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New Strategies for Imaging of Brain Cancer with RadiopharmaceuticalsBrust, P.
Brain cancer is a challenge for the health care system because of major problems for treatment. Radical surgery is not possible. Radiation treatment is restricted by missing borderlines, and drug treatment is limited by the blood-brain barrier. Therefore, glioblastoma multiforme, the most aggressive type of primary brain tumors, has a median overall survival of only ~12 months. Although new molecular pathways are being constantly discovered, translation of basic science into clinical practice is rather slow. Major obstacles in the resistance to therapy are heterogeneity of brain tumors, multiple genetic alterations, and their diffuse, infiltrative behavior. Hence monitoring of pathways related to tumor etiology and growth is highly important.
Positron emission tomography (PET) offers the potential to identify key signaling and metabolic pathways in tumors and to discover drugs for targeted therapy. An important prerequisite for PET is the development of radiolabeled molecules (radiotracer) to investigate impaired brain functions in living human subjects. Fluorine-18 is currently the most favorable radionuclide that is routinely used for radiolabeling because of its half-life of 109.8 min. The presentation will focus on the development of fluorine-18 labelled radiotracers bridging from basic science to biomedical application and focusing on four targets of major importance for brain cancer.
Results and Discussion:
Cannabinoids are known to induce apoptosis of glioma cells and the extent of cannabinoid CB2 receptor expression is related to tumor malignancy. The challenge in radiotracer development is the high expression of CB1 receptors. Therefore our strategies will be presented to achieve highly selective PET radiotracers for CB2 receptors.
The immunosuppressive effects of adenosine and the adenosine-triggered activation of catabolic energy production account for pro-cancer roles of extracellular adenosine. Accordingly, plasma-membrane-bound adenosine receptors were identified as new targets in the immunotherapy of brain tumors. Currently, we have PET radiotracers for A2A and A2B receptors under development, which are regarded as potential tools for therapy monitoring.
Sigma receptors, previously regarded as opioid receptors, are comprised of the σ1 and σ2 subtypes and represent orphan receptors of different families. While the σ1 receptor is a molecular chaperone, which interacts with various ion channels and G-protein coupled receptors, the σ2 receptor (TMEM97) is an intracellular protein located at the endoplasmatic reticulum that binds numerous drugs. There is evidence that both subtypes are important for glioblastoma growth thus facilitating the ongoing development of selective PET radiotracers for both subtypes in our department.
Furthermore, as other cancers glioblastoma is characterized by metabolic reprogramming to preferentially undergo aerobic glycolysis. The elevated production of lactate is accompanied by the increased expression of monocarboxylate transporters (MCTs). Accordingly a therapeutic approach targeting MCTs is a promising strategy in brain cancer treatment. A PET radiotracer for peripheral MCT1/MCT4 imaging has already been developed by us and will be discussed concerning its suitability for glioblastoma imaging.
Numerous attempts are ongoing for molecular characterization of brain cancer with PET radiopharmaceuticals. It is expected that they will support in the future patient stratification and hence individualized therapy.
International Symposium on Trends in Radiopharmaceuticals - ISTR 2019, 28.10.-01.11.2019, Wien, Österreich