The overall objective of the proposed two-year research plan is to: (1) Evaluate the effects of a new class of tetracycline derivatives, called chemically modified tetracyclines (CMTs), for their ability to inhibit human melanoma tumor vasculogenesis and angiogenesis; (2) To address specific biological mechanisms affected by CMTs (such as MMP activity, endothelial and tumor cell migratory and invasive ability); and (3) To provide important laboratory-based evidence demonstrating the potential utility of this class of compounds in inhibiting angiogenic events critical for invasion and metastasis. The proposed research strategy addresses the differences in the biological parameters of tumor vasculogenesis - the formation of microvessels by melanoma tumor cells (which express endothelial markers) vs. angiogenesis - the formation of microvessels by endothelial cells. Tumor vasculogenesis is a new concept that we have recently introduced, and this proposal specifically focuses on the mechanisms underlying the inhibition of these two fundamental processes -- which collectively contribute to the metastatic dissemination of human melanoma. The two tumor models chosen for this study are uveal melanoma and cutaneous melanoma, which exhibit different pathways of metastatic dissemination which will allow us to discriminate between vasculogenesis and angiogenesis -- and will provide important new targets for therapeutic intervention.
Aim 1 : Evaluate the effects of a new class of chemically modified tetracyclines (CMTs) on human melanoma tumor vasculogenesis -- in 3-D in vitro models and in orthotopic in vivo models. Hypothesis: Specific CMTs will inhibit the ability of human melanoma tumor cells to form tumor vessels via suppression of MMPs and invasive ability -- thus, abrogating metastasis.
Aim 2 : Determine the effects of CMTs on angiogenesis and mechanisms associated with angiogenesis involved in the support of primary tumors and metastatic foci. Hypothesis: The process of angiogenesis will be inhibited by CMTs through the inhibition of tumor cell/endothelial cell interactions and MMP production.
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