oa EDITORIAL [Hot topic: New Therapeutic Advances and Perspectives in Tumour Angiogenesis (Guest Editor: Eddy Pasquier)]

Our understanding of the process of tumour vascularization and the consequences of targeting the tumour vasculature to treat cancer has considerably evolved since the seminal hypothesis, formulated by Judah Folkman almost 40 years ago, that tumour growth and metastasis rely on the formation of a new vascular network. As the cellular mechanisms and the molecular pathways involved in tumour angiogenesis have started to unravel, new actors have come into play and new therapeutic targets have emerged. This hot-topic issue of Current Cancer Drug Targets on the “New therapeutic advances and perspectives in tumour angiogenesis” focuses on the current status, future prospects and challenges of anti-vascular therapies. First, the different therapeutic targets that may be exploited to block tumour angiogenesis in childhood cancer patients are explored and their current clinical development is reviewed. Then, the pro-angiogenic functions of two novel therapeutic targets, namely heat shock protein (HSP) 90 and histone deacetylase (HDAC), are outlined and the pre-clinical and clinical development of their specific inhibitors is examined. Finally, the technical challenges associated with the detection and analysis of endothelial progenitor cells (EPCs) are explained to help understand the actual controversy in this research field and highlight the potential of this unique cell population to be used as therapeutic tool in clinical oncology. Can Tumour Vasculature be an Efficacious Target in Paediatric Oncology? Following the first FDA approval of the anti-VEGF antibody, bevacizumab, in 2004, angiogenesis inhibitors have now become part of the standard of care for several types of adult cancer. Numerous clinical studies have been completed in various other tumour types and more trials are currently ongoing. In paediatric oncology, although clinical data remain sparse, anti-angiogenic agents are also being increasingly investigated. Already approved anti-angiogenic agents, such as bevacizumab, are increasingly used for the treatment of advanced and/or highrisk paediatric tumours, such as high-grade glioma, metastatic neuroblastoma and sarcoma. Furthermore, several new targets, including integrins and receptor tyrosine kinases, have emerged and are also increasingly investigated in pre-clinical models of childhood cancer and early clinical trials. Another anti-angiogenic strategy relies on metronomic chemotherapy, which is defined by the frequent administration of chemotherapeutic drugs at concentrations well below the maximum tolerated dose and with no prolonged drug-free break. The review by Andre et al. published in this special issue provides an extensive overview of these different anti-angiogenic strategies and their current clinical development for the treatment of childhood cancer. The authors further discuss a crucial issue that warrants sustained attention, especially in paediatric oncology, which is the long-term safety of anti-angiogenic therapies, since interfering with angiogenesis may hamper normal growth and development of children. So far, anti-angiogenic agents have indeed been used, with relative success, in paediatric patients with advanced and poor-prognosis disease and high-risk of relapse, making it difficult to adequately assess potential long-term side effects due to the low number of long-term survivors. HSP90, a Pivotal Co-Factor in Angiogenic Signalling Pathways As reviewed by Staufer and Stoeltzing in this issue, HSP90 is directly involved, through its chaperone activity, in several pro-angiogenic signalling cascades and especially PI-3K dependent pathways, including HIF-1α, eNOS and MAPK signalling. HSP90 therefore plays an essential role in hypoxia signalling and is also crucial to the activity of various pro-angiogenic receptors, such as VEGFR-2, integrin αvβ3, angiopoietin-1 and neuropilin-1. With such a central position and numerous client proteins involved in angiogenesis signalling, HSP90 appears as an attractive therapeutic target for anti-angiogenic cancer treatment. Although the results of early clinical studies of HSP90 inhibitors as single agents have been quite disappointing, the results of ongoing phase II trials combining HSP90 inhibitors and conventional chemotherapy or proteasome inhibitor are highly anticipated. HDAC Inhibitors, the Next “Big Thing” in Medical Oncology? With more than 1 publication a day for the last 3 years, HDAC inhibitors (HDACi) currently represent one of most active fields of re- search in experimental cancer therapeutics. The contribution of HDACs to tumour angiogenesis was first evidenced less than 10 years ago. However, as explained in this issue, major advances have been made since this initial discovery and our understanding of both the pro- angiogenic functions of HDACs and the anti-angiogenic properties of HDACi has considerably increased. By directly and indirectly regulat- ing the expression of numerous genes involved in angiogenesis, HDACs are at the crossroads of several pro-angiogenic pathways including HIF-1α and VEGF/VEGFR signalling. Therefore, it is not surprising to see the list of HDACi with potent anti-angiogenic properties regu- larly expand. The review by Mottet and Castronovo explains the pro-angiogenic functions of HDACs and provides a snapshot of the current clinical development of HDACi. Endothelial Progenitor Cells, How to Look Beyond the Controversy? For new anti-angiogenic targets such as HSP90 and HDACs, as for any anti-vascular strategy, powerful diagnostic, predictive and surrogate markers are crucially needed. Endothelial progenitor cells (EPCs) were recently shown to be involved in tumour vascularization and response to anti-vascular treatment, and thus represent promising biomarkers. However, the definition, origin and role of EPCs remain controversial. As explained in detail in this issue, the debate surrounding the role of EPCs in tumour vascularization and their potential as reliable biomarkers partially originates from the technical challenges associated with their accurate detection and characterization. In addition, preclinical and clinical studies have reported variable levels of mobilization and recruitment of EPCs, according to the models and settings. Recent findings have shed some light on the mechanisms involved in the recruitment of bone marrow-derived pro-angiogenic cells and provided a possible explanation for this discrepancy of results. One positive aspect of any scientific controversy is the consequent eagerness of researchers to try and solve the puzzle. The actual controversy surrounding EPCs have recently drawn the attention of both scientists and clinicians to this field of research, resulting in significant breakthroughs, detailed in the review article by Pasquier and Dias. The myriad of possibilities offered by the very existence of a cell population that is potentially capable of generating new endothelial cells, promoting de novo formation of blood vessels and healing vascular injury, is likely to lead to major therapeutic advances in cancer and other angiogenesis-related disorders. However, standardization of detection methods and optimization of isolation protocols are crucially needed in order to get better insights into the biology of EPCs and other bone marrow-derived pro-angiogenic cells. The establishment of such powerful biomarkers represents one of the key challenges for the antiangiogenic strategies reviewed in this special issue and the development of global, combinatorial and personalized therapeutic approaches to treat cancer.