Kenneth W. Brunson

The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions.

Bruce S. McEwen , Christine A. Biron , Kenneth W. Brunson , Karen Bulloch , William H. Chambers , Firdaus S. Dhabhar , Ronald H. Goldfarb , Richard P. Kitson , Andrew H. Miller , Robert L. Spencer , Jay M. Weiss d a Laboratory of Neuroendocrinology, Rockefeller UniÕersity, 1230 York AÕenue, Box 165, New York, NY 10021, USA b DiÕision of Biology and Medicine, Brown UniÕersity, ProÕidence, RI, USA c Pittsburgh Cancer Institute, UniÕersity of Pittsburgh, School of Medicine, Pittsburgh, PA, USA d Department of Psychiatry and BehaÕioral Sciences, Emory UniÕersity School of Medicine, Atlanta, GA, USA

Therapeutic agents for treatment of established metastases and inhibitors of metastatic spread: preclinical and clinical progress.

This article reviews recently described agents for the treatment of established metastases or inhibitors of metastatic spread. Recent progress in both preclinical models of experimental metastasis and clinical evaluation is highlighted. Where possible, distinctions are made between therapeutic agents for established metastatic tumors and those that merely interfere with the process of metastasis. The approaches emphasized include radiotherapy, cytotoxic chemotherapy, targeting the metastatic process and tumor metastases (adhesion, invasion, and angiogenesis), and modulation of the immune response, including chemoimmunotherapy. Emphasis has been placed on the necessity of using appropriate animal models of metastatic disease for the discovery and development of novel and effective antimetastatic therapeutic agents. Also addressed is the likelihood that future approaches to the metastasis problem will employ novel combined antimetastatic therapeutic modalities.

A KDR-binding peptide (ST100,059) can block angiogenesis, melanoma tumor growth and metastasis in vitro and in vivo

A major goal of treatment strategies for cancer is the development of agents which can block primary tumor growth and development as well as the progression of tumor metastasis without any treatment associated side effects. Using mini peptide display (MPD) technology, we generated peptides that can bind to the human vascular endothelial growth factor (VEGF) receptor KDR. These peptides were evaluated for their ability to block angiogenesis, tumor growth and metastasis in vitro and in vivo. A D-amino acid peptide with high serum stability (ST100,059) was found to have the most potent activity in vitro as indicated by inhibition of VEGF stimulation of endothelial cells. It was also found to be the most active of the series in blocking VEGF-mediated activity in vivo, as measured in Matrigel-filled angioreactors implanted in mice. ST100,059 blocks VEGF-induced MAPK phosphorylation, as well as inhibits VEGF-induced changes in gene expression in HUVEC cells. In in vivo studies, treatment of female C57BL/6 mice inoculated with B16 mouse melanoma cells with ST100,059 resulted in a dose-dependent decrease in tumor volume and lung metastasis as compared to control groups of animals receiving vehicle alone. These studies demonstrate that by using MPD, peptides can be identified with enhanced affinity relative to those discovered using phage display. Based on these studies we have identified one such peptide ST100,059 which can effectively block tumor growth and metastasis due to its anti-angiogenic effects and ability to block intracellular signaling pathways involved in tumor progression.

Experimental Brain Metastasis

Tumor metastasis is a complex, multistep process that appears to be dependent upon a number of host and tumor properties (Fidler 1975a; Weiss 1977a; Fidler and Nicolson 1979; Nicolson 1978a). First, emergent malignant tumor cells must be able to survive and grow in a potentially hostile environment and proliferate to form a primary tumor. Once a primary tumor is established, invasion of surrounding normal tissues may take place by mechanical infiltration (Eaves 1973), enzymatic digestion (Dresden et al. 1972), or both. If a primary tumor is able to penetrate blood vessels, malignant cells can be transported to distant sites. Several factors probably influence tumor-cell detachment (Weiss 1977b) and survival in the circulation. While in the blood, tumor cells (or cell emboli) can interact with a variety of humoral or cellular components (such as lymphocytes, platelets, endothelial cells). The hostile environment of the circulatory system probably causes the death of most blood-borne malignant cells originating from solid tumors; only a small percentage of tumor cells actually survive to form secondary tumors (Fidler 1970, 1976). Survival at a distant site appears to involve successful implantation in the microcirculation, extravasation and establishment of a proper environment for subsequent vascularization and growth.

Overview of Current Understanding of Tumor Spread

Progressive stages of malignant neoplastic growth can lead to cancer metastasis which is the major cause of treatment’ failure, moribidity, and death for patients with solid malignant tumors (5, 12, 33, 44, 45, 51, 56, 58, 59). Although the treatment modalities of radiotherapy, chemotherapy, and surgery effectively treat approximately 50 per cent of patients who develop malignant tumors, the majority of patients who are refractile to these therapeutic modalities succumb to the direct or indirect effect of tumor metastases or to adverse consequences associated with these therapeutic approaches (5, 33). At the time of diagnosis of primary tumors, approximately 50 per cent of patients with solid malignant tumors already host subclinical micrometastases, which may subsequently expand and contribute to direct anatomical compromise. In fact, a detected metastatic lesion in a particular organ may indicate the presence of other occult micrometastases. The heterogeneity of metastatic subpopulations and their scattered anatomic distribution may indeed limit or prevent effective surgical or chemotherapeutic intervention (5, 33).

Immunosuppression by Metastatic Tumors

The role of the immune response in preventing or limiting tumor growth as well as affecting the outcome of tumor metastases has long been debated among cancer biologists. A general consensus has emerged which depicts the major components of the immune system which are involved in immune surveillance and immunologic mechanisms of tumor cell killing to be cell-mediated: T-cell mediated cytotoxicity, macrophage mediated cytotoxicity (including antibody-dependent cell-mediated cytotoxicity, or ADCC, which may involve the macrophage as well as certain other cell populations) and natural killer (NK) cell cytotoxicity of tumor cells (2, 4, 6, 29). All too obviously, these mechanisms are not always completely effective in controlling the development, progressive outgrowth and metastasis of tumor cells. Cancer cells may circumvent control by the immune system in various ‘escape’ mechanisms, such as antigenic modulation, growth in immunologically ‘privileged’ sites, production of excess antigen or antigen-antibody complexes (including ‘blocking factors’), or immunosuppression.

Selected Aspects of Differentiation in Malignant Neoplastic Growth

It is widely accepted that malignant disease is associated with disorders in differentiation. Indeed, it has been observed that the patient with cancer is a product of abnormal cell differentiation (16). It is therefore likely that an understanding of cellular differentiation and an understanding of the development of neoplasia can lead to new strategies for the diagnosis and therapy of malignant disease. Many experimental research areas have been explored in the study of differentiation and cancer including: genetic control; chromosome abnormalities; growth regulation of malignant tumor cells; differentiation of stem cells; and the regulation of differentiation as a potential therapeutic modality (1, 21, 24, 25). This chapter will review molecular and cellular aspects of differentiation, its relevance to tumor progression and malignancy, and discuss the significance of these findings to therapeutic approaches for the control of malignant diseases.

Observations of Primary and Secondary Lesions in the Same Patient

Invasive neoplastic growth can lead to cancer metastasis, and cancer mortality is most often related to cancer metastasis rather than the primary lesion (16). In an effort to learn more about human cancer metastasis, a number of animal tumor models have been developed in the last several years in an attempt to critically examine parameters of primary versus metastatic cancer lesions. Some of these models have explored differences between primary tumors and metastatic cell lines derived from them which develop lesions preferentially in specific secondary organs, such as lungs (13), liver (8, 36, 39), brain (10) or ovaries (9). Metastatic variant cell lines have often been noted to differ from primary cell lines in several characteristics, such as antigenicity (4, 12, 21, 22, 23, 25, 33, 34, 36), resistance to killing by host cells (17, 27) and drug resistance (1, 32, 42).

Oncogene Products as Potential Therapeutic Targets for Control of Established Metastatic Disease

An explosive pace of research has developed in the last several years exploring the role of oncogenes and their products (see preceding Chapters, 10–14, this volume). The potential of elucidating the molecular mechanisms operative in neoplastic transformation has generated widespread excitement and research interest within the scientific community, particularly among cancer biologists. A large component of research performed in this area has been directed towards understanding the biochemical and molecular basis of the initiation and promotion of the transformed phenotype of cells that have undergone oncogenic transfection in cell culture (4, 26, 46, 47, 51, 89, 90). A variety of studies have also indicated that oncogenes and their products may also contribute to additional aspects of tumor progression (5, 46, 47, 62, 87). Most recently, a number of research groups have carried out investigations to ascertain whether oncogenes and their encoded gene products contribute to the progressive stages of malignant neoplastic growth resulting in tumor invasion in tumor invasion and metastatic spread (1, 6, 7, 19, 20, 21, 22, 49, 68, 80, 85).