Our aim is to develop innovative molecular imaging technologies that will provide improved image-guided therapy and novel theranostic treatment strategies for brain cancer.
High-grade glioma (HGG) is one of the most common and deadly types of brain cancer. The prognosis of patients with HGG is poor despite recent advances in surgical tumour removal techniques and the delivery of adjuvant (additional) therapies. Several factors contribute to the devastating outcomes. These include the following. First, the current imaging technology that is used for diagnosis is magnetic resonance imaging (MRI), and MRI has a limited ability to provide clinically relevant information about the pathology and behaviour of the tumour, making it difficult to accurately plan treatment and monitor the early response to treatment. Second, the current therapies for HGG have limited effectiveness against proliferating HGG tumour cells, which are ultra-invasive. To improve the outcomes for patients, new diagnostic imaging technologies that incorporate targeted 'theranostic' (diagnostic and therapeutic) frameworks are urgently required.
We propose to address this problem by developing new quantitative biomarkers of early treatment response based on an imaging technology called positron emission tomography (PET) using the tracer FDOPA (3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine). We will use this technology to better understand and define tumour metabolism. We have shown that FDOPA PET improves the delineation of tumour margins for treatment planning and, in terms of the monitoring of outcomes, can predict overall survival as early as four weeks after therapy begins. This approach allows rapid feedback about whether a different treatment regimen is needed, as well as provides a new framework to accelerate the translation of novel therapies into the clinic.
It is well recognised that tumour hypoxia levels modulate tumour cell plasticity and possibly response to therapy. My group is also investigating the clinical utility of FMISO ([18F]-fluoromisonidazole) PET imaging to better understand the effect of tumour hypoxia (low oxygen levels) on treatment outcomes.
Moreover, a crucial component of our research is developing novel theranostic agents for individualised treatment of brain cancer. The main idea is directly delivering tumour-killing (cytotoxic) agents to brain tumours (and not normal tissue) and imaging this delivery. We have constructed theranostics using antibodies that bind to two molecules that are abundant on HGG cells: EphA2 and EphA3. Labelling these antibodies with an imaging isotope (such as copper-64) and a therapeutic isotope (such as lutetium-177 or yttrium-90) allows us to visualise the delivery of the theranostic agent directly to tumour cells. This framework is flexible, as drug 'payloads' can also be attached to the theranostic agent.
We are also developing new-generation theranostics comprising single-chain variable fragments (scFvs) specific for the EphA2 and EphA3 receptors. These scFvs have better pharmacological profiles than the standard antibody approaches for delivering cytotoxic agents to cancer cells.
We are currently using FDOPA PET imaging in clinical studies to determine whether PET imaging with FDOPA can be used early in treatment to predict the progression of the disease and/or how long patients will survive. This information will enable clinicians to alter therapy at an early stage. In terms of clinical trials, we are using this imaging technology in a study of valproic acid (VPA) in patients with HGG at the Royal Brisbane and Women’s Hospital. VPA is usually given to reduce seizures but seems to extend the lifespan of patients with brain cancer. The novelty of this trial is that we are using FDOPA PET as an end point marker, thereby reducing the cost and duration of the study.
In addition, my team is studying antibodies that specifically target brain cancer as agents for imaging and treatment. We have shown that a copper-64-labelled antibody that recognises EphA2 (from one of our collaborators, Dr Bryan Day) has considerable potential as both an imaging agent and a possible theranostic for HGG. In 2015, we propose to conduct first-in-human studies with this imaging agent in patients with HGG. If successful, in 2016–2017 we will fast-track this agent as a possible theranostic for patients with recurrent tumours.
The combinations of imaging agents and technologies that we develop will help optimise treatment strategies for patients with brain cancer. These tools will ultimately allow clinicians to easily monitor patients’ progress and to adapt treatment regimens, as well as to prevent the unnecessary treatment of patients who are unlikely to respond. Our tools will also allow us to measure the outcome of clinical trials in a more effective manner, accelerating the translation of new therapies into the clinic. In addition, we aim to develop more effective treatments by generating theranostics that specifically target a patient’s brain cancer cells and deliver a cytotoxic agent while allowing clinicians to monitor the progress of the cancer.
Team & Partners
The clinical imaging studies involve a large team of dedicated clinicians from several institutions—the Royal Brisbane and Women’s Hospital (Drs Mike Fay and Paul Thomas) and the University of Queensland (Professor Jennifer Martin)—and scientists from the CSIRO (Dr Nick Dowson).
The Eph-specific antibody theranostic work involves collaborators from the QIMR Berghofer Medical Research Institute (Dr Bryan Day, Dr Brett Stringer and Professor Andrew Boyd), along with colleagues Professor Andrew Whittaker and Dr Simon Puttick from the Australian Institute for Bioengineering and Nanotechnology (University of Queensland).
I am also a member of the Brain Cancer Discovery Collaborative, a national team of brain cancer scientists and clinicians, and these technologies will be available to the collaborative for completing testing of candidate drugs in the test tube (in vitro) and in animals (in vivo) and for conducting clinical trials.
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