Peter D. Brown

Preclinical and clinical studies of MMP inhibitors in cancer.

ABSTRACT: The role of matrix metalloproteinases in tumor angiogenesis and growth is now well recognized for models of both human and animal cancer. Clinical studies currently under way with the prototype matrix metalloproteinase inhibitor, marimastat, will establish whether inhibitors of these enzymes are of benefit in the treatment of different types of human cancer. On chronic therapy in humans, marimastat induces a reversible tendinitis that can also be detected in certain animal species. This paper compares the ability of broad‐spectrum and various types of selective matrix metalloproteinase inhibitors to induce tendinitis and to exhibit anticancer effects in an animal cancer model. Under conditions in which both systemic exposure and inhibitor potency are controlled, selective inhibitors are less pro‐tendinitic, but are weaker anticancer agents than broad‐spectrum agents such as marimastat. The clinical relevance of these findings is discussed.

Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis.

Matrix metalloproteinase (MMP) activity has been associated with tumor invasion and metastasis in many different tumor types, but recent studies also support a role for these enzymes in earlier stages of the tumor progression continuum. Specifically, the expression pattern of MMPs in benign human and mouse gastrointestinal tumors suggests that they may function in the development or growth of non‐invasive tumors. To address the contribution of MMP activity to the development of intestinal adenomas, we administered the synthetic MMP inhibitor batimastat and expressed the tissue inhibitor of metalloproteinases‐1 (TIMP‐1) in the gastrointestinal tract of Min mice, which spontaneously develop pre‐malignant small and large intestinal tumors. Batimastat administration resulted in a 48% decrease in the number of Min tumors. This reduction in tumor number is similar to that observed in mice lacking the metalloproteinase matrilysin, and demonstrates the therapeutic and chemopreventive potential of MMP inhibitors for pre‐malignant intestinal tumors. In contrast, forced TIMP‐1 expression in transgenic mice had no effect or, in one line, unexpectedly augmented Min tumor multiplicity by 32%. This observation supports an in vivo tumor‐promoting activity of TIMP‐1 that could be related to the growth stimulatory effects of TIMP that have been documented in vitro. Taken together, these 2 approaches of modulating MMP activity in Min mice support a critical function of MMPs in Min tumorigenesis, underscore the importance of an MMP/ inhibitor balance in maintaining tissue homeostasis and demonstrate that endogenous MMP inhibitors can have complex effects in particular cellular contexts.Int. J. Cancer 78:629–635, 1998.

Role of type IV collagenases in human breast cancer

In breast cancer, as in most other malignant human tumors, the most ominous aspect of the oncogenic process is the local invasion and subsequent metastasis of the primary tumor. The single most important prognostic factor in patients with breast cancer is the presence of neoplastic cells in the axillary lymph nodes [1]. If these nodes are positive for cancer cells, there is the potential for the dissemination of tumor cells to the lungs, adrenals, liver, bone, and brain. The growth of metastatic foci at these distant sites is the most common cause of death for patients with breast cancer. Although our understanding of the pathogenesis of metastasis formation has increased, progress has been slowed by the profound complexity of the metastatic cascade. One successful strategy for dealing with this complexity has been to separate the metastatic process into a series of steps and to define specific genes or gene products that are activated at each step [2]. This has led to the emergence of several basic themes, which have allowed identification of new strategies for the diagnosis and therapy of breast cancer.

Hydroxamic Acid Matrix Metalloproteinase Inhibitors

It is now apparent that the matrix metalloproteinases (MMPs) play a key role in the remodeling of basement membrane that is associated with tumor metastasis, growth, and angiogenesis. Thus there is considerable interest in the design of MMP inhibitors (MMPIs) (1–6) as they promise to provide a novel noncytotoxic means of treating human cancer. Furthermore, pharmacological studies of MMPIs in animal models of human disease suggest that the potential therapeutic applications will encompass other endpoints such as arthritis and multiple-sclerosis. Recently, evidence has shown that MMP inhibitors can also reduce the production of TNF-α by inhibiting a TNF-α converting enzyme (TACE) (7–9). As a consequence, this “dual activity” may be of benefit in diseases which involve both inflammation and matrix remodeling. In this chapter we review the hydroxamic acid class of MMPIs with specific reference to the research program at British Biotech and the compounds batimastat 1 (BB-94) and marimastat 2 (BB-2516) (Fig. 1). Batimastat was the first MMPI to enter human clinical trials in cancer patients. This compound has been superseded by the orally active MMPI marimastat which is now under Phase III clinical evaluation in late-stage cancer patients. Here we present an overview of the medicinal chemistry relating to batimastat and marimastat, discuss the preclinical evaluation of compounds of this class in animal models of cancer and other human diseases and review the current clinical status for marimastat.