Clinical translation of [¹⁸F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer.

Abstract

Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [¹⁸F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [¹⁸F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Breast tumour SUV_max of [¹⁸F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [¹⁸F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first-line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [¹⁸F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [¹⁸F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. This study highlights the potential use of [¹⁸F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.