title: PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies.
abstract: Purpose To demonstrate that positron emission tomography (PET) with fluorine 18 (18F) fluorthanatrace (FTT) depicts activated poly (adenosine diphosphate-ribose)polymerase (PARP) expression and is feasible for clinical trial evaluation. Materials and Methods All studies were conducted prospectively from February 2012 through July 2015 under protocols approved by the local animal studies committee and institutional review board. The area under the receiver operating characteristic curve (AUC, in g/mL· min) for18F-FTT was assessed in normal mouse organs before and after treatment with olaparib (n = 14), a PARP inhibitor, or iniparib (n = 11), which has no PARP inhibitory activity. Murine biodistribution studies were performed to support human translational studies. Eight human subjects with cancer and eight healthy volunteers underwent imaging to verify the human radiation dosimetry of18F-FTT. The Wilcoxon signed rank test was used to assess for differences among treatment groups for the mouse studies. Results In mice, olaparib, but not iniparib, significantly reduced the18F-FTT AUC in the spine (median difference before and after treatment and interquartile range [IQR]: -17 g/mL· min and 10 g/mL · min, respectively [P = .0001], for olaparib and -3 g/mL · min and 13 g/mL · min [P = .70] for iniparib) and in nodes (median difference and interquartile range [IQR] before and after treatment: -23 g/mL · min and 13 g/mL · min [P = .0001] for olaparib; -9 g/mL · min and 17 g/mL · min [P = .05] for iniparib). The effective dose was estimated at 6.9 mSv for a 370-MBq18F-FTT dose in humans. In humans, the organs with the highest uptake on images were the spleen and pancreas. Among five subjects with measurable tumors, increased18F-FTT uptake was seen in one subject with pancreatic adenocarcinoma and another with liver cancer. Conclusion The results suggest that18F-FTT uptake reflects PARP expression and that its radiation dosimetry profile is compatible with those of agents currently in clinical use.©RSNA, 2016 Online supplemental material is available for this article.
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Loren S
authors.initials: LS
authors.lastname: Michel
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Samantha
authors.initials: S
authors.lastname: Dyroff
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Brooks
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Spayd
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Sora
authors.initials: S
authors.lastname: Lim
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Jacquelyn T
authors.initials: JT
authors.lastname: Engle
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Sharon
authors.initials: S
authors.lastname: Phillips
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tan
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Bognar
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Richard
authors.initials: R
authors.lastname: Laforest
authors.affiliation: From the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY (L.S.M.); Division of Radiological Sciences, Mallinckrodt Institute of Radiology (S.D., F.J.B., K.J.S., J.T.E., S.P., C.B., W.C., D.Z., R.L., D.L.C.), and Department of Internal Medicine (S.L., B.T., A.W.G.), Washington University School of Medicine, 510 S Kingshighway Blvd, Campus Box 8225, St Louis, MO 63110; and Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa (R.H.M.).
authors.forename: Delphine L
authors.initials: DL
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011446:Prospective Studies; D011874:Radiometry
chemical_list: D001549:Benzamides; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D005462:Fluorine Radioisotopes; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C090712:iniparib; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib