%0 Journal Article
%T VEGF Spliced Variants: Possible Role of Anti-Angiogenesis Therapy
%A Caroline Hilmi
%A M¨Ślanie Guyot
%A Gilles Pag¨¨s
%J Journal of Nucleic Acids
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/162692
%X Angiogenesis has been targeted in retinopathies, psoriasis, and a variety of cancers (colon, breast, lung, and kidney). Among these tumour types, clear cell renal cell carcinomas (RCCs) are the most vascularized tumours due to mutations of the von Hippel Lindau gene resulting in HIF-1 alpha stabilisation and overexpression of Vascular Endothelial Growth Factor (VEGF). Surgical nephrectomy remains the most efficient curative treatment for patients with noninvasive disease, while VEGF targeting has resulted in varying degrees of success for treating metastatic disease. VEGF pre-mRNA undergoes alternative splicing generating pro-angiogenic isoforms. However, the recent identification of novel splice variants of VEGF with anti-angiogenic properties has provided some insight for the lack of current treatment efficacy. Here we discuss an explanation for the relapse to anti-angiogenesis treatment as being due to either an initial or acquired resistance to the therapy. We also discuss targeting angiogenesis via SR (serine/arginine-rich) proteins implicated in VEGF splicing. 1. Introduction Therapies targeting angiogenesis seek to either decrease VEGF levels or to block its receptors resulting in the inhibition of downstream signalling pathways such as RAS/RAF/MEK/ERK and PI3 Kinase. Thus, molecules used in the clinic block VEGF or inhibit the tyrosine kinase activity of the VEGF receptors. These classical strategies evidently target endothelial cells and thus prevent angiogenesis but may also inhibit autocrine proliferative/survival pathways due to abnormal expression of VEGF receptors by tumour cells of different origins [1¨C9]. The main treatment commonly used is Bevacizumab (BVZ), a humanized IgG1 monoclonal antibody against VEGF [10]. A phase II clinical trial has shown that BVZ can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer [11]. However, only the BVZ plus interferon alpha (IFN) treatment has obtained approval by the Food and Drugs administration (FDA) in the United States of America and the European Medicines Agency (EMA) in Europe following phase III clinical assays [12, 13]. These clinical assays have demonstrated an increase in progression-free survival associated with the treatment combining IFN and BVZ compared to IFN alone. Unfortunately, BVZ plus IFN did not improve overall survival when compared to IFN monotherapy [14, 15]. Other treatments targeting the different VEGF receptors are Receptor Tyrosine Kinase Inhibitors (RTKI) such as sunitinib targeting VEGFR2, PDGFR, FLT3, and c-Kit or
%U http://www.hindawi.com/journals/jna/2012/162692/