Abstract LB-227: Pilot clinical trials of FSPG (BAY 94-9392): An 18F-labeled glutamate derivative for PET imaging of system xC- activity in tumors
Authors: Baek Sora , Mittra Erik , Choi Chang-Min , Gong Gyungyub , Oh Seung Jun , Mosci Camila , Kumar Meena , Chin Frederick T. , Fels Lueder M. , Stephens Andrew W. , Koglin Norman , Mueller Andre , Dinkelborg Ludger M. , Moon Dae Hyuk , Gambhir Sanjiv S. 
Published: August 2012

Abstract
Visualizing adaptations of tumor metabolism by employing positron emission tomography (PET) with a specific imaging probe has the potential to better characterize tumors with higher sensitivity and specificity. The glutamate-cystine exchanger (system xC-, a SLC7A11/SLC3A2 heterodimer) is an important transporter in tumor cells and a promising new target for imaging. This exchanger transports the amino acids L-cystine and L-glutamate, thus providing a rate-limiting precursor for glutathione biosynthesis. This contributes to redox maintenance, which is especially important in tumor cells. Recently, it was reported that a splice variant of the stem cell marker CD44 stabilizes the xCT subunit of system xC- at the cell membrane and promotes its proper function. FSPG (BAY 94-9392) is an 18F-labeled glutamate derivative that provides specific visualization of system xC- activity with PET/CT. Through this multicenter pilot trial, FSPG has successfully been translated into cancer patients and shows favorable pharmacokinetics and an absence of adverse events. A favorable biodistribution pattern previously seen in mice was also confirmed in these patients with different tumor types. A high lesion detection rate (80-100%) was found in lung cancer (n=10), hepatocellular cancer (n=5), head and neck cancer (n=5), and colorectal cancer (n=5) patients who also had positive FDG-PET/CT scans. Importantly, very low background uptake in healthy brain parenchyma enabled the detection of high-grade brain cancers as well as small brain metastases and skull base lesions (n=4) not well seen with FDG-PET. Primary breast tumors (n=4) and a low-grade brain tumor, however, showed minimal uptake of FSPG. Immunohistochemical (IHC) analyses on these subjects’ pathology samples showed significant correlation between FSPG uptake and protein expression of both the xCT subunit and CD44. In breast tumor samples specifically, IHC showed that absence of CD44 results in low signal from FSPG-PET even if xCT is present, indicating the importance of CD44 co-expression for system xC- function. Future clinical studies will further explore the potential of this compound in additional tumor types and expand upon the initial findings in a larger number of subjects. Here we present the first clinical examples demonstrating the ability of the tracer to measure system xC- activity in patients. FSPG-PET/CT may provide improved characterization and sensitivity of tumor detection in patients and further improve the understanding of the role of system xC- in cancer biology. It could be a valuable tool for improved tumor classification in patients, linking uptake of the tracer with malignancy and cancer stem cell properties of tumors. Furthermore, the ability to noninvasively probe this important pathway in humans may allow for more rational treatment planning, patient stratification and better development of new drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-227. doi:1538-7445.AM2012-LB-227