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Publication [Download PDF]: Alexandra Tyulyandina, Daniel Harrison, Wei Yin, et al. Invest New Drugs 35: 127–133. doi: 10.1007/s10637-016-0400-5
Based on data from 2013-2015, about 38% of the population will be diagnosed with some type of cancer during their lifetime, and there is an ongoing need for improved treatment techniques. Some chemotherapy agents are specific to cancer types while others, such as those that target proliferation, DNA damage, and angiogenesis, are effective against many cancer types. Inhibitors of vascular endothelial growth factors (VEGFs) and vascular endothelial growth factor receptors (VEGFRs) such as bevacizumab, sorafenib and levatinib, are well-known anti-angiogenesis chemotherapy agents. Combination treatments are also a common treatment regimen for synergistic antitumor effects and overcoming resistance.
Fibroblast growth factors and their receptors (FGFs, FGFRs) are involved in the regulation of proliferation, migration, differentiation and survival; their aberrant activity has been linked to several cancer types as well as VEGF/VEGFR-targeting agent resistance. Development of FGFR inhibitors led to several small-molecule inhibitors of the FGFR ATP-binding site, located on the intracellular tyrosine kinase domain, as well as monoclonal antibodies that target the active site, located on the extracellular domain. Tsimafeyeu et al. (European Journal of Cancer, 2016) presented an allosteric small-molecule selective inhibitor, alofanib (RPT835) that binds to the FGFR2 extracellular domain. Using services provided by Altogen Labs, this study characterized the in vitro and in vivo preclinical profile of alofanib across several cancer cell models. Inhibitory concentrations, cell growth inhibition values, tumor growth and angiogenesis analyses were performed.
In order to determine the effect of alofanib on FGF-stimulated cellular proliferation independent of cytotoxicity, cell growth inhibition values (GI50) were calculated and were determined to be in the nM range. Immunoblotting assays of whole cell lysates were used to look at the effect of alofanib on FGFR activity (via substrate phosphorylation levels), apoptosis levels, and FGFR1-3 expression levels. In vitro angiogenesis was analyzed via endothelial cell proliferation, wound healing assays (a measure of migration), tubule growth formation, and CD31 histological staining. In vivo angiogenesis was analyzed via histological staining of xenograft tumors. Tumor volume and body weight loss were used as in vivo measurements of growth inhibition and cytotoxicity. Overall, results suggested that alofanib treatment results in inhibition of proliferation, decreased FGFR activity, induction of apoptosis, inhibition of angiogenesis, and reduction in migration in FGFR2 expressing cell models. The antitumor activity of alofanib was comparable to known chemotherapy agents brivanib and bevacizumab. This data supports the further patient evaluation of alofanib treatment.
Altogen Labs is a contract research organization (CRO) that offers the services mentioned above and more. This Austin, TX based company is dedicated to providing top quality services for academics, biotechnology and pharmaceutical needs. Services range from drug evaluation in vivo and in vitro with IC50, GI50, angiogenesis, and gene and cell expression analysis to generation of stable RNAi cell lines. Experienced Altogen scientists are available for consult every step of the way from experiment design to analysis. The priority for Altogen labs is to provide a seamless and efficient quality experience for clients.