Title: Molecular Imaging
Funder: Cancer Research UK

Abstract: Resecting brain tumours with radioactive amino acids and light: Accurate surgical resection in glioma is essential because the extent of resection correlates with survival and over-resection can cause severe morbidities such as paraplegia. We applied a new biomedical imaging technique, Cerenkov luminescence imaging (CLI), to guide the surgical removal of brain tumours. CLI is a novel optical intraoperative imaging modality that has demonstrated clinical feasibility in breast cancer surgery. What is lacking, and why our work is important, is proof that CLI has an advantage over current approaches for intraoperative imaging. We directly compared a novel CLI probe, the radiolabelled amino acid analogue [18F]fluoro-ethyl-tyrosine (FET), with the gold standard intraoperative method, 5-ALA fluorescence imaging, in multiple animal models of glioblastoma. 5-ALA was approved in 2014 by the European Medicines Agency for image-guided surgery of high-grade glioma due to an improvement in progression-free survival. Targeting glioma with CLI and FET exploits the metabolic reprogramming that is a hallmark of malignant transformation. Our results show that CLI with FET is more accurate and quantitative than 5-ALA fluorescence imaging when guiding brain tumour resection. Given the superiority of FET CLI and the rapid clinical translation of CLI, this technique has the potential to have a clinically meaningful impact in glioblastoma surgery. FET CLI could also be used for intraoperative imaging of low-grade glioma where there are no tools for visualising the tumour during surgery. Imaging oncogenesis - novel multi-transgenic vectors for somatic delivery of radionuclide reporter genes: Oncogenesis, the transformation of normal cells into premalignant lesions and cancer, is optimally modelled using genetically engineered mouse models. The best of these recapitulate the genetic and microenvironmental heterogeneity which is often found in clinical cancer patients. However, it is frequently difficult to visualise oncogenesis as tumours develop at autochthonous sites with varying latency. This is the first example of a radionuclide reporter gene being used to monitor real-time spontaneous tumour development. This is important, as unlike bioluminescent approaches, it enables sensitive three-dimensional imaging of tumour development in vivo that is unaffected by overlying tissue-depth or tissue pigmentation. Unlike adenoviral- or adeno-associated virus–transduction–based approaches, lentiviral vectors stably integrate into the genome of infected cells. Thus they are useful for delivering transgene expression to both the transduced cell as well as to subsequent progeny. We exploit that feature to both initiate and permanently label tumour development from normal murine somatic cells with inherited ‘silent’ tumour initiating genes. This approach has significant advantages over conventional germline transgenic approaches. It enables in vivo measurements with extremely high signal-to-noise ratios, since background is practically absent from non-labelled cells. The approach is versatile as the vector can be readily customised to modify reporter readout or the capacity to add or subtract specific gene expression from the base/ inherited conditional genotype without additional transgenic mouse strain development or breeding. It should also be useful for inducing tumours in organs other than the lung, such as the pancreas and prostate, thus facilitating sensitive tomographic imaging at these sites. The long-term goals of this research are not only to visualise 3D tumour development in preclinical models of cancer but to enable rapid and accurate non-invasive monitoring of cancer therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS