title: Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models.
abstract: High-grade gliomas are often characterized by hypoxia, which is associated with both poor long-term prognosis and therapy resistance. The adverse role hypoxia plays in treatment resistance and disease progression has led to the development of hypoxia imaging methods and hypoxia-targeted treatments. Here, we determined the tumor hypoxia and vascular perfusion characteristics of 2 rat orthotopic glioma models using 18-fluoromisonidozole positron emission tomography. In addition, we determined tumor response to the hypoxia-activated prodrug evofosfamide (TH-302) in these rat glioma models. C6 tumors exhibited more hypoxia and were less perfused than 9L tumors. On the basis of these differences in their tumor hypoxic burden, treatment with evofosfamide resulted in 4- and 2-fold decreases in tumor growth rates of C6 and 9L tumors, respectively. This work shows that imaging methods sensitive to tumor hypoxia and perfusion are able to predict response to hypoxia-targeted agents. This has implications for improved patient selection, particularly in clinical trials, for treatment with hypoxia-activated cytotoxic prodrugs, such as evofosfamide.
authors.affiliation: Institute of Imaging Science, Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, Tennessee; Department of Imaging Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Stokes
authors.affiliation: Threshold Pharmaceuticals Inc., South San Francisco, California.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Hart
authors.affiliation: Institute of Imaging Science, Department of Radiology and Radiological Sciences, Vanderbilt University, Nashville, Tennessee; Department of Imaging Research, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: C Chad
authors.initials: CC
authors.lastname: Quarles
keywords: 18F-FMISO PET; TH-302; evofosfamide; glioma; hypoxia imaging; hypoxia-activated prodrugs