Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma

Authors

• Robert T. Wicks, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Javad Azadi, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Antonella Mangraviti, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Irma Zhang, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Lee Hwang, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Avadhut Joshi, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Hansen Bow, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Marianne Hutt-Cabezas, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Kristin L. Martin, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Michelle A. Rudek, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Ming Zhao, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Henry Brem, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).
• Betty M. Tyler, Department of Neurosurgery (R.T.W., J.A., A.M., I.Z., L.H., A.J., H.B., M.H.-C., K.L.M., H.B., B.M.T.); Departments of Oncology, Ophthalmology, and Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland (H.B.); Division of Chemical Therapeutics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (M.A.R., M.Z.).

Document Type

Article

Abstract

BACKGROUND: 3-bromopyruvate (3-BrPA) and dichloroacetate (DCA) are inhibitors of cancer-cell specific aerobic glycolysis. Their application in glioma is limited by 3-BrPA's inability to cross the blood-brain-barrier and DCA's dose-limiting toxicity. The safety and efficacy of intracranial delivery of these compounds were assessed. METHODS: Cytotoxicity of 3-BrPA and DCA were analyzed in U87, 9L, and F98 glioma cell lines. 3-BrPA and DCA were incorporated into biodegradable pCPP:SA wafers, and the maximally tolerated dose was determined in F344 rats. Efficacies of the intracranial 3-BrPA wafer and DCA wafer were assessed in a rodent allograft model of high-grade glioma, both as a monotherapy and in combination with temozolomide (TMZ) and radiation therapy (XRT). RESULTS: 3-BrPA and DCA were found to have similar IC50 values across the 3 glioma cell lines. 5% 3-BrPA wafer-treated animals had significantly increased survival compared with controls (P = .0027). The median survival of rats with the 50% DCA wafer increased significantly compared with both the oral DCA group (P = .050) and the controls (P = .02). Rats implanted on day 0 with a 5% 3-BrPA wafer in combination with TMZ had significantly increased survival over either therapy alone. No statistical difference in survival was noted when the wafers were added to the combination therapy of TMZ and XRT, but the 5% 3-BrPA wafer given on day 0 in combination with TMZ and XRT resulted in long-term survivorship of 30%. CONCLUSION: Intracranial delivery of 3-BrPA and DCA polymer was safe and significantly increased survival in an animal model of glioma, a potential novel therapeutic approach. The combination of intracranial 3-BrPA and TMZ provided a synergistic effect.

Medical Subject Headings

Absorbable Implants; Animals; Antineoplastic Agents (administration & dosage, toxicity); Antineoplastic Agents, Alkylating (administration & dosage, toxicity); Brain Neoplasms (metabolism, prevention & control, radiotherapy); Cell Line, Tumor; Cell Proliferation (drug effects); Combined Modality Therapy; Dacarbazine (administration & dosage, analogs & derivatives, toxicity); Dichloroacetic Acid (administration & dosage, toxicity); Drug Administration Routes; Drug Combinations; Drug Delivery Systems; Female; Glioblastoma (metabolism, prevention & control, radiotherapy); Glycolysis (drug effects); Humans; Kaplan-Meier Estimate; Polymers; Pyruvates (administration & dosage, toxicity); Rats; Rats, Inbred F344; Temozolomide

Publication Date

1-1-2015

Publication Title

Neuro-oncology

E-ISSN

1523-5866

Volume

17

Issue

1

First Page

70

Last Page

80

PubMed ID

25053853

Digital Object Identifier (DOI)

10.1093/neuonc/nou143

Recommended Citation

Wicks, Robert T.; Azadi, Javad; Mangraviti, Antonella; Zhang, Irma; Hwang, Lee; Joshi, Avadhut; Bow, Hansen; Hutt-Cabezas, Marianne; Martin, Kristin L.; Rudek, Michelle A.; Zhao, Ming; Brem, Henry; and Tyler, Betty M., "Local delivery of cancer-cell glycolytic inhibitors in high-grade glioma" (2015). Neurosurgery. 2317.
https://scholar.barrowneuro.org/neurosurgery/2317