Anti-angiogenic therapy, a new player in the field of sarcoma treatment
Introduction
Microscopically small tumors can arise because of loss of control of cell proliferation. At a size of 1–2 mm diffusion becomes inadequate and proliferation is counterbalanced by necrosis. For further growth and invasive ability the tumor has to gain angiogenic properties by expressing several pro-angiogenic factors, e.g. vascular endothelial growth factor (VEGF), thereby changing the equilibrium between pro- and anti-angiogenic substances. This process is called the angiogenic switch and is triggered by oncogenic mutations, mechanic stress and hypoxia [1]. Hypoxia acts through the activity of hypoxia-inducible factor, HIF-1α, which forms an active transcription factor for proteins (among which are glucose receptors and VEGF) that allows the cells to adapt to a low pO2 environment [2]. Endothelial cells and their precursors are stimulated to migrate to the extracellular matrix, proliferate and organize into new capillaries, a complex process that is still incompletely understood. Integrins, a family of transmembrane molecules which mediate numerous cell–cell and cell–matrix interactions such as cell adhesion, proliferation and apoptosis, are involved in this process. An important integrin is αvβ3, which is highly expressed in endothelial cells during angiogenesis. The VEGF family of tumor-secreted angiogenic factors (VEGF-A, VEGF-B, VEGF-C, and VEGF-D), and their receptors (VEGFR-1, -2, and -3 and Neuropilin), are only one group in a complex interaction of pro- and anti-angiogenic factors. They appear however to have a crucial role in tumor angiogenesis and enhancement of vascular permeability, which may in part be explained because VEGF acts as a mediator for indirect-acting angiogenic factors [3]. The different pathways in the cell combined make a complicated structure with numerous options for targeting.
In this review we describe the results of (pre)clinical studies concerning angiogenesis in sarcomas. Various anti-angiogenic compounds have been developed. These compounds, their targets and mechanism of action are listed in Table 1. The results of clinical trials with anti-angiogenic agents that included sarcoma patients are provided in Table 2. As an indication for future possibilities we also highlighted some clinical trials presently ongoing or recruiting patients (Table 3). At present (September 2013) there are 64 ongoing trials including sarcoma patients (23 on pazopanib, 19 on bevacizumab, 6 on sorafenib, 8 on sunitinib, 2 on cediranib, 1 comparing sunitinib with cediranib, 1 on regorafenib and 4 on dasatinib (for an up to date overview see www.clinicaltrials.gov)).
Section snippets
Gastrointestinal stromal tumors (GIST)
Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcomas of the gastrointestinal tract. Most GISTs contain gain-of-function mutations in c-KIT or in platelet-derived growth factor receptor-A (PDGFRA). Inhibition of KIT and PDGFRA by tyrosine kinase inhibitors (TKIs) like imatinib has revolutionized the treatment of GISTs. However, more than half of the patients develop resistance to imatinib after two years and therefore novel compounds are needed.
Response monitoring in angiogenesis treatment
Despite the rapid progress in the development of drugs that target angiogenesis, the choice of an appropriate method to monitor treatment response remains a big challenge. Unlike chemotherapeutic agents, angiogenesis inhibitors slow or stop tumor growth rather than causing tumor shrinkage. Therefore, the standard response evaluation criteria with RECIST are likely not optimal in assessing response to angiogenesis inhibitors. Furthermore, a method to early predict tumor response to angiogenesis
Conclusion
In conclusion, significant evidence for a role for anti-angiogenic therapies in the majority of sarcoma subtypes exists. Careful patient selection and sensitive, objective and highly reproducible treatment evaluation methods are essential to prevent decision-making about new drugs based on apparent failure in small studies containing only few possible responders. In addition to VEGFR, other RTKs have been implicated in sarcomas and more and more evidence is emerging that the simultaneous
Role of the funding source
Study sponsors had no involvement in preparing or writing the article.
Conflict of interest statement
YMH Versleijen-Jonkers and WTA van der Graaf received financial research support from Pfizer and Novartis and WTA van der Graaf also from GSK.
Reviewers
Professor Serge Leyvraz, CHUV – Centre Hospitalier Universitaire Vaudois, Oncology Department, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.
Professor Jean-Yves Blay, Chair, Centre Leon Berard, Department of Medicine, 28, rue Laennec, F-69008 Lyon Cedex 03, France.
Yvonne M.H. Versleijen-Jonkers, PhD is supervisor of the preclinical sarcoma research group at the department of Medical Oncology from the Radboud University Medical Center, Nijmegen, the Netherlands. The aim of her research is to design an optimal treatment strategy for sarcoma patients. This is done by rationally positioning and incorporating the novel concept of targeted therapies and molecular imaging in current treatment strategies to enable individualization of therapy and consequently
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Yvonne M.H. Versleijen-Jonkers, PhD is supervisor of the preclinical sarcoma research group at the department of Medical Oncology from the Radboud University Medical Center, Nijmegen, the Netherlands. The aim of her research is to design an optimal treatment strategy for sarcoma patients. This is done by rationally positioning and incorporating the novel concept of targeted therapies and molecular imaging in current treatment strategies to enable individualization of therapy and consequently protect patients against the toxic effects of ineffective treatment.