mmpc-logo mmpc-logo
twitter-logo    bluesky-logo
| Create Account | login
Publication
Ultrasound Molecular Imaging of VEGFR-2 in Clear-Cell Renal Cell Carcinoma
Tracks Disease Response to Antiangiogenic and Notch-Inhibition Therapy.
Authors Rojas JD, Lin F, Chiang YC, Chytil A, Chong DC, Bautch VL, Rathmell WK, Dayton
PA
Submitted By Submitted Externally on 1/25/2018
Status Published
Journal Theranostics
Year 2018
Date Published
Volume : Pages 8 : 141 - 155
PubMed Reference 29290798
Abstract Metastatic clear-cell renal cell carcinoma (ccRCC) affects thousands of patients
worldwide each year. Antiangiogenic therapy has been shown to have beneficial
effects initially, but resistance is eventually developed. Therefore, it is
important to accurately track the response of cancer to different therapeutics
in order to appropriately adjust the therapy to maximize efficacy. Change in
tumor volume is the current gold standard for determining efficacy of treatment.
However, functional variations can occur much earlier than measurable volume
changes. Contrast-enhanced ultrasound (CEUS) is an important tool for assessing
tumor progression and response to therapy, since it can monitor functional
changes in the physiology. In this study, we demonstrate how ultrasound
molecular imaging (USMI) can accurately track the evolution of the disease and
molecular response to treatment. Methods A cohort of NSG (NOD/scid/gamma) mice
was injected with ccRCC cells and treated with either the VEGF inhibitor SU
(Sunitinib malate, Selleckchem, TX, USA) or the Notch pathway inhibitor GSI
(Gamma secretase inhibitor, PF-03084014, Pfizer, New York, NY, USA), or started
on SU and later switched to GSI (Switch group). The therapies used in the study
focus on disrupting angiogenesis and proper vessel development. SU inhibits
signaling of vascular endothelial growth factor (VEGF), which is responsible for
the sprouting of new vasculature, and GSI inhibits the Notch pathway, which is a
key factor in the correct maturation of newly formed vasculature. Microbubble
contrast agents targeted to VEGFR-2 (VEGF Receptor) were delivered as a bolus,
and the bound agents were imaged in 3D after the free-flowing contrast was
cleared from the body. Additionally, the tumors were harvested at the end of the
study and stained for CD31. Results The results show that MI can detect changes
in VEGFR-2 expression in the group treated with SU within a week of the start of
treatment, while differences in volume only become apparent after the mice have
been treated for three weeks. Furthermore, USMI can detect response to therapy
in 92% of cases after 1 week of treatment, while the detection rate is only 40%
for volume measurements. The amount of targeting for the GSI and Control groups
was high throughout the duration of the study, while that of the SU and Switch
groups remained low. However, the amount of targeting in the Switch group
increased to levels similar to those of the Control group after the treatment
was switched to GSI. CD31 staining indicates significantly lower levels of
patent vasculature for the SU group compared to the Control and GSI groups.
Therefore, the results parallel the expected physiological changes in the tumor,
since GSI promotes angiogenesis through the VEGF pathway, while SU inhibits it.
Conclusion This study demonstrates that MI can track disease progression and
assess functional changes in tumors before changes in volume are apparent, and
thus, CEUS can be a valuable tool for assessing response to therapy in disease.
Future work is required to determine whether levels of VEGFR-2 targeting
correlate with eventual survival outcomes.




Back to Top

Menu

Home
Contact
About MMPC
Animal Husbandry
Tests Data
Search Data
Analysis
Clients
MMPC Centers

Newsletter

Interested in receiving MMPC News?
twitter-logo Mouse Phenotyping
@NationalMMPC


2017 National MMPC. All Rights Reserved.