Glioblastoma is the most frequent primary brain tumour and the most malignant glial neoplasm (glioma) with predominantly astrocytic differentiation. Due to their invasive nature, glioblastomas cannot be completely resected, and despite progress in radio- and chemotherapy, less than half of patients survive more than a year. Microglia cells populate gliomas in large numbers and are especially numerous in malignant astrocytic tumours. Microglia are so common in these neoplasms as to contribute to tumour mass.
It is our long-term goal to develop the techniques that enable the reprogramming of microglia for therapeutic purposes. Malignant gliomas and especially glioblastomas attract microglia/macrophages in large numbers and subsequently control their activity eliciting mainly supportive functions that facilitate tumour growth. We find intriguing the question of whether this “fatal attraction” can be utilized against the tumour, i.e. by employing bone-marrow transplantation of genetically modified, tumour-targeting microglia precursors that may carry a (radio)cytotoxic payload.
We have established the first model of background free tumour imaging and we would like to use it to test the following hypothesis: Glioma-expressed TSPO is a highly sensitive marker of tumor progression that allows early preclinical detection of glioma, evaluation of its likely growth characteristics and assessment of the functional (metabolic) state of the cancer cells.
The model will enable us to dissect host from tumour responses.
It is the first model of its kind.
A high value outcome will be the most accurate in vivo/in vitro description to date of the relative contribution that the cancer cells make to the total tumour physiology, which includes the host's response.
The model allows to undertake critical refinement of the kinetic modeling of the imaging tracer that will inform experimental and future clinical studies well beyond the current study.
Our knock-out model enables the removal of signal contributions from the host tissue leaving only tumour cells as the biological source of the signal (i.e. ligand retention) without, as our feasibility data demonstrate, affecting the critical aspects of the tumour's behavior, namely growth and invasion.
The first component of the model is a glioma cell line. The GL261 glioma cell line is widely in use. The tumour cells are syngeneic to our new TSPO knock-out mouse. A GL261 tumour presents as a diffusely growing neoplasm, which closely resembles human glioblastoma. It clearly qualifies as a glioma and thus as a good model when applying diagnostic neuropathological criteria.
The second component of our model is our novel global 18-kDa translocator protein (TSPO) knockout mouse. Imaging of glioma using ligands for the TSPO is well established. It has been reported that in human glioma the intensity and extent of TSPO protein expression shows a strong direct correlation with the grade of glioma malignancy. The highest expression of TSPO is found in glioblastoma, especially around areas of necrosis, and there is a strong negative correlation between TSPO expression and survival. Recent years have seen a rapid development of radioligands for TSPO, which is now a recognized target for molecular imaging and for targeted drug delivery to tumors.
The opportunity ID for this research opportunity is 1951