The long term objective is to demonstrate the efficacy, safety, and cost-effectiveness of thrombospondin-I (TSP-I) peptides containing the CSVTCG sequence or mimetics, either alone or in combination with other agents, to treat cancer metastasis. The specific aim of this STTR proposal is to test the hypothesis that heparin binding sequences flanking the sequence CSVTCG, present in the type 1 repeats of TSP-I, potentiates the antimetastatic activity of CSVTCG. Recent data in the literature showing that these heparin-binding sequences inhibit breast cancer progression and our data showing that CSVTCG peptides inhibit tumor cell metastasis provide a strong rationale for these studies. We propose to synthesize 10 peptides and test their activity in in vitro assays that should be predictive of their antimetastatic activity. These assays are inhibition of TSP-I tumor cell binding, affinity of peptide binding to cloned TSP-I receptor and TSP-I mediated tumor cell invasion. Peptides displaying the greatest activity in these assays will then be evaluated in two experimental animal models of tumor cell metastasis- a mouse melanoma spontaneous metastasis model and a human xenograft orthotopic breast carcinoma model. These studies will identify peptides that will be further evaluated for toxicity and pharmacokinetics in a Phase II proposal. Phase II studies will provide information for optimal dose and treatment schedules required for testing of these compounds in man. PROPOSED COMMERCIAL APPLICATION: Improving cancer survival and quality of life is a major goal of cancer research. The therapies developed in this proposal will be used to treat metastatic disease for all forms of cancer. We will initially target lung cancer since the mortality rates for this cancer are the highest. An agent that reduces mortality and improves quality of life would have a significant clinical and economic impact by reducing the length of hospital stay and the associated costs and risks.
