Molecular Imaging Research Achievements, awards and prizes

• Research Home
>
• Laboratory Research
>
• Cancer Therapeutics Program
>
• Molecular Imaging and Targeted Therapeutics
>
• Molecular Imaging Research Achievements, awards and prizes

Molecular Imaging Research Achievements, awards and prizes - Research at Peter Mac

Recent Achievements MELANOMA IMAGING

Malignant melanoma is among the most aggressive and invasive tumour types, for which current treatments are rarely effective, making it an important target for improved diagnostic and therapeutic methods. A class of compounds called benzamides (BZAs) has been suggested as possible melanoma imaging agents as these bind tightly and irreversibly to melanin, a pigmented protein found in large amounts in most melanoma cells. Because of this tight binding property, BZAs have the potential to act as ‘diagnostic/therapeutic pairs’– that is, when labelled with a PET radionuclide, they can be used for diagnostic imaging of metastatic lesions or recurrences, then labelled with a high energy therapeutic radionuclide for treatment. Past studies have concentrated on BZA analogues labelled with isotopes of iodine for both imaging and therapy. However, iodine isotopes suitable for PET imaging are virtually unavailable in Australia and very difficult to access worldwide. Together with collaborators at the Australian nuclear science and Technology Organisation (ANSTO) and the CRCBID, we have synthesised a novel BZA compound that can be labelled with 18-fluorine (18F), making it an outstanding candidate as a diagnostic imaging agent for melanoma. We have developed high yielding chemistries for 18F labelling of this compound, which has shown excellent imaging properties in animal models of metastatic melanoma. In addition, we are developing a mouse model to test 18F-BZA for PET imaging of sentinel lymph nodes in melanoma. This new tracer has potential as a highly effective clinical PET imaging agent to improve diagnosis and treatment of metastatic melanoma. First-in-human clinical trials are planned for late in 2009.

TARGETING AMINO ACID TRANSPORT FOR CANCER IMAGING

Due to the increased metabolic rate of many tumour types, 18-Fluorine labelled glucose (FDG) is an extremely effective agent for PET imaging of cancers. However, in tissues with high intrinsic metabolic rates such as brain or heart, or in settings of inflammation or diabetes, FDG-PET has reduced sensitivity. In addition to high glucose utilisation, growth and proliferation of tumour cells require continual production of protein. Thus, many cancer cells have increased expression of amino acid transporters. We have developed methods for 18F-labelling of tyrosine and methionine analogues which have now been used successfully for preclinical and clinical imaging for specific tumour types. These tracers are particularly exciting for brain tumour localisation and characterisation.

PET IMAGING OF SOMATOSTATIN RECEPTORS IN NEUROENDOCRINE TUMOURS

Neuroendocrine tumours (NET) are rare tumours usually occurring in the gut, lung and pancreas. These generally follow an indolent but metastatic course and are resistant to conventional cancer therapies. NETs often have low uptake of FDG and are not well visualised by FDG-PET. NETs are characterised by high expression of somatostatin (SST) receptors, especially SSTR2, and this has been exploited for single photon emission tomography (SPECT) imaging using indium-labelled SST peptide analogues (111-In-octreotide). However, SPECT imaging lacks the high resolution of PET and is thus somewhat ineffective for visualisation of small metastatic lesions, reducing its usefulness for staging or treatment monitoring. This is important since there are now radionuclide therapies that are highly effective in controlling progression and symptoms of NET. We have characterised a model system for the development of 68-gallium labelled octreotides for PET imaging. Our recent acquisition of a gallium generator will make it possible to develop improved imaging capabilities for NET, including development of individualised dose and therapeutic combination planning.

IMAGING TUMOUR HYPOXIA

Many rapidly growing solid tumours lack normal blood flow and thus have low oxygen tension in central regions. Cells populating these hypoxic areas exit the cell cycle and enter a resting phase in which they are extremely resistant to most anti-cancer therapies. Often these hypoxic cells remain after treatment and have the ability to seed repopulation once they re-enter the cell cycle. There are drugs that can specifically sensitise hypoxic cells to therapy if their presence can be identified before treatment. We have improved methods for 18-F labelling of a compound that binds to proteins in hypoxic conditions. This compound has proved to be highly effective for PET imaging of hypoxic tumour cells in mouse models of human cancers. Pre-clinical imaging underpins a strong clinical program in hypoxia imaging in which Peter Mac is recognised to be internationally competitive.

IMAGING APOPTOSIS IN CANCER CELLS

Treatment with targeted therapeutics has the potential to cause rapid apoptosis in tumour cells but detectable shrinkage of the tumour mass may take weeks or months. The ability to directly image apoptotic death would be very helpful to assess effectiveness, especially with novel or experimental therapies. A common method for assessment of apoptosis in tissue culture cells uses a fluorescently labelled annexin that binds to lipids on the surface of apoptotic cells. When labelled with 18F for PET imaging, however, annexin often loses its binding properties. We are working on better labelling methods and modifications of annexin to improve its properties for PET imaging of apoptosis.