The future of imaging: developing the tools for monitoring response to therapy in oncology: the 2009 Sir James MacKenzie Davidson Memorial lecture

Abstract

Since the days of Sir James MacKenzie Davidson, radiology discoveries have been shaping the way patients are managed. The lecture on which this review is based focused not on anatomical imaging, which already has a great impact on patient management, but on the molecular imaging of cancer targets and pathways. In this post-genomic era, we have several tools at our disposal to enable the discovery of new probes for stratifying patients for therapy and for monitoring response to therapy sooner than is possible using conventional cross-sectional imaging methods. I describe a chemical library approach to discovering new imaging agents, as well as novel methods for improving the metabolic stability of existing probes. Finally, I describe the evaluation of these probes for clinical use in both pre-clinical and clinical validation. The chemical library approach is exemplified by the discovery of isatin sulfonamide probes for imaging apoptosis in tumours. This approach allowed important desirable features of radiopharmaceuticals to be incorporated into the design strategy. A lead compound, [(18)F]ICMT11, is selectively taken up in vitro in cancer cells and in vivo in tumours undergoing apoptosis. Improvement of the metabolic stability of a probe is exemplified by work on [(18)F]fluoro-[1,2-(2)H(2)]choline ("[(18)F]-D4-choline"), a novel probe for imaging choline metabolism. Deuterium substitution significantly reduced the systemic metabolism of this compound relative to that of non-deuteriated analogues, supporting its future clinical use. In order for probes to be useful for monitoring response a number of validation and/or qualification studies need to be performed, including assessments of whether the probe measures the target or pathway of interest in a specific and reproducible manner, whether the probe is stable to metabolism in vivo, what is the best time to assess response with these probes and finally whether changes in radiotracer uptake are associated with clinical outcome. [(18)F]Fluorothymidine, a probe for proliferation imaging has been validated and qualified for use in breast cancer. In summary, the ability to create new molecules that can report on specific targets and pathways provides a strategy for studying response to treatment in cancer earlier than it is currently possible. This could fundamentally change the way medicine is practised in the next 5-10 years.

[18F]-SuPAR: A Radiofluorinated Probe for Noninvasive Imaging of DNA Damage-Dependent Poly(ADP-ribose) Polymerase Activity

“…Stable isotopes of copper ([ 63 Cu]) and fluorine ([ 19 F]) were utilized in vitro in order to hone the chemical library of potential probe candidates. 13 From the % automodification calculated for fluorinated, DOTA[Cu], fluorescent, and biotinylated probes (Figure 2), neither the fluorescent nor the biotinylated probes showed appreciable substrate activity by EMSA. A nonlinear relationship between the PEG linker length and substrate potential was discovered for PEG linkers ranging from zero to three PEG units (Figure 2B), with F-PEG 2 -NAD showing the highest substrate activity after native substrate (NAD).…”

“…10,11 Molecular imaging is a powerful tool for assessing a target biomarker noninvasively and longitudinally over the entire volume of the tumor. 12,13 A number of radiolabeled derivatives of PARP-1/2 inhibitors have been explored for imaging the expression of PARP-1/2 as companion diagnostics for PARP inhibitor therapy. 14−22 These imaging probes bind to PARP-1/ 2 and outcompete NAD for the catalytic site of the enzyme 5,23 (Figure 1C).…”

Policy Focus

“…However, measuring the activity of these molecules and overcoming the difficulty of target transiency can enable both the detection of disease prior to outward signs and symptoms, and the assessment of the success or failure of therapy prior to disease progression (Aboagye, 2006;Aboagye, 2010). Molecular imaging is a powerful tool for assessing a target biomolecular machine non-invasively and longitudinally over an entire volume of interest in living subjects (James & Gambhir, 2012).…”

Voxel-level mapping of tracer kinetics in PET studies: A statistical approach emphasizing tissue life tables

“…The use of PET for metabolic imaging of cancer and its response to therapy is of current clinical interest [Aboagye (2010), Krohn et al (2007) and Mankoff et al (2007)]. While PET-FDG imaging is an indicator of glucose metabolism, other aspects of cancer biology may also be useful.…”