VEGFR2-Targeted Three-Dimensional Ultrasound Imaging Can Predict Responses to Antiangiogenic Therapy in Preclinical Models of Colon Cancer

Abstract

Three-dimensional (3D) imaging capabilities to assess responses to anticancer therapies are needed to minimize sampling errors common to two-dimensional approaches as a result of spatial heterogeneity in tumors. Recently, the feasibility and reproducibility of 3D ultrasound molecular imaging (USMI) using contrast agents which target molecular markers has greatly improved, due to the development of clinical 3D matrix array transducers. Here we report preclinical proof of concept studies showing that 3DUSMI of VEGFR2/KDR expression accurately gauge longitudinal treatment responses to anti-angiogenesis therapy, in responding versus non-responding mouse models of colon cancer. Tumors in these models exhibited differential patterns of VEGFR2-targeted 3DUSMI signals during the course of anti-angiogenic treatment with bevacizumab. In responding tumors, the VEGFR2 signal decreased as soon as 24 hours after therapy was started, whereas in non-responding tumors there was no change in signal at any time point. The early decrease in VEGFR2 signal was highly predictive of treatment outcome at the end of therapy. Our results offer a preclinical proof that 3DUSMI can predict responses to anti-angiogenic therapy, warranting further investigation of its clinical translatability to predicting treatment outcomes in patients.

Early prediction of tumor response to bevacizumab treatment in murine colon cancer models using three-dimensional dynamic contrast-enhanced ultrasound imaging

“…A recent study has shown that both 3D ultrasound molecular imaging with clinical grade VEGFR2-targeted microbubbles and 3D DCE-US with FDA-approved non-targeted microbubbles could provide complementary molecular and functional in vivo information on antiangiogenic treatment effects [11]. Also, early changes in molecular ultrasound imaging signal was highly predictive of later treatment outcomes in another study in a mouse colon cancer xenograft model [33]. Our findings are complementary to these results and demonstrate for the first time that early decrease of PE and AUC values obtained by 3D DCE-US can be predictive of treatment response following several treatment administration cycles.…”

Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy

“…In recent years, several studies have demonstrated the ability of USMI to monitor disease response to anti-angiogenic therapy 48 - 53 . Furthermore, a few studies have demonstrated that USMI can predict response to therapy in different tumor models; Streeter et al found that USMI is capable of differentiating between patient-derived xenografts that respond to aurora-A kinase inhibition and non-responders earlier than tumor volume as an indicator 54 , and Sirsi et al and Wang et al demonstrated that USMI targeting VEGFR-2 can predict tumor response to anti-angiogenic therapy before there are measurable changes in tumor volume 55 , 56 . However, to our knowledge, all previous work has used group statistics to show the effectiveness of USMI to track disease progression, and while measuring differences in response to therapy between populations can provide valuable information for the overall treatment of disease, tracking and predicting response in individuals is more relevant for clinical translation.…”

Multimodal Genetic Approach for Molecular Imaging of Vasculature in a Mouse Model of Melanoma

“…Recent reports have shown promise for 3D CEU imaging of tumor vasculature [34–37]. Our results demonstrated a highly sensitive and versatile approach to study tumor vasculature that allows the use of several in vivo 2D and 3D imaging methods.…”