There are a number of ways in which the properties of TSP-1 and -2 could be used to inhibit the vascularity and/or growth and metastasis of tumors. For example, TSP-1 binds VEGF directly, and the complex can be endocytosed by the scavenger receptor, LRP1 (Greenaway et al. 2007
). This clearance function is analogous to that by which TSPs reduce the levels of MMP2 (Yang et al. 2001
) and MMP9 (Hahn-Dantona et al. 2001
) in the pericellular environment. Similarly, other anti-angiogenic functions of TSP-1 and -2, described in this review, could be exploited. However, approaches that require administration of intact TSP are clearly not feasible in a clinical setting, and neither are cell-based therapies or therapies that depend on the use of viruses as delivery agents (Hahn et al. 2004
; see review by Mirochnik et al. 2008
, for a more complete review of the limitations of therapy with TSP-1).
On the other hand, peptides that mimic sequences in the type I repeats of TSP-1 show considerable promise as anti-tumor agents. Haviv et al. (2005
) synthesized a series of peptides based on a sequence in the second type I repeat of human TSP-1. Selected peptides, modified to increase their stability in vivo, were then tested for their anti-angiogenic properties by several criteria: inhibition of tube formation by human microvascular EC; induction of apoptosis; inhibition of EC migration; and inhibition of capillary sprout formation. Two of the peptides, ABT-526 and ABT-510, which showed the most promise, were then tested for their effectiveness as inhibitors of angiogenesis and tumor progression in animals. ABT-526 was found to be effective in the inhibition of neovascularization in a rat cornea model, and ABT-510 reduced the growth of a syngeneic Lewis lung carcinoma in mice (Haviv et al. 2005
The type I TSP repeats are also present in a number of related proteins other than the TSPs, such as pigment epithelium-derived factor (PEDF), WISP-1, and brain angiogenesis inhibitor-1(BAI-1). PEDF has been shown to be a potent inhibitor of angiogenesis in the mammalian eye (Dawson et al. 1999
). WISP-1 contains an 18 amino acid sequence, termed wispostatin-1, which is very similar to the Mal II and Mal III sequences in the type I repeats of TSP-1. Cano et al. (2009
) found that wispostatin-1 inhibited the migration and proliferation of human retinal EC, abolished FGF-induced retinal neo-vascularization in a corneal micropocket assay, and inhibited laser-induced choroidal neo-vascularization in mice. BAI-1, which contains five TSP type I repeats, can be cleaved at a conserved proteolytic cleavage site to release a soluble anti-angiogenic fragment termed vasculostatin, which contains these repeats (Kaur et al. 2005
). Vasculostatin suppresses the growth of malignant gliomas in rats and inhibits the migration of human dermal microvascular EC, but not that of human umbilical vein EC. These effects are dependent on the presence of CD36 on EC (Kaur et al. 2009
). Most recently, Ren et al. (2009
) have evaluated the ability of a ‘double hit,’ consisting of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and a TRAIL receptor 2 agonist antibody (Lexatumumab), which is directed to the type I repeats in TSP-1, to inhibit the progression of human colon cancer in nude mice and to induce apoptosis in human dermal microvascular EC. Favorable results were observed in both assays.
Perhaps the most encouraging studies that set the stage for the use of TSP peptide mimetics in the treatment of tumors in patients, involve the TSP-1-derived peptides, ABT-526 and ABT-510, developed by Haviv et al. (2005
). Hoekstra et al. (2006
), in a Phase I study, reported that the inclusion of ABT-510 in a course of therapy with 5-fluorouracil and leucovorin showed no ill effects in patients with solid tumors. Two studies in dogs are also encouraging. ABT-510 and ABT-526 were used to treat malignant tumors in 242 pet dogs. No dose-limiting toxicity was observed in any of the animals, and 42 of the dogs showed a greater than 50% reduction in tumor size (Rusk et al. 2006a
). In a second study of pet dogs with relapsed non-Hodgkin’s lymphoma, ABT-526 was added to chemotherapy with lomusine. Whereas no difference was observed in the rate of response, there was a significant increase in its duration, with no attendant toxicity (Rusk et al. 2006b
). In a different animal model, Greenaway et al. (2009
) showed that ABT-510 was effective in the induction of apoptosis of syngeneic mouse epithelial cancer cells, introduced into the bursa of C57BL/6 mice. Finally, in a recent phase II study, Baker et al. (2008
) treated patients with advanced soft tissue sarcoma with ABT-510. Although a favorable safety profile was observed, and the rate of disease control and overall survival were encouraging, the authors concluded that compelling evidence for the efficacy of ABT-510 as a single agent in this disease had not been achieved.
Additional trials with these two peptide mimetics are clearly necessary, and are likely to be performed. Hopefully, a reduction in the morbidity of some human cancers that results from a combinational therapy, including TSP derivatives, will be forthcoming.