batimastat and Melanoma

Matrix metalloproteinases (MMPs) are a homologous family of enzymes that are involved in tissue remodeling and morphogenesis. Collectively, these enzymes are capable of degrading all components of the extracellular matrix, and they play an important role in normal physiologic conditions, such as wound healing and other processes involving tissue remodeling. However, increased activity of these enzymes now has been observed in a number of different pathological conditions, and it has been hypothesized that such increased activity of MMPs might play a role in the pathogenesis of these conditions. Cancer is one such condition; extracellular matrices constitute the principal barrier to tumor growth and spread, and there is growing experimental evidence that malignant tumors utilize MMPs to overcome these barriers. Consequently, inhibitors of MMPs represent an attractive target for a new class of anticancer agents. Marimastat and batimastat are potent broad-spectrum inhibitors of all major MMPs and have been shown to prevent or reduce spread and growth of a number of different malignant tumors in numerous animal models. Both agents are now in advanced clinical testing in a number of different solid tumors in North America and Europe. The purpose of this paper is to review available preclinical and emerging clinical data, using batimastat and marimastat as prototype MMP inhibitors in the cancer area.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Enzyme Inhibitors; Female; Hemangioma; Humans; Hydroxamic Acids; Melanoma; Metalloendopeptidases; Mice; Ovarian Neoplasms; Pancreatic Neoplasms; Phenylalanine; Protease Inhibitors; Skin Neoplasms; Thiophenes

Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell-mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell-based cancer therapy.

Topics: ADAM Proteins; ADAM10 Protein; ADAM17 Protein; Amyloid Precursor Protein Secretases; B7 Antigens; Cell Line, Tumor; Dipeptides; HCT116 Cells; HeLa Cells; Humans; Hydroxamic Acids; Killer Cells, Natural; Lymphocyte Activation; MCF-7 Cells; Melanoma; Membrane Proteins; Natural Cytotoxicity Triggering Receptor 3; Phenylalanine; Protease Inhibitors; RNA Interference; RNA, Messenger; RNA, Small Interfering; Thiophenes; Tumor Escape; Up-Regulation