Abstract
Abstract Introduction: The histone deacetylases (HDACs) family of enzymes are overexpressed in human cancers including pancreatic cancer. Past issues with non-specific and off-target inhibition have limited the clinical utility of HDAC inhibitors, but class-specific inhibitors appear more promising. Targeting class-IIa HDACs 4, 5, 7 and 9 has been shown to reprogram the tumor-associated macrophages which triggers therapeutic immune responses. We previously targeted trifluoromethyloxadiazole (TFMO) for radiolabeling with F-18, since this chemical group has high selectivity to class-IIa HDACs. Then, we applied this radiolabeling strategy to TMP195, a potent class-IIa HDAC inhibitor which contains the TFMO moiety. Our objective was to test 18F-TMP195 for therapy and molecular imaging of pancreatic cancer. Methods: A bromodifluoromethyloxadiazole precursor was developed and then treated with cesium 18F-fluoride (Cs18F) to generate 18F-TFMO. This methodology was applied to formulate 18F-TMP195. The expression of Class IIa HDACs in PDAC cell lines (AsPC-1, MIAPaCa-2, and PANC-1) and normal pancreatic duct cells (hTERT-HPNE) was measured by western blot assay. Cytotoxicity of TMP195 was measured in cultured PDAC cell lines and hTERT-HPNE cells. SAHA, a non-specific HDAC inhibitor, was used as control. PDAC uptake of radiolabeled drug (18F-TMP195) was measured to evaluate specific binding to endogenous Class IIa HDACs in PDAC cells. Finally, 18F-TMP195 uptake was evaluated in vivo by PET imaging in pancreatic cancers xenografted in NOD/SCID mice. Results: All 3 PDAC cell lines exhibited high expression levels of Class IIa HDACs, whereas low expression was observed in hTERT-HPNE cells. TMP-195 exhibited cytotoxic effects in all 3 PDAC cell lines. 18F-TMP195 was successfully synthesized for the first time in our laboratory. Radio-ligand cellular uptake tests measured by radioactivity accumulated in cells demonstrated significantly higher uptake of 18F-TMP195 in PDAC cells than hTERT-HPNE cells. Treatment with cold TMP195, but not SAHA, blocked uptake of radiolabeled drugs by PDAC cells compared to 18F-TMP195 alone or 18F-TMP195 + SAHA, thus supporting the selective targeting of TMP195 to the active site of Class IIa HDACs. The in vivo 18F-TMP195-PET imaging showed significant accumulation of the radiotracer in tumor tissue compared to adjacent non-tumor tissue. Conclusion: 18F-TMP195 was successfully formulated utilizing single radiochemical synthetic-step protocol. Our studies indicate that this class of drugs selectively targets Class-IIa HDACs in PDAC and suggest that selective class-IIa HDACs are promising targets with potential for molecular imaging of PDAC in vivo. Therefore, class-IIa HDAC expression patterns in PDAC present potential for development of diagnostic imaging agents to predict response to treatment. Citation Format: Mei Gao, Miranda Lin, Joseph Kim, Nashaat Turkman. Molecular imaging of class-IIa histone deacetylases in pancreatic cancer as a biomarker of response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4101.
Published Version
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