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

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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. Mol Cancer

Original languageEnglish (US)
Pages (from-to)190-201
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number1
DOIs
StatePublished - Jan 2010

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Matrix Metalloproteinases
Neoplasms
Gelatinases
Mitogen-Activated Protein Kinases
Heterografts
Endothelial Cells
Therapeutics
Tumor Biomarkers
Anaplastic Thyroid Carcinoma
anthrax toxin
Point Mutation
Recombinant Proteins
Blood Vessels
Neoplasm Metastasis
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma. / Alfano, Randall W.; Leppla, Stephen H.; Liu, Shihui; Bugge, Thomas H.; Ortiz, Janelle M.; Lairmore, Terry C.; Duesbery, Nicholas S.; Mitchell, Ian C.; Nwariaku, Fiemu; Frankel, Arthur E.

In: Molecular Cancer Therapeutics, Vol. 9, No. 1, 01.2010, p. 190-201.

Research output: Contribution to journalArticle

Alfano, Randall W. ; Leppla, Stephen H. ; Liu, Shihui ; Bugge, Thomas H. ; Ortiz, Janelle M. ; Lairmore, Terry C. ; Duesbery, Nicholas S. ; Mitchell, Ian C. ; Nwariaku, Fiemu ; Frankel, Arthur E. / Inhibition of tumor angiogenesis by the matrix metalloproteinase-activated anthrax lethal toxin in an orthotopic model of anaplastic thyroid carcinoma. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 1. pp. 190-201.
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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. Mol Cancer",
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