Abstract A222: Assessment of tumor response to therapy with the caspase-3/7 specific [18F]ICMT-11 PET imaging tracer

Abstract

Abstract Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific in vivo molecular imaging probes. We recently designed a library of isatin-5 sulfonamides and selected [18F]ICMT-11 for further evaluation on the basis of sub-nanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. We have demonstrated that [18F]ICMT-11 binds to a range of drug-induced apoptotic cancer cells in vitro and to 38C13 murine lymphoma xenografts in vivo by up to 2-fold at 24 h post-treatment compared to vehicle treatment. We further associated the increased signal intensity in tumors after drug treatment - detected by whole body in vivo microPET imaging - with increased apoptosis detected by immunohistochemistry, and have therefore characterized [18F]ICMT-11 as a caspase-3/7 specific PET imaging radiotracer for the assessment of tumor apoptosis that could find utility in anticancer drug development and the monitoring of early responses to therapy. In the present study, we have investigated the sensitivity of [18F]ICMT-11 compared to [18F]DG in a longitudinal experimental protocol where the same tumor bearing mouse is subjected to pre- ,24h and 48h post-cyclophosphamide treatment microPET imaging. The tumor volumes have been recorded throughout the study for comparison with PET generated data. [18F]ICMT-11 PET images and imaging variables were characterized by a weak baseline tumor uptake in pretreated animals, which increased after 24h cyclophosphamide treatment, then decreased at 48h posttreatment to levels greater than that of baseline (NUV60 = 0.05±0.01, 0.12±0.03 and 0.09±0.03 at pre-, 24h and 48h post-treatment, respectively). In contrast, [18F]DG PET images and imaging variables showed a high tumor uptake in pretreated animals, as expected, that decreased progressively at 24 and 48h posttreatment (NUV60=3.33±0.24, 1.95±0.16 and 1.26±0.10 at pre-, 24h and 48h post-treatment, respectively). The changes in [18F]ICMT-11 and [18F]DG uptake occurred in parallel with small reduction (94.3%±6.0 that of the pretreated mice tumor volumes) of the tumor volume at 24h posttreatment compared to pretreatment, and a more drastic shrinkage (29.9%±3.6 that of the pretreated mice tumor volumes) at 48h posttreatment. We showed that both [18F]ICMT-11 and [18F]DG PET can be use to monitor response to cyclophosphamide treatment in our longitudinal experimental model. At 24h and 48h posttreatment, [18F]ICMT-11 PET imaging detects increased tumor apoptosis and [18F]DG PET detects decreased tumor metabolic activity. At 24h posttreatment, the increased [18F]ICMT-11 and decreased [18F]DG PET tumor intensity signals are associated with only a small decrease in tumor volumes. In contrast, we observed a drastic tumor shrinkage at 48h posttreatment that was, however, associated with less tumor apoptosis detected by [18F]ICMT-11 and almost no tumor metabolic activity. It is possible that the early increase in tumor apoptosis (24 h) led to tumor shrinkage. Our future studies will investigate [18F]ICMT-11 PET imaging assessment of tumor response to therapy using a specific apoptosis targeting drug in the same longitudinal experimental model. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A222.