Development of Metabolism Radiotracers to Probe Disease Pathology in Human Subjects with Cancer

Our group is interested in discovery and development of novel radiotracers for probing disease biology. In this quinquenium, we propose a translational programme that aims to develop the next generation of imaging approaches for investigation of disease biology in humans based on metabolism. Imaging using positron emission tomography (PET) remains one of the most direct ways of interrogating molecular mechanisms derailed in many diseases including cancer. PET methods are non-destructive and allow tissue biology to be investigated in the species of interest - the human being - non-invasively without associated sampling errors or tissue alterations that occur with biopsy-based approaches. Availability of appropriate probes and their validation in humans remains the major bottleneck in this field of research. Using cancer as the model, we have over the past five years advanced new probes for PET into human imaging to allow associated molecular mechanisms to be investigated. Of current interest is how tumours reprogramme their metabolism, which is difficult to measure by traditional methods in living organs and tissues. In the coming 5 years we will introduce two new imaging probes into humans and complete work on another. These probes detect how tissues burn fatty acids, store energy in the form of glycogen and make synthesise the precursors for membranes. The connectivity of this programme - chemistry design, automation, regulatory, mathematical modelling, and comparing imaging output to pathology - will allow us to provide the tools for translating our post-genome understanding of reprogrammed tumour metabolism into scientific investigation of diseased tissues in situ in humans, while developing candidate probes with potential for managing patients.

Our group is interested in discovery and development of novel radiotracers for probing disease biology. In this quinquenium, we propose a translational programme that aims to develop the next generation of metabolism imaging tracers for investigation of disease biology in humans. Imaging using positron emission tomography (PET) remains one of the most direct ways of interrogating molecular mechanisms derailed in many diseases including cancer. PET methods are non-destructive and allow tissue biology to be investigated in the species of interest - the human being - non-invasively without associated sampling errors or tissue alterations that occur with biopsy-based approaches. Availability of appropriate probes and their validation in humans remains the major bottleneck in this field of research. Using cancer as the model, we have over the past five years advanced new probes for PET into human imaging to allow associated molecular mechanisms to be investigated. Of current interest is the reprogrammed tumour metabolism - the result of multiple signalling pathways - which is difficult to measure, as the probes require bidirectional transit through the plasma membrane of cells within the target tissue and localisation within the cell only when the specific pathology exists. In the coming 5 years we aim to complete biological validation of a choline kinase radiotracer recently transitioned into humans, as well as introduce two new imaging probes discovered from our preclinical programme for assessing glycogenesis and fatty acid oxidation. The connectivity of this programme - chemistry design, automation, regulatory, mathematical modelling, and clinical imaging-pathology correlative science - will allow us to provide the tools for translating our post-genome understanding of reprogrammed tumour metabolism into scientific investigation of pathology in situ in humans, while developing candidate probes with potential for managing patients.

We are developing new probes for imaging cancer and other diseases. Cancer currently affects 1 in 2 people and will soon become the most common cause of death worldwide. Current treatments are non-curative, toxic and costly with most patients only having a small benefit to reduce disease burden. Detection and accurate prediction of early response to therapy or resistance will ultimately permit the goal of personalized medicine to be delivered to patients. Furthermore the very rapid changes in molecular targets and pathways associated with anti-cancer treatment, evident in days rather than months means that, with respect to patient management, we can in the future detect response to therapy by imaging much earlier than current clinical standards of radiological shrinkage. For patients who do not respond to therapy, our strategy will prevent months of ineffective and potentially toxic therapy, together with a significant saving of the NHS healthcare budget. This strategy also permits objective evaluation of new classes of mechanism-based cancer drugs directed at signalling and tumour microenvironment targets that are largely cytostatic in their mode of action. Our validation studies will be conducted in cancers of unmet need. In 5 years we hope to develop a method that will allow intra-therapy dose modification in patients with brain tumours; develop a method that will allow patients with metastatic renal cancer or TNBC to be stratified upfront of receiving potentially toxic and expensive therapies. Being metabolism probes, our imaging agents may also find utility in other diseases including diabetes, cardiovascular and pulmonary diseases, in-born errors of metabolism and neurodegeneration. The availability of these methodologies following our validation work will open up opportunities in these areas for which obtaining matched pathology tissues for validation is almost impossible. Lastly, our knowledge on the genomic/molecular basis of such pathology will be advanced by our studies.