Koen Vermeulen1, Muneer Ahamed2, Kaat Luyten3, Guy Bormans4. 1. Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 2. Centre for Advanced Imaging, University of Queensland, Brisbane, Australia. 3. Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Leuven, Belgium. 4. Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. Electronic address: guy.bormans@kuleuven.be.
Abstract
INTRODUCTION: HDAC6, a structural and functional distinct member of the HDAC-family, shows great promise as a target to treat several cancers and neurodegenerative diseases. Several clinical trials are evaluating HDAC6 inhibitors in solid tumours and haematological malignancies, but so far no HDAC6 inhibitor has received marketing authorisation. The availability of an HDAC6-specific PET tracer can potentially aid in cancer diagnosis, select patients for HDAC6 inhibitor treatment and accelerate HDAC6 drug development. We have evaluated the HDAC6 PET tracer [11C]KB631, in vitro and in vivo in B16.F10 melanoma inoculated mice. METHODS: In vitro binding specificity was evaluated by autoradiography studies on rodent brain, B16.F10 melanoma and PC3 prostate carcinoma cryosections. Biodistribution and quantification of plasma radio-metabolites was determined in NMRI-mice in control conditions and after blocking with KB631, Ricolinostat and SAHA. Tracer tumour uptake was evaluated in B16.F10 melanoma inoculated C57BL/6 mice. RESULTS: In vitro autoradiography studies showed HDAC6-selective binding to rodent brain, B16.F10 melanoma and PC3 prostate carcinoma tissue slices. Tracer binding in several organs of interest could be partially blocked in NMRI-mice pre-treated with KB631, Ricolinostat or SAHA, indicating specific tracer binding. A biodistribution and 90-min dynamic μPET study on B16.F10 melanoma mice, pre-treated with vehicle or Ricolinostat (50 mg/kg), indicated HDAC6-specific tumour uptake. CONCLUSIONS: [11C]KB631 shows HDAC6-selective binding in mouse B16.F10 melanoma tumours in vitro and in vivo. [11C]KB631 PET can be used for in vivo investigation of the expression of HDAC6 in tumours. ADVANCES IN KNOWLEDGE: [11C]KB631 shows increased expression of HDAC6 in mouse B16.F10 melanoma tumours and can be used to visualise target engagement of HDAC6 inhibitors.
INTRODUCTION:HDAC6, a structural and functional distinct member of the HDAC-family, shows great promise as a target to treat several cancers and neurodegenerative diseases. Several clinical trials are evaluating HDAC6 inhibitors in solid tumours and haematological malignancies, but so far no HDAC6 inhibitor has received marketing authorisation. The availability of an HDAC6-specific PET tracer can potentially aid in cancer diagnosis, select patients for HDAC6 inhibitor treatment and accelerate HDAC6 drug development. We have evaluated the HDAC6 PET tracer [11C]KB631, in vitro and in vivo in B16.F10 melanoma inoculated mice. METHODS: In vitro binding specificity was evaluated by autoradiography studies on rodent brain, B16.F10 melanoma and PC3 prostate carcinoma cryosections. Biodistribution and quantification of plasma radio-metabolites was determined in NMRI-mice in control conditions and after blocking with KB631, Ricolinostat and SAHA. Tracer tumour uptake was evaluated in B16.F10 melanoma inoculated C57BL/6 mice. RESULTS: In vitro autoradiography studies showed HDAC6-selective binding to rodent brain, B16.F10 melanoma and PC3 prostate carcinoma tissue slices. Tracer binding in several organs of interest could be partially blocked in NMRI-mice pre-treated with KB631, Ricolinostat or SAHA, indicating specific tracer binding. A biodistribution and 90-min dynamic μPET study on B16.F10 melanomamice, pre-treated with vehicle or Ricolinostat (50 mg/kg), indicated HDAC6-specific tumour uptake. CONCLUSIONS: [11C]KB631 shows HDAC6-selective binding in mouse B16.F10 melanoma tumours in vitro and in vivo. [11C]KB631 PET can be used for in vivo investigation of the expression of HDAC6 in tumours. ADVANCES IN KNOWLEDGE: [11C]KB631 shows increased expression of HDAC6 in mouse B16.F10 melanoma tumours and can be used to visualise target engagement of HDAC6 inhibitors.
Authors: Sofie Celen; Johanna Rokka; Tonya M Gilbert; Michel Koole; Isabeau Vermeulen; Kim Serdons; Frederick A Schroeder; Florence F Wagner; Tom Bleeser; Baileigh G Hightower; Jiyun Hu; Dania Rahal; M Hassan Beyzavi; Wim Vanduffel; Koen Van Laere; Janice E Kranz; Jacob M Hooker; Guy Bormans; Christopher J Cawthorne Journal: ACS Chem Neurosci Date: 2020-03-19 Impact factor: 4.418
Authors: Michel Koole; Donatienne Van Weehaeghe; Kim Serdons; Marissa Herbots; Christopher Cawthorne; Sofie Celen; Frederick A Schroeder; Jacob M Hooker; Guy Bormans; Jan de Hoon; Janice E Kranz; Koen Van Laere; Tonya M Gilbert Journal: Eur J Nucl Med Mol Imaging Date: 2020-07-08 Impact factor: 9.236