ReviewKeynotePET, MRI, and simultaneous PET/MRI in the development of diagnostic and therapeutic strategies for glioma
Graphical abstract
Introduction
Glioma is the most commonly occurring primary brain tumour, signified by its invasive potential and increased capacity for proliferation [1]. Despite continuing advances in imaging, neurosurgical and radiation therapy techniques, prognosis remains poor, with a median survival of only 12–18 months 2, 3, 4, 5. The development of novel treatment strategies is integral to overcoming the significant challenge of improving the survival rate for patients with glioma. Ever since the proposal of a ‘magic bullet’ by Paul Erlich [6], the drug discovery process has been heavily focussed on delivering therapy directly to the site of disease. A plethora of molecules have been recruited to the cause, with many shown to have high specificity to a particular target. Biomacromolecules derived from nature have shown particular success and there is a wealth of literature surrounding the use of monoclonal antibodies, fragments of monoclonal antibodies, small chain variable fragments, and peptide or oligonucleic acid aptamers as targeted therapeutics. By conjugation to appropriate moieties, these highly specific molecules can be effectively transformed to target recognised pathways driving cancer 7, 8.
Molecular-imaging techniques have been integral to the development of advanced therapeutics in two major capacities. First, by labelling potential therapeutics with imaging modalities, such as optical dyes, positron-emitting atoms or contrast-enhancing molecules for computerised tomography (CT; high X-ray cross-section materials) or MRI (paramagnetic materials), researchers can validate the specificity of a potential therapeutic in vivo by imaging the biodistribution of the material directly. This enables an informed development process where the effects of small, systematic changes to the material on the specificity of delivery can be monitored. Second, by directly imaging diagnostic biomarkers of cancer, the efficacy of therapy can be followed during the treatment process. The potential power of combination therapy in cancer has long been recognised [9] and, as such, a complimentary approach to imaging, multimodal imaging, offers particular power in drug discovery. By combining two imaging modalities, multiple factors relating to the efficacy of a therapeutic platform or multiple therapeutic platforms can be imaged simultaneously. The fusion of two key imaging technologies for drug discovery, PET and MRI, has recently been realised on both the clinical and preclinical scale. Here, we focus on the impact of preclinical PET, MRI, and their simultaneous acquisition on the development of novel therapeutic and diagnostic strategies for glioma.
Section snippets
PET in glioma
The use of nuclear imaging for oncology-related drug development has continued to grow, primarily because the information provided is distinctly different to that available through other imaging techniques, such as MRI and CT. The nuclear-imaging techniques of single photon emission computed tomography (SPECT) and PET are intrinsically molecular-imaging techniques because the gamma photon that is detected originates from a point source. As such, with judicious choice of tracer, both techniques
Conventional MRI
MRI is currently the gold standard in glioma imaging, providing a variety of high-resolution anatomical and functional information for diagnosis and treatment planning. Conventional MRI sequences [T2-weighted spin echo (SE) and T1-weighted gradient echo (GE) and variations thereof] offer greater contrast between grey matter, white matter, and cerebral spinal fluid compared with CT, enabling delineation of structures within the brain (Fig. 2).
This facilitates the analysis of the anatomical
PET/MRI in glioma
PET/MRI combines two extremely flexible and powerful imaging modalities. PET has the advantages of high sensitivity and numerous biologically relevant tracers with a drawback of low spatial and temporal resolution. MRI offers not only high spatial and temporal resolution to compliment PET but, as outlined above, also has a broad diversity of acquisition protocols that provide different soft tissue contrasts and highly functional information. The development of multimodal imaging systems is
Concluding remarks
The examples presented here illustrate the broad potential for combined PET/MRI in preclinical glioma research. The particular strength of simultaneous acquisition in PET/MRI has been highlighted. Ultimately, the inclusion of PET/MRI as an imaging modality in drug development for glioma will rely on proven evidence of benefit. However, it is becoming more evident that the ability to image multiple aspects of the cancer process in a temporally connected way has significant potential to develop
Acknowledgements
We thank the team at RAPID PET laboratories, Sir Charles Gairdner Hospital, Perth, WA, Australia for production of 64Cu. We thank the team at Queensland PET, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia for the production of 18F-FDOPA and the Australian National Imaging Facility for instrument access. This work was supported by the Australian National Health and Medical Research Council (APP1021759).
Simon Puttick is a research fellow at the Australian Institute for Bioengineering and Nanotechnology at the University of Queensland. He is currently developing polymeric bionanoconjugates as targeted theranostic agents and new simultaneous PET/MRI strategies for improved diagnosis and treatment planning in oncology. His particular research interest lies in combining parametric MRI methods with novel PET acquisition methods to probe the distribution of potential therapeutic platforms with
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Simon Puttick is a research fellow at the Australian Institute for Bioengineering and Nanotechnology at the University of Queensland. He is currently developing polymeric bionanoconjugates as targeted theranostic agents and new simultaneous PET/MRI strategies for improved diagnosis and treatment planning in oncology. His particular research interest lies in combining parametric MRI methods with novel PET acquisition methods to probe the distribution of potential therapeutic platforms with respect to diagnostic biomarkers in cancer.
Christopher M. Bell is a PhD student in medical imaging at the University of Queensland in Australia. He obtained his bachelor degrees in computer software architecture and physics in 2012, graduating from the Queensland University of Technology with distinctions. During this time, he obtained numerous scholarships to investigate the biophysics of articular cartilage. He began his PhD in 2013 in partnership with the Australian e-Health Research Centre of CSIRO in Brisbane, Australia, focussing on glioma, obtaining multiple scholarships, including the prestigious Australian Postgraduate Award.
Nicholas Dowson Before joining the CSIRO in Australia, Nicholas Dowson worked at Siemens Molecular Imaging in the UK. His current interests are in developing registration and kinetic analysis algorithms to extract information from medical images to assist clinical decision-making and improve outcomes for patients, with a particular focus on PET and oncology. He has a PhD from the University of Surrey.
Stephen Rose is a science leader within the CSIRO–Digital Productivity Flagship, one of the leading Australian biomedical image analysis laboratories. He is also acting director of the newly established Herston Imaging Research Faculty (HIRF) in Queensland, Australia. Stephen is currently developing novel MRI and PET molecular imaging platforms in several neuroimaging research programs in oncology, neurodegenerative, and brain development disorders. His particular research interest lies in combining metabolic PET imaging with structural connectomics, improving our understanding of how brain injury or pathology impacts neural networks.
Michael Fay is a radiation oncologist at Genesis Cancer Care in Newcastle. He is an honorary senior staff specialist at Royal Brisbane and Women's Hospital. He is dual trained in medical and radiation oncology and undertakes research in functional imaging applied to oncology. He is the principal investigator of several clinical brain tumour trials through the Trans-Tasman Radiation Oncology Group. He is currently completing his PhD in advanced imaging applied to brain tumour treatment and spent most of 2014 in a radiobiology lab in Tübingen, Germany.
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These authors contributed equally to this article.