Dynamic ¹⁸F-FLT PET imaging of spatiotemporal changes in tumor cell proliferation and vasculature reveals the mechanistic actions of anti-angiogenic therapy

Abstract

Anti-angiogenic therapies target tumor vasculature and tumor cells, thus a concurrent assessment of these targets would lead to a greater understanding of therapeutic resistance and facilitate development of improved therapeutic strategies. We utilize dynamic 3'-deoxy-3'-F-fluorothymidine positron emission tomography (F-FLT PET) scanning to concurrently assess changes in tumor cell proliferation and vasculature during anti-angiogenic therapy, providing insight into how these therapies may be used effectively with combination chemotherapy. Thirty-three patients with advanced solid malignancies underwent treatment with vascular endothelial growth factor receptor inhibitor (VEGFR-TKI) axitinib on an intermittent schedule (two-weeks-on/one-week-off). Patients had up to three dynamic F-FLT PET/CT scans: at baseline, after two weeks of continuous VEGFR-TKI treatment, and following a one week treatment break.F-FLT kinetics were analyzed using a two-tissue compartment kinetic model. Kinetic parameters V and K were extracted to quantify changes in tumor vasculature and the F-FLT flux constant K was calculated to quantify changes in tumor cell proliferation. Two weeks of continuous axitinib exposure led to decreases in V (median -21%, P = 0.07), K (median -39%, P < 0.01), and K (median -37%, P< 0.01), corresponding to diminished tumor vasculature and cell proliferation that may antagonize treatment with concurrent chemotherapy. Axitinib treatment breaks led to significant increases in V (median +42%, P< 0.01), K (median +46%, P< 0.01), and K (median +39%, P< 0.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rho ⩽ -0.70, P < 0.01) were found between changes in tumor vasculature during axitinib exposure weeks and changes in tumor vasculature during treatment breaks. Imaging with dynamic F-FLT PET revealed new insights relating to the interplay of vascular and proliferative pharmacodynamics of axitinib therapy, facilitating a greater understanding of the mechanistic actions of VEGFR-TKIs. Increases in tumor vasculature and cell proliferation during VEGFR-TKI treatment breaks, suggests this period is an optimal time to schedule synergistic chemotherapy and warrants further investigation.

Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

“…The design and preparation of custom OP PET tracers was undertaken with the goal of examining: a) PK distributions, b) PD fates including the in vivo inactivation and labeling of AChE rich tissues, c) spatio-temporal imaging (Clarkson and Kupinski, 2009; Scarpelli et al, 2018) ( e.g ., Fig. 4) and, d) conducting challenge studies in which displacement or blocking of the OP tracer from AChE-rich regions could be observed and quantified.…”

Clinical value of 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography for diagnosis, staging and assessing therapy response in lung cancer

“…The assessment of pharmacodynamic endpoints is another extremely important function for [ 18 F]FLT. Scarpelli et al [38,39] demonstrated that the increase of [ 18 F] FLT uptake is apparently caused by the washout period during treatment. This type of study, which evaluates the pharmacodynamic endpoints, is of great importance to develop better understanding of drug resistance mechanisms, as it helps clinicians to tailor more effective treatments and to minimise systematic toxicity caused by ineffective drugs [38].…”

“…Multiple studies have found high potential of [ 18 F]FLT to predict LC response to targeted therapy. Yang et al analysed the prediction of response to anti-angiogenic [38,39]. In the static PET study, SUVmax was decreased −11% in cycle 1 treatment with the anti-angiogenic x-82.…”

“…After administration of cycle 2 x-82 combined with the chemotherapy docetaxel on day 21, SUVmax was greatly decreased to −44% (34). Decline of cell tumour proliferation and vasculature were also exhibited 2 weeks after treatment with axitinib followed by an increase in washout period during the week of treatment break [39]. Assessment of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) response with [ 18 F]FLT is also an active area of research.…”

Monitoring Response to Transarterial Chemoembolization in Hepatocellular Carcinoma Using 18F-Fluorothymidine PET

“…In line with our hypothesis, we report a significant reduction in K 1 following TACE, illustrating abrupt reduction in tissue perfusion. This is in sharp contrast with anti-angiogenic chemotherapy where an increase in the K 1 due to vessel normalization and reduced interstitial pressure can accompany response (27). Dynamic studies using 11C-acetate report a reduced K 1 in HCC lesions supplied by the hepatic artery compared with benign lesions supplied by the portal vein as the radiotracer concentration time-course is initially delayed in the portal vein as passes through the splanchnic circulation(28).…”