Preclinical evaluation of antiangiogenic thrombospondin-1 peptide mimetics, ABT-526 and ABT-510, in companion dogs with naturally occurring cancers.
OBJECTIVE
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.


METHODS
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.
Rusk
Anthony
A
Animal Clinical Investigation, LLC, Columbia, Maryland, USA. trusk@animalci.com
McKeegan
Evelyn
E
Haviv
Fortuna
F
Majest
Sandra
S
Henkin
Jack
J
Khanna
Chand
C
D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D019700:Thrombospondin 1 / Q000009:adverse effects / Q000819:agonists / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D010446:Peptide Fragments; D019700:Thrombospondin 1; C477606:acetyl-sarcosyl-glycyl-valyl-isoleucyl-threonyl-norvalyl-isoleucyl-arginyl-proline ethylamide