Journal
CANCER RESEARCH
Volume 70, Issue 11, Pages 4520-4527Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-4311
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Funding
- Wallace H. Coulter Foundation
- Cancer Research Coordinating Committee
- USPHS [R01 DK 21739]
- Burroughs Wellcome Fund
- Brain Tumor Society
- Accelerate Brain Cancer Cure
- Samuel G. Waxman Foundation
- NIH [P50CA097257, T32 CA108462-01]
- Campini Foundation
- American Brain Tumor Association
- NATIONAL CANCER INSTITUTE [P50CA097257, T32CA108462] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R56DK021739, R01DK021739] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [K08NS063456] Funding Source: NIH RePORTER
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Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor with median survival of only 12 to 15 months under the current standard of care. To both increase tumor specificity and decrease nonspecific side effects, recent experimental strategies in the treatment of GBM have focused on targeting cell surface receptors, including the transferrin (Tf) receptor, that are overexpressed in many cancers. A major limitation of Tf-based therapeutics is the short association of Tf within the cell to deliver its payload. We previously developed two mutant Tf molecules, K206E/R632A Tf and K206E/K534A Tf, in which iron is locked into each of the two homologous lobes. Relative to wild-type Tf, we showed enhanced delivery of diphtheria toxin (DT) from these mutants to a monolayer culture of HeLa cells. Here, we extend the application of our Tf mutants to the treatment of GBM. In vitro treatment of Tf mutants to a monolayer culture of glioma cells showed enhanced cellular association as well as enhanced delivery of conjugated DT. Treatment of GBM xenografts with mutant Tf-conjugated DT resulted in pronounced regression in vivo, indicating their potential use as drug carriers. Cancer Res; 70(11); 4520-7. (c) 2010 AACR.
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