Linifanib: current status and future potential in cancer therapy Expert Rev. Anticancer Ther. Early online, 1–11 (2015) Caterina Aversa 1 , Francesco Leone 1 , Giorgia Zucchini 2 , Guido Serini 3 , Elena Geuna 2 , Andrea Milani 2 , Donatella Valdembri 3 , Rossella Martinello 1 and Filippo Montemurro* 2 1 Department of Oncology, University of Torino Medical School, Torino, Italy 2 Investigative Clinical Oncology (INCO), Fondazione del Piemonte per l’Oncologia- Candiolo Cancer Institute (IRCCs), Turin, Italy 3 Laboratory of Cell Adhesion Dynamics, Department of Oncology, University of Torino School of Medicine and Fondazione del Piemonte per l’Oncologia- Candiolo Cancer Institute (IRCCs), Candiolo, Italy *Author for correspondence: Tel.: +39 011 993 3958 Fax: +39 011 962 1525 filippo.montemurro@ircc.it Angiogenesis is one of the major mechanisms controlling tumor proliferation and metastatic spreading. Targeting of pro-angiogenic factors and their downstream effectors represents an appealing therapeutic option in the treatment of different cancer types. Linifanib (ABT-869) is a novel tyrosine-kinase inhibitor (TKI) inhibitor and its anti-angiogenic activity has been explored in numerous clinical trials. Here, we review preclinical development of linifanib focusing on its pharmacodynamic and pharmacokinetic characteristics and briefly summarize its evaluation in clinical trials. Linifanib selectively targets VEGFR and PDGFR and has low off-target inhibitory activity. Preclinical and early-phase trials have been showing promising efficacy results However, although signals of anti-tumor activity have been proven in some malignancies, linifanib late-phase development has been facing some challenges due to limited efficacy and increased toxicities. New strategies aimed at finding biomarkers of response and minimizing toxicities are needed to allow the further development of a promising compound. KEYWORDS: ABT-869 . angiogenesis . chemotherapy . Linifanib . PDGF . VEGF Angiogenesis is a complex biological program that leads to the formation of new blood ves- sels from pre-existing ones [1]. It might be involved in physiological processes, such as wound healing and endometrium growth as part of normal tissue homeostasis, but also in pathological processes, such as inflammation and tumor development [2–4]. The formation of new vessels in tumors (neoangiogenesis) is recognized as a major driver for the genera- tion, growth and survival of many human neo- plasms [5–7]. Consequently, neoangiogenesis inhibition has been widely proposed as a promising therapeutic option. The angiogenic process is governed by several signaling pathways, many of which have been thoroughly studied (FIGURE 1). Still, VEGF and its homologs continue to represent the most well- characterized family of angiogenic growth fac- tors. As a result, VEGF-A, one of the members of this family, is the main target of current anti- angiogenic therapies. By binding heterodimers of the three VEGF receptors VEGFR1, VEGFR2 and VEGFR3, the different VEGF isoforms trigger intracellular pathways involved in endothelial cells (EC) proliferation, migra- tion, adhesion and permeability control [8,9]. Despite a similar molecular structure, VEGFRs contribute to angiogenesis in different manners and through different pathways (FIGURE 1) [10–13]. Beyond VEGF/VEGFR, other tyrosine- kinase receptor (TKI)-dependent pro-angiogenic pathways exists, such as that activated by bFGF, which is implicated in the development of acquired resistance in the presence of VEGF blockade [14] and the one controlled by B (PDGFB), that acts as a chemoattractant for pericytes, which are involved in the maturation and stabilization of newly formed blood vessels [15–17]. Migrated pericytes are then incor- porated into blood vessel walls, where their mat- uration is supported by the formation of direct cell-to-cell contacts with EC [18,19]. Over the past few decades, several attempts have been made to therapeutically impair the ability of tumors to elicit the formation of new blood vessels finally resulting in the approval, in 2003, of bevacizumab, the first anti-angiogenic monoclonal antibody targeting VEGF-A. Soon after, various compounds tar- geting relevant pathways involved in tumor angiogenesis were developed [20]. Most of these new agents are TK inhibitors (TKIs) which can simultaneously inhibit different targets in the informahealthcare.com 10.1586/14737140.2015.1042369 Ó 2015 Informa UK Ltd ISSN 1473-7140 1 Review Expert Review of Anticancer Therapy Downloaded from informahealthcare.com by 93.33.56.190 on 05/02/15 For personal use only.