (Figure 3). However, light can penetrate several millimeters and effective signal is observed by BLI in deeper tissues such as the lungs [180,[187][188][189], prostate [190][191][192], brain [193,194], pancreas [195,196], liver [197,198], head and neck [113], bone [199,200] and kidney [136,201] in mice. The most common implementation of BLI in oncology is simply to relate signal intensity to tumor burden and indeed several studies have shown that there is a strong correlation for untreated control tumors up to about 2 cm 3 [89,202].…”

“…Some primary tumors effectively yield spontaneous metastases, which are readily observed, although the primary tumor may need to be masked for effective imaging due to relative signal intensities (Figure 4c, d). Dynamic BLI was initially applied to known VDAs to establish the technique, e.g., CA4P [203] (Figures 3 & 4), CA1P [113], DMXAA [204], BPR0L075 [128], and ATO [171]. It has also been validated by comparing changes in BLI signal against alternative technologies such as MRI [203], ultrasound [171], photoacoustics [92] and histology (Figure 3), each of which has shown effectively correlated data.…”

Design, synthesis, and biological evaluation of 3′,4′,5′‐trimethoxy evodiamine derivatives as potential antitumor agents

“…Some microtubule targeting agents containing TMP structures have been found to inhibit microtubule polymerization and act as effective tumor‐VDAs against cancer. CA4P (Figure 1) (Liang et al, 2016; Quan et al, 2008; Zhang et al, 2013) and its similar OXi4503 (Bothwell et al, 2016), AVE8062 (Sessa et al, 2013), colchicine analog ZD6126 (LoRusso et al, 2008), BNC‐105 (Nowak et al, 2013), CKD‐516 (Lee et al, 2010) all have 3,4,5‐trimethoxyphenyl scaffold. As a pharmacophore of Tumor‐VDAs, Trimethoxyphenyl is retained as the necessary active part, and the bridge chain in the middle can be modified with amide bond, sulfonamide bond, and so on (Herdman et al, 2016; Nguyen et al, 2012; Yan et al, 2015).…”