Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy

Abstract

Noninvasive, real-time, quantitative measurement of key biomarkers associated with cancer therapeutic interventions could provide a better understanding of cancer biology. We investigated in this study whether incorporating multiple molecular imaging approaches could be used to guide dasatinib anti-Src therapy and aid in the rational design of a combination therapy regimen. Methods: Bioluminescence imaging, 18 F-FDG PET, integrin α v β 3 -targeted SPECT/ CT, and vascular endothelial growth factor-targeted near-infrared fluorescence imaging were performed before and after dasatinib treatment in a tumor mouse model. Results: There was no significant difference in the bioluminescence imaging signal or 18 F-FDG tumor uptake in dasatinib-treated tumors compared with the control tumors. However, the uptake of 99m T-3PRGD2 (integrin α v β 3 -specific) and DyLight755-ranibizumab (vascular endothelial growth factor-specific) in the dasatinib-treated tumors was significantly lower than that in the control tumors. In vitro studies confirmed the antiangiogenic effects of dasatinib but indicated a lack of cytotoxicity. Dasatinib plus cytotoxic docetaxel elicited marked synergistic tumor growth inhibition in vivo. Conclusion: Visualization of post-Src inhibition tumor signatures through multiple imaging approaches facilitates sensitive and quantitative measurement of cancer biomarkers in vivo, thus aiding in the rational design of dasatinib combination therapy.

Optimization of Early Response Monitoring and Prediction of Cancer Antiangiogenesis Therapy via Noninvasive PET Molecular Imaging Strategies of Multifactorial Bioparameters

“…In a new study, Gao et al reported that the Src inhibitor dasatinib reduced the uptake of 99m Tc-3PRGD2 in a dasatinib-resistant A549 human non-small cell lung cancer model 45 . They attributed this effect to the down-regulation of the host (murine) integrin β3 and the reduced RGD binding affinity for tumor (human) integrin α v β 3 because the expression of the tumor (human) integrin α v β 3 did not change according to the IHC assays.…”

“…Therefore, additional studies are necessary to investigate the interrelations between the uptake of RGD-based tracers and the integrins from host-guest origins following anti-cancer drug treatments, such as AAT. Furthermore, another question was raised for those two reports 18 , 45 whether RGD peptides alone could be sufficient enough to reflect tumor response to dasatinib therapy since dasatinib treatment lead to the uptake reduction of the radiolabeled RGD in both dasatinib-responsive U87MG tumor and dasatinib-resistant A549-fLuc tumor model. To strengthen the current study, a sunitinib-resistant tumor model is really necessary.…”

Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvβ6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition

“…The 4T1 murine breast cancer cell line was obtained from the American Type Culture Collection. Firefly luciferase stably transfected 4T1 (4T1-fLuc) cells were generated using a previously described method 22 . Cells were maintained in RPMI 1640 medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (FBS) at 37°C in humidified atmosphere containing 5% CO 2 .…”

Paradigms in Fluorescence Molecular Imaging: Maximizing Measurement of Biological Changes in Disease, Therapeutic Efficacy, and Toxicology/Safety

“…Other researchers have had similar findings, with Zhang and colleagues, in 2011 [34], using early time point imaging of AngioSense 750 to show that anti-VEGF treatment normalizes vascularity and decreases vascular leak. In a well-designed MIBA-2 study, Gao, et al [35] established that A549-luc tumor size, bioluminescence, and [ 18 F]FDG uptake were unaffected after 7 days of dasatinib treatment (Fig. 3, left panel).…”