Relationship between ornithine decarboxylase levels in anaplastic gliomas and progression-free survival in patients treated with DFMO–PCV chemotherapy

Authors

  • Victor A. Levin,

    Corresponding author
    1. Department of Neuro-Oncology and M. D. Anderson Clinical Oncology Program, The University of Texas M. D. Anderson Cancer Center, Houston, TX
    • Department of Neuro-Oncology, Unit 431, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301402, Houston, TX 77230-1402, USA
    Search for more papers by this author
    • Victor A. Levin is a founder of VBL Pharmaceuticals Inc., a company that intends to seek United States FDA approval for DFMO in the treatment of anaplastic gliomas.

  • Jacob L. Jochec,

    1. Department of Neuro-Oncology and M. D. Anderson Clinical Oncology Program, The University of Texas M. D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Lisa M. Shantz,

    1. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA
    Search for more papers by this author
  • Kenneth D. Aldape

    1. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX
    Search for more papers by this author

Abstract

The purpose of this study was to assess the relationship between progression-free survival (PFS) in patients treated with DFMO + PCV (procarbazine, CCNU, vincristine) chemotherapy for malignant gliomas with tumor cell ornithine decarboxylase (ODC) activity. Formalin-fixed slides were obtained for study patients with anaplastic gliomas (AGs) and glioblastoma treated on protocol DM92-035. ODC levels were measured using an antibody to ODC coupled to Alexa 647 dye (Ab-ODC-Alexa 647). Ab-ODC-Alexa 647 intensity in transgenic murine hearts of differing ODC activity was used to calculate ODC activity in tumor cell nucleoplasm. In total, tumor specimens for 31 of 114 (27%) patients treated on the AG strata and 10 patients from the GBM strata were obtained. We found that tumor ODC level heterogeneity increased with increasing tumor malignancy. In a Cox proportional hazards model, PFS was found to be inversely related to median tumor ODC activity, with an unadjusted hazard ratio for median ODC group (>3.3 vs. ≤3.3 nmol/30 min/μg protein) of 5.8 (p < 0.0001); a median PFS of 522 weeks for patients with AGs with median ODC activity ≤ 3.3 and 31 weeks for the 8 AG and 10 glioblastoma patients with ODC activity > 3.3 nmol/30 min/μg protein. Of AG tumors in which ODC activity was evaluated, 26% had ODC levels > 3.3 nmol/30 min/μg protein. This study shows that Ab-ODC-Alexa 647 fluorescence intensity can be used as a surrogate marker of ODC biochemical activity in AGs and can predict PFS to DFMO-based chemotherapy. © 2007 Wiley-Liss, Inc.

Ancillary