Preclinical Anti-Tumor Efficacy of ABT-510 (Thrombospondin-1 Mimetic Peptide), a Novel Anti-Angiogenic Agent, in Hematological Malignancies.

Abstract Thrombospondin-1 (TSP-1) is a multi-functional 420 kDa matrix protein implicated in cancer cell adhesion, migration, and invasion and is a potent anti-angiogenic agent. TSP-1 expression is inversely correlated with vascularization and malignant progression of breast and lung cancers but has not been extensively investigated in hematological malignancies. We found low total mRNA levels of TSP-1 expression by RT-PCR in half (7 out of 14) of human cell lines representing lymphoma, leukemia, and myeloma. We also found lower total mRNA TSP-1 levels in two thirds (10 out of 15) of primary patient leukemia samples as compared to human umbilical vein endothelial cells (HUVEC). Treatment of human leukemia and lymphoma cell lines with recombinant TSP-1 (100 mg/ml) or ABT-510 (a novel synthetic peptide derivative of TSP-1) decreased tumor cell proliferation as measured by tritiated thymidine incorporation. Single agent ABT-510 treatment (total daily doses 50–120 mg/kg i.p. daily) resulted in statistically significant reduction in tumor volumes of subcutaneous SKI-DLBCL (diffuse large B cell lymphoma) xenografts. ABT-510 treatment (60 mg/kg IP bid) in disseminated SKI-DLBCL lymphoma mouse models resulted in increased long-term survival consistent with delayed disease progression. We then examined the effects of ABT-510 treatment in combination with anthracycline chemotherapy used in standard lymphoma regimens (doxorubicin) or another anti-angiogenic agent (anti-hVEGF antibody Avastin) in subcutaneous lymphoma xenografts. Our results suggest an additive effect with concomitant ABT-510 (60 mg/kg bid) and doxorubicin (3 mg/kg TIW) treatment, but no additive effect with concomitant ABT-510 (60 mg/kg bid) and Avastin (3 mg/kg TIW) treatment. Conclusion: Our data suggest that decreased levels of thrombospondin-1, a matrix protein with endogenous anti-angiogenic activity, play a role in the growth of human hematological malignancies. Based on these results, the TSP-1 synthetic peptide, ABT-510, represents a novel anti-angiogenic therapeutic strategy for patients with these diseases and warrants additional preclinical investigation in combination regimens. (Of note, a phase II trial of single agent ABT-510 in refractory/relapsed lymphoma patients has recently completed enrollment).