Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma

Mol Imaging. 2016 May 5;15:1536012116644881. doi: 10.1177/1536012116644881. Print 2016.

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.

Keywords: indoleamine 2,3-dioxygenase; orthotopic mouse model; patient-derived xenograft; tryptophan 2,3-dioxygenase; α-[11C]-methyl-l-tryptophan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Biosynthetic Pathways
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Carbon Radioisotopes / chemistry
  • Cell Line, Tumor
  • Female
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Kynurenine / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Molecular Imaging / methods*
  • Neoplasm Transplantation
  • Positron-Emission Tomography / methods*
  • Tryptophan / chemistry
  • Tryptophan / pharmacokinetics*

Substances

  • Carbon Radioisotopes
  • Kynurenine
  • Tryptophan