Angiogenesis inhibitors in the treatment of lung cancer

https://doi.org/10.1016/j.critrevonc.2007.01.002Get rights and content

Abstract

Despite improvements in cytotoxic chemotherapy and combined modality therapies for lung cancer, the prognosis for patients remains poor, and the majority of patients die from the disease. Angiogenesis, i.e. the formation of new blood vessels, is important for tumor growth, invasion and metastasis and represents a rational target in the development of more effective treatments. The vascular endothelial growth factor (VEGF) signaling pathway plays a crucial role in the angiogenic process and consequently, inhibitors of this system are currently under development. The most studied anti-angiogenic agents include anti-VEGF monoclonal antibodies and VEGF receptor tyrosine kinase inhibitors. Recent clinical trials have yielded promising results. This article will review angiogenesis inhibitors targeting the VEGF pathway which are currently being developed for the treatment of lung cancer.

Introduction

Lung cancer remains a major health problem as the leading cause of cancer-related death worldwide [1]. Non-small cell lung cancer (NSCLC) includes squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma and represents approximately 80% of all lung cancers. Unfortunately, the majority of patients present with advanced NSCLC at the time of diagnosis and die from the disease. First-line therapy with cisplatin-based chemotherapy for advanced NSCLC has been shown to provide modest benefit, with an extension in survival of approximately 2 months [2]. The need for more effective treatments has led to the development of new therapeutic approaches targeting tumor biology. Angiogenesis, i.e. the formation of new blood vessels, plays a central role in tumor growth, invasion, and metastasis, and thus represents an attractive therapeutic target.

For tumors to grow beyond 1–2 mm in diameter, angiogenesis is essential in order to supply adequate oxygenation and nutrition to tissues [3]. Tumor angiogenesis is a complex process regulated by the delicate balance between several proangiogenic and antiangiogenic molecules released by tumor cells and host cells, including endothelial cells, macrophages, mast cells and stromal components (Table 1). The process is believed to be dependent on an ‘angiogenic switch’ which initiates a series of events starting with the release of tumor-related proangiogenic factors, leading to the activation of endothelial cells, the release of proteolytic enzymes, degradation of the basement membrane, followed by endothelial cell migration, proliferation, and capillary tube formation [4]. The new capillaries formed in tumors lack the same supporting architecture as their parent vessels and are thin-walled and highly permeable. Consequently, the leakiness of the new tumor vasculature provides access to the circulation for tumor cells to metastasise [5].

To date, a number of molecules regulating angiogenesis have been described. Of these, vascular endothelial growth factor (VEGF) is the most important growth factor controlling angiogenesis in normal and tumor cells [6].

Section snippets

The VEGF family

The VEGF family consists of six growth factors, VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PlGF) and three receptors, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4) [7] (Fig. 1). VEGF-A is the most well characterized member of the VEGF family and at least six isoforms have been identified due to alternate gene splicing [8].

Angiogenesis inhibitors

Recognition of the essential role of the VEGF/VEGFR pathway in angiogenesis has led to the development of inhibitors of VEGF/VEGFR and several agents are currently under investigation as potential therapies for lung cancer (Table 2). The monoclonal antibodies to VEGF and tyrosine kinase inhibitors to VEGFRs are among the most studied anti-angiogenic agents and will be the focus of this review.

Challenges

Several unique challenges face the development of anti-angiogenic agents in lung cancer. Fatal episodes of hemoptysis have occurred, although these appear to be more common in patients with squamous-cell tumors as compared to non-squamous histology. As these drugs continue to be developed, it will be important to identify patients at highest risk of pulmonary hemorrhage and to prevent potentially life-threatening events (e.g. with radiation therapy). The ECOG trial (E4599) which demonstrated a

Conclusions

The last decade has seen significant advances in our knowledge of angiogenesis and tumor development. Several anti-angiogenic agents have been developed as potential therapy for many tumor types, including lung cancer. The positive results from phase III studies of bevacizumab in combination with conventional cytotoxic chemotherapy in metastatic colorectal cancer, breast cancer and lung cancer have validated the importance of targeting angiogenesis in the treatment of these tumors. As a result,

Reviewer

Prof. Giorgio V. Scagliotti, Department of Clinical & Biological Sciences, Thoracic Oncology Unit, Regione Gonzole 10, I-10043 Orbassano, Torino, Italy.

Sophie Sun, M.D. is an assistant instructor in hematology/oncology at the University of Texas Southwestern Medical Center. She graduated from medical school at the University of Toronto and completed internal medicine residency at the University of Calgary and medical oncology fellowship at the University of British Columbia in Canada. Dr. Sun's research interests include clinical trials and the development of experimental therapeutics for lung cancer.

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    Sophie Sun, M.D. is an assistant instructor in hematology/oncology at the University of Texas Southwestern Medical Center. She graduated from medical school at the University of Toronto and completed internal medicine residency at the University of Calgary and medical oncology fellowship at the University of British Columbia in Canada. Dr. Sun's research interests include clinical trials and the development of experimental therapeutics for lung cancer.

    Joan H. Schiller, M.D. is professor and chief of the Division of Hematology/Oncology and deputy director of the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center. Prior to her current position, she was a professor of the Department of Medicine Section of Oncology at the University of Wisconsin in Madison. Dr. Schiller is chair of the Thoracic Oncology Committee of the Eastern Cooperative Oncology Group and her research focuses primarily on clinical trials and drug development in lung cancer.

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