Development and preclinical evaluation of novel SPECT and PET tracers for cell death imaging
29 mei 2017
Antwerp University Hospital (UZA), Auditorium Kinsbergen (route 12) - Wilrijkstraat 10 - 2650 Edegem
Organisatie / co-organisatie:
Faculty of Medicine and Health Sciences
Filipe Rijo Mendes Martins Elvas
Prof S. Stroobants & Prof L. Wyffels
PhD defence Filipe Rijo Mendes Martins Elvas - Faculty of Medicine and Health Sciences
Molecular imaging of cell death is of considerable interest in oncology to provide an early indication of the efficacy of a given anticancer treatment, without the need of invasive biopsies. The induction of cell death is frequently accompanied by the exposure of phosphatidylethanolamine in the cell membrane and intracellular caspase-3 activation, which can be detected using selective in vivo single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging.
In this dissertation we aimed at developing and evaluating novel cell death imaging SPECT and PET agents that target phosphatidylethanolamine and caspase-3 activity, respectively, with the ultimate goal of validating their use for monitoring tumor response to therapy in preclinical models of colorectal cancer.
Duramycin is a phosphatidylethanolamine-binding peptide which has been labeled with 99mTc. We demonstrated favorable dosimetry and pharmacokinetics for purified [99mTc]duramycin in healthy mice. Furthermore, [99mTc]duramycin was evaluated for the early detection of chemotherapy, radiotherapy and targeted therapy-induced tumor cell death in mouse models of colorectal cancer. [99mTc]duramycin uptake in COLO205 xenografts was significantly increased (p<0.001) in mice treated with irinotecan and combination therapy (irinotecan + oxaliplatin). Blocking with unlabeled duramycin demonstrated specific binding of the radiotracer. After tumor irradiation with 4.5 Gy, [99mTc]duramycin uptake in tumors increased significantly (p<0.001). In conatumumab-sensitive COLO205 tumors, the uptake of [99mTc]duramycin was increased 7-fold from baseline in conatumumab- versus IgG1-treated control mice (p<0.001). No response was detected in treatment-resistant HT29 tumors. Radioactivity in the tumors positively correlated with immunohistochemical proof of apoptosis. The performance of [99mTc]duramycin in assessing early response to targeted therapy was also directly compared to the clinical gold standard PET probe for monitoring response to therapy in oncology, [18F]fluoro-2‑deoxy-D-glucose ([18F]FDG). Unlike [99mTc]duramycin, [18F]FDG was not able to differentiate tumors responding to targeted therapy from non-responding tumors. These results indicate that [99mTc]duramycin holds promise as SPECT tracer for early response evaluation and support the clinical translation of [99mTc]duramycin.
To specifically target another key hallmark of cell death, the activation of effector caspase-3, 18F-labeled activity-based probe [18F]MICA-302 was developed and evaluated as a PET radiotracer to monitor effector caspase activity. [18F]MICA-302 was able to detect caspase-3 activity in vitro as established by SDS-PAGE using recombinant human caspases, tumor cells lysates and tumor homogenates. [18F]MICA-302 exhibited high stability, and fast blood clearance with predominantly renal excretion in normal mice. This class of probes warrants further development and preclinical evaluation to assess their value for monitoring response to therapy.