The objective of this proposal is to evaluate a new therapeutic strategy for the treatment of metastatic breast cancer. The treatment approach is based on the observation that solid tumors require a blood supply for continued growth, both at the primary site and at metastatic sites. Solid tumors are able to induce the formation of new blood vessels, referred to as angiogenesis, by directly secreting compounds that are angiogenic or by inducing surrounding nonmalignant cells to secrete angiogenic compounds. Many of these compounds have been identified using bioassays such as the chorioallantoic membrane assay of the chick embryo ( basic/acidic FGF, angiogenin, TNF-alpha, TGF-alpha/beta, VEGF, etc.). Using the same bioassays inhibitors of angiogenesis have been identified which include certain steroids progestins, angiostatic antibiotics, angiostatic polysaccharides, vitamin derivatives, interferons, cytokines, platelet- derived products, metalloproteinase inhibitors, and polyanionic compounds like suramin. Suramin is a unique compound (polysulfonated napthylurea) that demonstrates antineoplastic activity through several possible mechanisms. Suramin is able to bind to and /or antagonize a number of peptide growth factors including acidic / basic FGF and TGF-beta which are known angiogenic compounds. FGF expression may be important in the development of the metastatic phenotype and the progression of breast tumors from estrogen-dependent to estrogen -independent. In addition FGFs have been identified in a number of solid tumors including breast cancer. Suramin can also induce differentiation in cell lines; inhibit mitochondrial function, glycolysis,steroidogenesis, membrane ion pumps and protein C kinase.
Specific Aim 1 is to conduct a clinical trial in patients with metastatic breast cancer in order to evaluate the efficacy and toxicity of suramin as an antineoplastic agent.
Specific Aim 2 involves several correlative laboratory studies to be done in conjunction with the clinical trial in an effort to define how suramin inhibits tumor angiogenesis. a) Tumor tissue will be analyzed pre-and post- therapy to assess vascular density. b) Patient sera will be analyzed to determine if suramin alters angiogenic activity as detected by the endothelial cell migration assay and endothelial cell mitogenesis assay. c) An effort will be made to identify angiogenic modulators in patients exhibiting a biological response to suramin treatment. This proposal can serve as a template for the evaluation of other compounds that may inhibit angiogenesis.
| Gradishar, W J; Soff, G; Liu, J et al. (2000) A pilot trial of suramin in metastatic breast cancer to assess antiangiogenic activity in individual patients. Oncology 58:324-33 |
| Gradishar, W J; Tallman, M S; Abrams, J S (1996) High-dose chemotherapy for breast cancer. Ann Intern Med 125:599-604 |
