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  • br Clinical development of FGFR inhibitors in

    2021-11-26


    Clinical development of FGFR inhibitors in breast cancer The rationale to explore the role of FGFR inhibitors in patients with breast cancer comes from a variety of sources. These include genomic aberrations frequently identified in the FGF/FGFR pathway in breast cancer, the increased sensitivity to FGFR inhibition observed in FGFR-amplified breast cancer cell lines and tumor models, and the contribution of FGF/FGFR pathway to drug resistance to both hormonotherapy and different targeted agents. The FGF/FGFR network may be blocked at different levels. One possibility is upstream intervention to inhibit ligand binding with an FGF ligand trap or with antagonistic peptide mimics. A second possibility is action at the FGFR level. Currently, the most common strategy is the development of FGFR TKIs, although other approaches are available, such as FGFR-specific monoclonal Human EPOR / Erythropoietin Receptor Protein (Fc Tag) and RNA aptamers. Finally, downstream intervention that blocks effector proteins of the FGF/FGFR system is also possible; however, this method is difficult to perform without adverse effects, as many of the proteins involved also play a role in other signaling pathways and healthy cells [35]. Focusing on breast cancer, the predominant approach is targeting FGFRs with small molecule TKIs. These drugs are classified as nonselective, which target a wide range of kinases, and selective FGFR inhibitors (Table 2).
    Future directions
    Combinatorial drug therapy using FGFR inhibitors in breast cancer
    Conclusions Although there is a clear rationale to target the FGF/FGFR signaling pathway in breast cancer, preliminary results from various clinical trials testing FGFR inhibitors have shown only small signs of clinical efficacy, even in patient populations specifically selected for FGF-aberrant breast tumors (Table 3). At the present time, only lucitanib (E-3810) has demonstrated significant antitumor activity in preliminary phase I trials, and data from phase II studies are awaited. Whether this observed lack of efficacy in patients with breast cancer is due to ineffective compounds, inadequate patient selection, or simply the absence of oncogenic potential of FGFR genomic aberrations is still a matter of debate. Despite the oncogenic potential of FGFR amplifications in preclinical models, this alteration may not represent a big enough clue to allow for the identification of a sensitive patient population. These FGFR amplifications may not be sufficiently important to promote breast cancer growth, they may not have a driver role in breast carcinogenesis, or maybe the problem lies in the inability to reliably identify patients with FGFR amplification. According to preclinical results, FGFR protein or mRNA levels could be a better predictive biomarker of response to FGFR inhibitors, but this hypothesis has yet to be confirmed in breast cancer patients.
    Introduction Fracture healing constitutes a complex and delicate physiological process. Reportedly, as many as 10% of these fractures lead to delayed union or nonunion [1]. Having demonstrated that loss of bone volume and/or insufficient number of progenitor cells are considered common reasons of nonunion, but the most common characteristic of nonunion is damaged vascularization [2]. Currently, criteria for treating nonunion include bone grafting and/or distraction osteogenesis; nevertheless, limited graft material availability, pain from graft harvesting and metastasis, and bad angiogenesis constitute apparent limitations for these treatment regimens. Therefore, these most serious cases are badly in need of the enhancement of angiogenesis. Magnesium (Mg) and its alloys as a type of different biodegradable materials have been used in the musculoskeletal field for a long time [3]; Mg-based implants have been used in clinical applications [4,5]. Mg and Mg-containing alloys were characterized by excellent biocompatibility, biodegradability and mechanical properties similar to bone [[6], [7], [8]]; besides, Mg could promote osteoblast differentiation in vitro [9,10] and induce the formation of new bone in vivo [8], showing high osteogenesis potential. Nevertheless, the fast degradation and the local high alkaline pH value of magnesium-based alloys result in tissue damages during the healing process, which hinders their further application [11]. This high corrosion rate is basically resulted from microcurrent reaction between magnesium matrix and second phases or impurities [12]. Thus, alloying and deformation process are often utilized to elevate Mg-based alloy corrosion resistance. But actually, the choice of elements is limited to a small group, and those frequently added into magnesium, such as aluminum or zirconium, are not suitable because they are proved to induce underlying health issues in human body, according to research [13]. Song et al. [14] have pointed out a small group of elements that could be added into Mg matrix with low toxicity and help retard the degradation process: Zn, Mn, Ca and several rare earth elements in low concentration. It's been reported that adding Zn can not only elevate the mechanics performance of Mg-based alloys, but also have antibacterial effects [15]. Also, Zn is one of the essential elements in human body which makes it a typical choice in bio-magnesium alloys. The addition of another essential element Mn could significantly help elevate the corrosion resistance because Mn could help eliminate Human EPOR / Erythropoietin Receptor Protein (Fc Tag) the harmful element Fe in Mg matrix [12]. Several researches have reported that Mg–Zn–Mn alloy shows excellent mechanical properties and corrosion resistance [16,17]. Besides, ZM21 alloy is found to be able to support cellular growth on its surface, exhibiting great cytocompatibility [18]. However, researches on Mg–Zn–Mn alloy only stretch to the in vitro extent; the specific roles of Mg-based Mg–Zn–Mn alloy in endothelial cell angiogenesis remain unclear. In the present study, we prepared the extracts of Mg–Zn–Mn alloy at different concentrations and examined the effects of these extracts upon the angiogenesis of human umbilical vein endothelial cells (HUVECs).