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Antiangiogenic Therapy for Lung Cancer: Small-Molecule Inhibitors
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
AEE788: AEE788 is an orally active, small-molecule, multitargeted kinase inhibitor with potent inhibitory activity against multiple tyrosine kinases, including EGFR, HER2, and VEGFR-2. The phase-I study was conducted to assess its safety, PK, PD, MTD, and optimal biologic dose in patients with advanced solid tumors. AEE788 was given by mouth (PO) at 25, 50, 100, 150, 225, 300, 400, 450, 500, and 550 mg/day in 28-day cycles to 3 to 6 patient cohorts. Twenty-four-hour PK profiles were performed on days 1, 15, 28. PK parameters of AEE788 and AQM674 (active metabolite) were computed by model-independent methods. PD markers were analyzed in skin and tumor biopsies pre- and posttreatment. Sixty-nine patients were treated with a median of two cycles (range < 1–10). AEE788 and AQM674 concentrations varied widely and increased with dose and duration. IC50 values were estimated for pEGFR (42 nM), pMAPK (38 nM), Ki67 (7 nM) in SK and pEGFR (28 nM), pMAPK (22 nM) in tumors. A dose-dependent inhibition of EGFR signaling in skin and tumor was observed; profound receptor inhibition is achieved with ≥300 mg/day. As expected, inhibition of endothelial pMAPK and Ki67 occurred at higher doses than EGFR inhibition (≥300 mg). Exposure-dependent effects were observed and estimated IC50 corresponded to the preclinical data (63). In addition to inhibiting cutaneous cancer cell growth by blocking EGFR and VEGFR signaling pathways in vitro, AEE788 inhibited in vivo tumor growth by inducing tumor and endothelial cell apoptosis (64).
Effects of multi-kinase inhibitors on the activity of cytochrome P450 2J2
Published in Xenobiotica, 2022
Ayaka Kojima, Masayuki Nadai, Norie Murayama, Hiroshi Yamazaki, Miki Katoh
AA, AEE788, apatinib, astemizole, axitinib, lenvatinib, and pazopanib were purchased from Cayman Chemicals (Ann Arbour, MI, USA). Brivanib, cediranib, foretinib, linifanib, motesanib, orantinib, semaxinib, tivozanib, vandetanib, and vatalanib were obtained from AdooQ Biosciences (Irvine, CA, USA). Cabozantinib S-malate and nintedanib were purchased from LC Laboratories (Woburn, MA, USA) and MedChem Express (Monmouth Junction, NJ, USA), respectively. Danazol and midazolam were obtained from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). O-Desmethylastemizole was purchased from Toronto Research Chemicals (North York, ON, Canada). Regorafenib and sorafenib were obtained from ChemScene (Monmouth Junction, NJ, USA). Sunitinib was purchased from Selleck Chemicals (Houston, TX, USA). Recombinant human CYP2J2 microsomes were purchased from Corning (Corning, NY, USA). The 14,15-EET/DHET ELISA kit was purchased from Detroit R&D Systems (Detroit, MI, USA).
A bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacy
Published in Journal of Drug Targeting, 2022
Xiao-Fang Guo, Yue-Yue Zhang, Jia Kang, Qiao-Hua Dou, Xiao-Fei Zhu
Both EGFR and VEGFR are important targets for cancer therapy, the combined inhibition of both signalling pathway represents a promising approach to the treatment of cancers with a synergistic effect [20]. The dual inhibition of EGFR/VEGF(R) signalling pathway includes two strategies: the combination of two targeted drugs acting on EGFR or VEGF(R) and the development of multi-target tyrosine kinase inhibitors, such as vandetanib and AEE788 [21–24]. Many researches have confirmed that dual inhibition of EGFR and VEGF(R) signal pathways by both strategies has a more significant effect on the treatment of some cancers, even for patients with resistance to EGFR inhibitors [18–22,25]. However, the combination of two single targeted drugs may increase the side effects and bring economic burden to patients. Moreover, the mechanisms of multi-target tyrosine inhibitors have not been fully elucidated, and it is impossible to achieve the optimal inhibitory concentration for all the targets, and the off-target effect is also a problem that should notice.
Determining the appropriate treatment for different EGFR mutations in non-small cell lung cancer patients
Published in Expert Review of Respiratory Medicine, 2020
Simona Scodes, Federico Cappuzzo
S781 mutation on exon 20 is generally associated with sensitivity to EGFR TKIs, although controversial information are available and some authors reported these mutations as responsive to first generation TKIs [68,69] others as resistant [70]. In vitro studies showed that S768I mutation was less sensitive to either gefitinib or erlotinib than G719S and L861Q but sensitive to AEE788, a tyrosine kinase inhibitor of both EGFR and VEGF pathway [71]; in contrast, computational studies, conducted to evaluate the association between responsiveness to EGFR TKIs and changes in EGFR protein conformation due to nonsynonymous single nucleotide polymorphism using sophisticated software, demonstrated sensitivity to first generation TKIs [72]. Outcomes of patients with this rare mutation are better when it is included in a complex mutation with G719X (ORR approximately 50% and median PFS of 8–10 months).