Preclinical Evaluation of Antiangiogenic Thrombospondin-1 Peptide Mimetics, ABT-526 and ABT-510, in Companion Dogs with Naturally Occurring Cancers

• Published in: Clinical cancer research Vol. 12; no. 24; pp. 7444 - 7455
• Main Authors: RUSK, Anthony, MCKEEGAN, Evelyn, HAVIV, Fortuna, MAJEST, Sandra, HENKIN, Jack, KHANNA, Chand
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-12-2006
• Subjects: angiogenesis; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - blood; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic agents; Biological and medical sciences; cancer; Cell Movement - drug effects; dog; Dogs; Drug Screening Assays, Antitumor; Endothelial Cells - drug effects; Female; Humans; Male; Medical sciences; Neoplasms - drug therapy; Oligopeptides - adverse effects; Oligopeptides - blood; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Peptide Fragments - adverse effects; Peptide Fragments - blood; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Pharmacology. Drug treatments; preclinical; therapy; Thrombospondin 1 - adverse effects; Thrombospondin 1 - agonists; Thrombospondin 1 - blood; Thrombospondin 1 - pharmacology; Thrombospondin 1 - therapeutic use; thrombospondin-1; Tumor Cells, Cultured; Fissipedia; Evaluation; Carnivora; Peptidomimetic compound; Preclinical trial; Malignant tumor; Thrombospondin 1; Vertebrata; Mammalia; Animal; Antiangiogenic agent; Dog; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0109

Purpose: The angiogenic phenotype of malignant cancers has been established as a target for cancer therapy. ABT-526 and ABT-510, two
peptide mimetics of thrombospondin-1 (TSP-1), block angiogenesis in vitro and in vivo and slow tumor growth in mice. To guide the clinical development of these drugs, translational studies in dogs with naturally
occurring cancers were initiated.
Experimental Design: A prospective open-label trial using ABT-510 or ABT-526 in pet dogs with measurable malignant spontaneously arising tumors.
Endpoints included safety, pharmacokinetics, antitumor activity, and preliminary assessment of changes in circulating endothelial
cell populations.
Results: Two-hundred and forty-two dogs were sequentially entered to this open-label trial. The elimination half-life for ABT-510
and ABT-526 was 0.7 and 0.8 h, respectively (range, 0.5-1 h). No dose-limiting toxicities were seen in any dogs ( N = 242). Forty-two dogs receiving peptide had objective responses (>50% reduction in tumor size; n = 6) or significant disease stabilization. Most objective responses were seen after 60 days of exposure to the TSP-1 peptide.
Antitumor activity was similar for both peptides and was seen in several histologies, including mammary carcinoma, head and
neck carcinoma, soft tissue sarcoma, cutaneous T-cell lymphoma, and non–Hodgkin's lymphoma. Assessment of circulating endothelial
cell populations in a small subset of dogs suggested that effective exposure to TSP-1 peptides may be associated with reductions
in circulating endothelial cells.
Conclusions: These results support the safety and activity of ABT-526 and ABT-510 in dogs with naturally occurring malignant cancers.
Data from this preclinical trial support the development of TSP-1 mimetic peptides as anticancer agents.