Evaluation of the impact of transient interruption of antiangiogenic treatment using ultrasound-based techniques in a murine model of hepatocellular carcinoma

Abstract

BackgroundDevelopment of escape pathways from antiangiogenic treatments was reported to be associated with enhanced tumor aggressiveness and rebound effect was suggested after treatment stop. Aim of the study was to evaluate tumor response simulating different conditions of administration of antiangiogenic treatment (transient or definitive treatment stop) in a mouse model of hepatocellular carcinoma.MethodsSubcutaneous tumors were created by inoculating 5×106 Huh7 cells into the right flank of 14 nude mice. When tumor size reached 5–10 mm, mice were divided in 3 groups: group 1 was treated with placebo, group 2 was treated with sorafenib (62 mg/kg via gavage) but temporarily suspended from day +5 to +9, whereas in group 3 sorafenib was definitively stopped at day +5. At day +13 all mice were sacrificed, collecting masses for Western-Blot analyses. Volume was calculated with B-mode ultrasonography at day 0, +5, +9, +11 and +13. VEGFR2-targeted contrast-enhanced ultrasound using BR55 (Bracco Imaging) was performed at day +5 and +13 and elastonosography (Esaote) at day +9 and +11 to assess tumor stiffness.ResultsMedian growth percentage delta at day +13 versus day 0 was 197% (115–329) in group 1, 81% (48–144) in group 2 and 111% (27–167) in group 3. Median growth delta at day +13 with respect to day +5 was 79% (48–127), 37% (−14128) and 81% (15–87) in groups 1, 2 and 3, respectively. Quantification of targeted-CEUS at day +13 showed higher values in group 3 (509 Arbitrary Units AI, range 293–652) than group 1 (275 AI, range 191–494) and group 2 (181 AI, range 63–318) (p = 0.033). Western-Blot analysis demonstrated higher VEGFR2 expression in group 3 with respect to group 1 and 2.ConclusionsA transient interruption of antiangiogenic treatment does not impede restoration of tumor response, while a definitive interruption tends to stimulate a rebound of angiogenesis to higher level than without treatment.

Combination of transcatheter arterial chemoembolization and interrupted dosing sorafenib improves patient survival in early–intermediate stage hepatocellular carcinoma

“…The optimal timing of sorafenib discontinuation remains under debate. [ 30 – 32 ] In a mouse model evaluating the impact of sorafenib discontinuation, [ 33 ] it was found that transient sorafenib interruption did not impede restoration of tumor response, but definitive sorafenib interruption tended to stimulate a rebound in angiogenesis to a higher level than if sorafenib treatment had never been given. In a retrospective cohort study of patients with advanced HCC, [ 31 ] where even radiologic PD had been confirmed, continuing with sorafenib therapy improved patient survival compared with sorafenib discontinuation.…”

A Lipopeptide-Based αvβ3 Integrin-Targeted Ultrasound Contrast Agent for Molecular Imaging of Tumor Angiogenesis

“…BR55, a VEGFR2-specific ultrasound contrast agent, was developed with a similar method and quickly entered clinical trials since its first publication . Numerous studies have reported the usefulness of BR55 as an ultrasound molecular probe in detecting early-stage tumors or liver dysplasia (Bzyl et al 2013;Grouls et al 2013;Sugimoto et al 2012;Tardy et al 2010), in functional diagnosis of differently aggressive breast cancers (Bzyl et al 2011) and in monitoring or evaluating anti-angiogenic cancer therapy (Marinelli et al 2014;Pysz et al 2010). The RGD peptides and mimics can be used to probe integrin functions in various biological systems.…”

VEGFR2-Targeted Contrast-Enhanced Ultrasound to Distinguish between Two Anti-Angiogenic Treatments

“…Studies have reported its specificity and capacity to assess VEGFR2 expression in vivo (BaronToaldo et al 2015;Marinelli et al 2014;Pochon et al 2010;Tardy et al 2010;Willmann et al 2008), as well as its ability to monitor anti-angiogenic treatments (BaronToaldo et al 2015;Marinelli et al 2014;Pysz et al 2010). Marinelli et al (2014) and BaronToaldo et al (2015) monitored sorafenib therapy in hepatocelular carcinoma models using BR55 and detected early changes in VEGFR2 expression. Pysz et al (2010) reported detection of the anti-VEGFR2 antibody blockade using BR55 in a human colon cancer xenograft model in mice.…”