Abstract 5202: Comparison of [124I]-FIAC and [18F]-FAC as potential biomarkers to predict response to gemcitabine therapy in pancreatic cancers
Authors: Gangangari Kishore K. , Punzalan Blesida , Huang Brendan , Pillarsetty NagaVaraKishore 
Published: July 2016

Pancreatic cancer (PaCa) is one of the most lethal kinds of cancers because it is virtually symptom free in early stages, metastasizes rapidly and is difficult to resect. Gemcitabine (GEM) as a single agent or in conjunction with radiation is the most commonly used in the management of PaCa. But GEM has shown efficacy only in a small but select group of patients. While the role of key transporters and enzymes has been implicated in sensitizing or conferring resistance to gemcitabine, no clear correlation has been establishe. Currently, there is no a priori way to determine invasively or non-invasively which PaCa patients stand to benefit from GEM therapy. Any biomarker that can act as a prognostic indicator of GEM response will greatly aid in optimizing treatment regimen, reducing unnecessary side effects and subjecting resistant patients to aggressive therapies. Our goal is to develop a PET imaging based biomarker to predict response to GEM therapy in pancreatic cancer patients non-invasively. [18F]-FAC was evaluated as biomarker for GEM response in leukemia models but the short half life (t1/2 = 110 min) combined with background gut activity can complicate image analysis. Therefore our goal was to develop a longer lived analog of GEM that can act as a surrogate marker. Based on modeling studies and ability to label with longer lived isotope (Iodine-124; t1/2 = 4.18 d) we concentrated our efforts on evaluating I-124 labeled 1-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodocytosine ([124I]-FIAC) as a positron emission tomography (PET) biomarker of GEM response.

[124I]-FIAC was synthesized by iodination of 1-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-cytosine (FAC) with [124I]-NaI using chloramine-T as an oxidant. In vitro phosphorylation efficacy studies were carried out on GEM, FAC and FIAC using recombinant deoxycytidine kinase (dCK) enzyme. In vitro kinetic uptake assay was performed on representattive pancreatic cancer cells lines AsPc-1 and MiaPaCa-2. Subcutaneous tumor xenografts were established in athymic nude mice. [124I]-FIAC was administered intravenously via tail vein and its uptake was studied by PET imaging and sacrificial biodistribution studies at 4, 24, 48 and 72 h. Imaging and biodistribution studies using [18F]-FAC were also performed in tumor bearing mice at 1 and 4 h.

[124I]-FIAC was synthesized in &gt;17% yields with &gt;99% radiochemical purity. The efficiency of phosphorylation was in the following order GEM ∼ FAC &gt; FIAC. Cellular uptake assays showed that [124I]-FIAC was taken up preferentially (4X) by AsPc-1 in comparison to MiaPaCa-2.

[124I]-FIAC and [18F]-FAC were synthesized and compared for their efficacy to serve as potential biomarker for gemcitabine response in pancreatic cancer models in vitro and in vivo. Preliminary studies indicated that [124I]-FIAC and [18F]-FAC behave differently in these models with former showing preferential uptake in AsPC-1 cells and xenografts.

Citation Format: Kishore K. Gangangari, Blesida Punzalan, Brendan Huang, NagaVaraKishore Pillarsetty. Comparison of [124I]-FIAC and [18F]-FAC as potential biomarkers to predict response to gemcitabine therapy in pancreatic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5202.