Angiogenesis and cancer: A cross-talk between basic science and clinical trials (the “do ut des” paradigm)

https://doi.org/10.1016/j.critrevonc.2006.02.007Get rights and content

Abstract

Angiogenesis plays a crucial role in facilitating tumor growth and the metastatic process, and it is the result of a dynamic balance between pro-angiogenic factors, like vascular endothelial growth factor (VEGF) and platelet-derived growth factor, and antiangiogenic factors, like thrombospondin-1 and angiostatin. Many drugs that target human tumors, like bevacizumab and some VEGF-receptor tyrosine-kinase inhibitors (e.g., BAY 43-9006, SU11248 and PTK787/ZK222584) have been studied in clinical trials, with favorable toxicity reports and encouraging results in advanced colorectal cancer, renal cell cancer, breast cancer and non-squamous non-small cell lung cancer, either combined with chemotherapy, or in monotherapy. Another potential approach to inhibiting angiogenesis is through metronomic chemotherapy (low doses of chemotherapy for long periods of time). This review describes the mechanisms of the angiogenic process and evaluates the recent data about antiangiogenic therapies in clinical trials.

Introduction

During the process of carcinogenesis, there is a progressive accumulation of changes in different genes leading to the insurgence of subpopulations of cells with specific biologic characteristics. This genetic instability is responsible for the activation of proto-oncogenes, the suppression (or decrease) in the activity of tumor-suppressor genes, unlimited cell growth and the loss of cells’ ability to undergo apoptosis, among others changes [1]. The metastatic process is the result of the systemic dissemination of cellular clones that have a pronounced tendency towards invading surrounding tissues.

Metastasis is one of the hallmarks of cancer. In cancer patients, metastatic lesions are often the source of their symptoms and their primary cause of death. In this context, angiogenesis plays a crucial role in facilitating the growth of the primary tumor and in generating metastasis. Moreover, angiogenesis also occurs physiologically, for instance, during the reproductive cycle and wound healing, and in pathological processes characterized by the presence of chronic inflammation, including psoriasis and arthritis.

The growth of a malignant tumor is heavily conditioned by adequate vasculature. Cancer cell survival is strictly dependent on optimal supplies of oxygen and nutrients, and also on the ability to eliminate toxic molecules. Oxygen, in fact, diffuses from capillaries to a distance of only 150–200 μm. As a consequence, to become clinically relevant, a tumor requires its own new and dedicated vasculature, which is mainly created by remodeling a pre-existing primitive network of blood vessels [2], [3], [4].

Section snippets

Regulation of angiogenesis

The regulation of angiogenesis both in physiologic and pathologic conditions is a complex, multistep process resulting from a dynamic balance between pro-angiogenic and antiangiogenic factors [5]. The mechanisms by which cancer cells stimulate pathological angiogenesis mimic those used by normal cells to foster physiological angiogenesis [6]. However, the tumor microvasculature is structurally, functionally and even genetically altered in comparison to that we observe in physiologic conditions

Angiogenesis as a therapeutic target in human tumors

Several attempts have been made to classify the therapeutic agents that interfere with the process of angiogenesis. This task, however, has revealed itself to be particularly arduous because of the large number of complex and mainly unpredictable mechanisms involved in the angiogenic cascade. Because of the variability in experimental models designed to assess angiogenesis, and suboptimal reproducibility between pre-clinical and clinical effects, a classification system based on the efficacy of

Integration of antiangiogenic drugs into the anticancer armamentarium

A review of phase 1 clinical trials in oncology sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute, USA between 1991 and 2002 was recently published [42]. This analysis revealed a very low rate of response in 15 trials (the overall response rate was 3.9%, and the complete response rate was 0.6%) when antiangiogenic drugs were used as single agents. In contrast, the rate of stable disease and less-than-partial response was found to be 31%. Interestingly, the

Metronomic chemotherapy

Among the various potential approaches to inhibiting angiogenesis, metronomic therapy merits particular mention. Metronomic chemotherapy (metroCT) refers to the frequent, even daily, administration of CT in doses below the MTD (maximum tolerated dose), for long periods of time, with no prolonged drug-free breaks [72]. In some pre-clinical models, metroCT was effective in treating tumors previously resistant to the same CT agents used in a non-metronomic way [73], [74]. It was also shown that

Toxicity issues

Antiangiogenic therapy is generally well tolerated. The previously described analysis of phase 1 trials did not report toxic death for any of the 402 patients assessed for toxicity when antiangiogenic agents where used as monotherapy [42]. Mature data on safety profiles are available for bevacizumab, following the results of recently reported phase II and phase III trials. Hypertension is a common but manageable side effect. The pathogenic mechanism still remains to be elucidated. In

Perspectives

The previous belief that endothelial cells within tumor vessels are genetically stable has been recently been cast into doubt, with studies reporting significant variability of the vascular characteristics, which are often tissue- and tumor-specific. In fact, several microenvironmental factors that are strictly dependent on the tumor may influence the genotype of the cells forming the tumor vasculature. The exact mechanisms of these genetic changes are not known, although different hypotheses

Reviewers

Jerome Fayette, M.D., Ph.D., Hopital Edouard Herriot, Medical Oncology Department, Pavilion E, 5, place d’Arsonval, FR-69003 Lyon, France.

Jean-Pierre Armand, M.D., Medical Oncology Department, Institut Gustave Roussy, 39, rue Camille Desmoulins, FR-94805 Villejuif, Cedex, France.

Prof. Alberto F. Sobrero, Medical Oncology, Ospedale S. Martino, Largo Benzi 10, IT-16132 Genova, Italy.

Prof. Gilberto Schwartsmann, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande so Sul,

Acknowledgments

The authors are indebted to Mrs. C. Straehle for her editorial assistance, and also to the Fonds National de la Recherche Scientifique (FNRS) and to the Associazione Italiana di Oncologia Medica (AIOM) for their grants to Gilberto de Castro Junior and to Fabio Puglisi, respectively. They are both visiting Research Fellows at the Medical Oncology Clinic, Institut Jules Bordet, in Brussels, Belgium.

Ahmad Awada M.D., Ph.D., was born in Lebanon and received his medical training at the Medical School of the Free University in Brussels, Belgium. At the Jules Bordet Institute in Brussels, he specialized in Internal Medicine and Medical Oncology. His clinical activities focus on the treatment of solid tumors and the development of new therapies and anticancer drugs in phases I and II clinical trials using both cytotoxic and molecular-targeted agents, some of them widely used in daily clinical

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    Ahmad Awada M.D., Ph.D., was born in Lebanon and received his medical training at the Medical School of the Free University in Brussels, Belgium. At the Jules Bordet Institute in Brussels, he specialized in Internal Medicine and Medical Oncology. His clinical activities focus on the treatment of solid tumors and the development of new therapies and anticancer drugs in phases I and II clinical trials using both cytotoxic and molecular-targeted agents, some of them widely used in daily clinical practice. Currently, he is the Head of the Medical Oncology Clinic of the Jules Bordet Institute, Brussels, and he also participates in several European Organisation for Research and Treatment of Cancer (EORTC) research groups. He is the author of over 70 peer-reviewed papers in high impact medical journals, as well as more than 20 book chapters. He is also the recipient of an award from the Belgian Royal Academy of Medicine.

    Nagi S. El Saghir, M.D., F.A.C.P., graduated from the Free University of Brussels, Belgium. He completed his residency at The Brooklyn Hospital of SUNY-Downstate in Brooklyn, and his Fellowship at St. Luke's, Roosevelt Hospital Center of Columbia University in New York. He was Clinical Instructor of Medicine at Long Island College Hospital and State University of New York, then Assistant Professor at King Saud University in Rihadh, Saudi Arabia, and later Clinical Assistant Professor at Oakwood Hospital and Wayne State University in Detroit, Michigan. He now is Clinical Associate Professor of Medicine and Hematology–Oncology at the American University of Beirut, Beirut, Lebanon, and also a member of the EORTC Breast Cancer Group.

    Gilberto de Castro Junior, M.D., M.Sc., received his M.D. degree at the University of São Paulo Medical School, São Paulo, Brazil and completed his residency and specialization in both Internal Medicine and Medical Oncology at the Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, Brazil. He received his M.Sc. degree in 2005 at the same University working on concurrent chemoradiation in patients with unresectable locally advanced head and neck cancer. He was a Fellow of the Clinique d’Oncologie Médicale, Institut Jules Bordet, Brussels, Belgium, between 2004 and 2005, sponsored by Fonds National de la Recherche Scientifique – Belgium. Nowadays, he works as an Attending Physician at the Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, Brazil, in cancer patient daily clinical care, clinical and translational research, and cancer education. His main areas of interest include head and neck cancer and new drug development.

    Evandro de Azambuja, M.D., MSc, was born in Brazil and received his medical training at the Medical School of the Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil. At the Hospital de Clínicas, Porto Alegre, Brazil, he did his specialization in Internal Medicine and Medical Oncology. He received his master degree in December 2002. He is the recipient of an Award from the Belgium Society of Medical Oncology, in Belgium. Nowadays, he is a fellow at Institut Jules Bordet, Brussels, Belgium and a current PhD student at the Federal University of Rio Grande do Sul, Porto Alegre, Brazil. He is the author of nine peer-reviewed papers in medical journals.

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