title: Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.
abstract: Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM.
authors.affiliation: Department of Neurosurgery, Wayne State University, Detroit, MI, USA Department of Oncology, Wayne State University, Detroit, MI, USA.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Guastella
authors.affiliation: Department of Neurosurgery, Wayne State University, Detroit, MI, USA.
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Michelhaugh
authors.affiliation: Department of Neurosurgery, Wayne State University, Detroit, MI, USA.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Klinger
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kupsky
authors.affiliation: Department of Pathology, Wayne State University, Detroit, MI, USA Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Polin
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, MI, USA Department of Radiology, Wayne State University, Detroit, MI, USA PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: Otto
authors.initials: O
authors.lastname: Muzik
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA Department of Pediatrics, Wayne State University, Detroit, MI, USA PET Center and Translational Imaging Laboratory, Children's Hospital of Michigan, Detroit, MI, USA Department of Neurology, Wayne State University, Detroit, MI, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Juhász
authors.affiliation: Department of Neurosurgery, Wayne State University, Detroit, MI, USA Department of Oncology, Wayne State University, Detroit, MI, USA Karmanos Cancer Institute, Detroit, MI, USA smittal@med.wayne.edu.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Mittal
mesh_terms: D000368:Aged; D000818:Animals; D053898:Biosynthetic Pathways; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes / Q000737:chemistry; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods*; D014364:Tryptophan / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D002250:Carbon Radioisotopes; D007737:Kynurenine; D014364:Tryptophan
keywords: indoleamine 2,3-dioxygenase; orthotopic mouse model; patient-derived xenograft; tryptophan 2,3-dioxygenase; α-[11C]-methyl-l-tryptophan