Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma.

Abstract

Patients with anaplastic thyroid carcinoma (ATC) typically succumb to their disease months after diagnosis despite aggressive therapy. A large percentage of ATCs have been shown to harbor the V600E B-Raf point mutation, leading to the constitutive activation of the mitogen-activated protein kinase pathway. ATC invasion, metastasis, and angiogenesis are in part dependent on the gelatinase class of matrix metalloproteinases (MMP). The explicit targeting of these two tumor markers may provide a novel therapeutic strategy for the treatment of ATC. The MMP-activated anthrax lethal toxin (LeTx), a novel recombinant protein toxin combination, shows potent mitogen-activated protein kinase pathway inhibition in gelatinase-expressing V600E B-Raf tumor cells in vitro. However, preliminary in vivo studies showed that the MMP-activated LeTx also exhibited dramatic antitumor activity against xenografts that did not show significant antiproliferative responses to the LeTx in vitro. Here, we show that the MMP-activated LeTx inhibits orthotopic ATC xenograft progression in both toxin-sensitive and toxin-resistant ATC cells via reduced endothelial cell recruitment and subsequent tumor vascularization. This in turn translates to an improved long-term survival that is comparable with that produced by the multikinase inhibitor sorafenib. Our results also indicate that therapy with the MMP-activated LeTx is extremely effective against advanced tumors with well-established vascular networks. Taken together, these results suggest that the MMP-activated LeTx-mediated endothelial cell targeting is the primary in vivo antitumor mechanism of this novel toxin. Therefore, the MMP-activated LeTx could be used not only in the clinical management of V600E B-Raf ATC but potentially in any solid tumor.

• Authors: Randall W Alfano, Stephen H Leppla, Shihui Liu, Thomas H Bugge, Janelle M Ortiz, Terry C Lairmore, Nicholas S Duesbery, Ian C Mitchell, Fiemu Nwariaku, Arthur E Frankel
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 1 Pg. 190-201 (Jan 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20053778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Bacterial
• Bacterial Toxins
• Benzenesulfonates
• Phenylurea Compounds
• Pyridines
• anthrax toxin
• Niacinamide
• Sorafenib
• Mitogen-Activated Protein Kinases
• Matrix Metalloproteinases

Topics

• Animals
• Antigens, Bacterial (pharmacology, therapeutic use)
• Bacterial Toxins (pharmacology, therapeutic use)
• Benzenesulfonates (pharmacology)
• Carcinoma (blood supply, drug therapy, enzymology, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Endocytosis (drug effects)
• Humans
• Matrix Metalloproteinases (metabolism)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Neovascularization, Pathologic (drug therapy)
• Niacinamide (analogs & derivatives)
• Phenylurea Compounds
• Pyridines (pharmacology)
• Sorafenib
• Survival Analysis
• Thyroid Neoplasms (blood supply, drug therapy, enzymology, pathology)
• Time Factors
• Xenograft Model Antitumor Assays