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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
VEGFR2-Targeted Contrast-Enhanced Ultrasound to Distinguish between Two Anti-Angiogenic Treatments
Thomas Payen1, Alexandre Dizeux1, Capucine Baldini1
1Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.
Abstract:
The aim of this study was to evaluate the capacity of BR55, an ultrasound contrast agent specifically targeting vascular endothelial growth factor receptor 2 (VEGFR2), to distinguish the specific anti-VEGFR2 therapy effect of sunitinib from other anti-angiogenic effects of a therapy (imatinib) that does not directly inhibit VEGFR2. Sunitinib, imatinib and placebo were administered daily for 11 d (264 h) to 45 BalbC mice bearing ectopic CT26 murine colorectal carcinomas. During the course of therapy, B-mode ultrasound, contrast-enhanced ultrasound and VEGFR2-targeted contrast-enhanced ultrasound were performed to assess tumor morphology, vascularization and VEGFR2 expression, respectively. The angiogenic effects on these three aspects were characterized using tumor volume, contrast-enhanced area and differential targeted enhancement. Necrosis, microvasculature and expression of VEGFR2 were also determined by histology and immunostaining. B-Mode imaging revealed that tumor growth was significantly decreased in sunitinib-treated mice at day 11 (p < 0.05), whereas imatinib did not affect growth. Functional evaluation revealed that the contrast-enhanced area decreased significantly (p < 0.02) and by similar amounts under both anti-angiogenic treatments by day 8 (192 h): -23% for imatinib and -21% for sunitinib. No significant decrease was observed in the placebo group. Targeted contrast-enhanced imaging revealed lower differential targeted enhancement, that is, lower levels of VEGFR2 expression, in sunitinib-treated mice relative to placebo-treated mice from 24 h (p < 0.05) and relative to both placebo- and imatinib-treated mice from 48 h (p < 0.05). Histologic assessment of tumors after the final imaging indicated that necrotic area was significantly higher for the sunitinib group (21%) than for the placebo (8%, p < 0.001) and imatinib (11%, p < 0.05) groups. VEGFR2-targeted ultrasound was able to sensitively differentiate the anti-VEGFR2 effect from the reduced area of tumor with functional flow produced by both anti-angiogenic agents. BR55 molecular imaging was, thus, able both to detect early therapeutic response to sunitinib in CT26 tumors as soon as 24 h after the beginning of the treatment and to provide early discrimination (48 h) between tumor response during anti-angiogenic therapy targeting VEGFR2 expression and response during anti-angiogenic therapy not directly acting on this receptor.
Insights
BR55 ultrasound contrast agent successfully differentiated sunitinib's specific anti-VEGFR2 effects from imatinib's broader anti-angiogenic impact. This molecular imaging tool detects early therapeutic response and distinguishes targeted therapy effects in tumors.
Area of Science:
- Oncology
- Radiology
- Pharmacology
Background:
- Anti-angiogenic therapies are crucial in cancer treatment.
- Distinguishing specific drug mechanisms is vital for personalized medicine.
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) is a key target in anti-angiogenic therapy.
Purpose of the Study:
- To evaluate BR55, a VEGFR2-targeted ultrasound contrast agent, for its ability to differentiate sunitinib's specific anti-VEGFR2 effects from imatinib's non-VEGFR2-specific anti-angiogenic effects.
- To assess the early detection of therapeutic response using VEGFR2-targeted contrast-enhanced ultrasound.
Main Methods:
- BalbC mice bearing CT26 colorectal carcinomas received sunitinib, imatinib, or placebo for 11 days.
- B-mode ultrasound, contrast-enhanced ultrasound, and VEGFR2-targeted contrast-enhanced ultrasound were used to assess tumor morphology, vascularization, and VEGFR2 expression.
- Histology and immunostaining were performed to determine tumor necrosis and VEGFR2 expression.
Main Results:
- Sunitinib significantly decreased tumor growth, while imatinib did not.
- Both sunitinib and imatinib reduced contrast-enhanced area, indicating decreased vascularization.
- VEGFR2-targeted ultrasound showed significantly lower VEGFR2 expression in sunitinib-treated mice compared to placebo and imatinib groups from 24-48 hours.
- Histology confirmed higher necrosis in sunitinib-treated tumors.
Conclusions:
- BR55 molecular imaging can sensitively differentiate the specific anti-VEGFR2 effect of sunitinib from other anti-angiogenic effects.
- VEGFR2-targeted ultrasound provides early detection of therapeutic response (as early as 24 hours) and discrimination between targeted and non-targeted anti-angiogenic therapies (by 48 hours).
- BR55 demonstrates potential as a valuable tool for monitoring anti-VEGFR2 cancer therapy response.
