Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models

Authors

Ashley M. Stokes, 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.
Charles P. Hart, Threshold Pharmaceuticals Inc., South San Francisco, California.
C Chad Quarles, 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.

Document Type

Article

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.

Keywords

18F-FMISO PET, TH-302, evofosfamide, glioma, hypoxia imaging, hypoxia-activated prodrugs

Publication Date

9-1-2016

Publication Title

Tomography (Ann Arbor, Mich.)

ISSN

2379-1381

Volume

2

Issue

3

First Page

229

Last Page

237

PubMed ID

27752544

Digital Object Identifier (DOI)

10.18383/j.tom.2016.00259

Recommended Citation

Stokes, Ashley M.; Hart, Charles P.; and Quarles, C Chad, "Hypoxia Imaging With PET Correlates With Antitumor Activity of the Hypoxia-Activated Prodrug Evofosfamide (TH-302) in Rodent Glioma Models" (2016). Translational Neuroscience. 1186.
https://scholar.barrowneuro.org/neurobiology/1186