This is a phase II, Single-arm,Open-label Study evaluating the safety and efficacy of CT053PTSA in Advanced Solid Tumors With MET Exon 14 Skipping Mutations

开始日期2022-11-27

申办/合作机构

广东东阳光药业有限公司

NCT04601610 / Terminated临床1/2期

An Open, Multi-center, Ib/II Clinical Trial of KN046 Combined With Ningatinib in the Treatment of Advanced Hepatocellular Carcinoma

This study is an open, multi-center clinical trial, the purpose is to study the safety and preliminary efficacy of KN046 combined with Ningatinib in subjects with advanced hepatocellular carcinoma.

开始日期2021-06-07

申办/合作机构

江苏康宁杰瑞生物制药有限公司

[+1]

100 项与 MerTK x VEGFR2 x c-Met x AXL 相关的临床结果

登录后查看更多信息

100 项与 MerTK x VEGFR2 x c-Met x AXL 相关的转化医学

登录后查看更多信息

0 项与 MerTK x VEGFR2 x c-Met x AXL 相关的专利（医药）

登录后查看更多信息

项与 MerTK x VEGFR2 x c-Met x AXL 相关的文献（医药）

2021-01-01·Toxicology Research and Application

Differential receptor tyrosine kinase phosphorylation in the uterus of rats following developmental exposure to tetrabromobisphenol A

Article

作者: Birnbaum, Linda S ; Saddler, Trey O ; Staup, Michael ; Yu, Linda ; Burwell, Alanna D ; Castro, Lysandra ; Dixon, Darlene ; Foley, Julie F ; Xue, William ; Liu, Jingli ; Santiago, Lindsay A ; Flagler, Norris D ; Shi, Min

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that induces endometrial adenocarcinoma and other uterine tumors in Wistar Han rats; however, early molecular events or biomarkers of TBBPA exposure remain unknown. We investigated the effects of TBBPA on growth factor receptor activation [phospho-receptor tyrosine kinases (RTKs)] in uteri of rats following early-life exposures. Pregnant Wistar Han rats were exposed to TBBPA (0, 0.1, 25, and 250 mg/kg bw/day) via oral gavage on gestation day 6 through weaning of pups on postnatal day (PND) 21. Pups were exposed in utero, through lactation, and by daily gavage from PND 22 to PND 90. Uterine horns were collected (at PND 21, PND 33, and PND 90) and formalin-fixed or frozen for histologic, immunohistochemical, phospho-RTK arrays, or western blot analysis. At PND 21, the phospho-RTKs, fibroblast growth factor receptor 2 and 3 (FGFR2 and FGFR3), neurotrophic tyrosine kinase receptor type 3 (TRKC), and EPH receptor A1 (EPHA1) were significantly increased at different treatment concentrations. Several phospho-RTKs were also significantly overexpressed at PND 33 which included epithelial growth factor receptor (EGFR), FGFR2, FGFR3, FGFR4, insulin-like growth factor receptor 1 (IGF1R), insulin receptor (INSR), AXL receptor tyrosine kinase (AXL), MER proto-oncogene, tyrosine kinase (MERTK), platelet derived growth factor receptor alpha and beta (PDGFRA and PDGFRB), ret proto-oncogene (RET), tyrosine kinase with immunoglobulin-like and EGF-like domains 1 and 2 (TIE1 and TIE2), TRKA, kinase insert domain receptor (KDR;VEGFR2), fms related receptor tyrosine kinase (FLT4; VEGFR3), and EPHA1 at different treatment concentrations. EGFR, a RTK overexpressed in endometrial cancer in women, remained significantly increased for all treatment groups at PND 90. Erb-B2 receptor tyrosine kinase 2 (ERBB2) and IGF1R were overexpressed at PND 33 and remained increased through PND 90, although ERBB2 was statistically significant at PND 90. The phospho-RTKs, FGFR3, AXL, TYRO3 protien tyrosine kinase (TYRO3; DTK), HGFR, TRKC, FLT1/VEGFR1, and EPHB2 and 4 were also statistically significant at PND 90 at different treatment doses. The downstream effector, phospho-MAPK44/42, was also increased in uteri of treated rats. Our findings show RTKs are dysregulated following early-life TBBPA exposures and their sustained activation may contribute to TBBPA-induced uterine tumors observed in rats later in life.

2017-02-01·Clinical Cancer Research1区 · 医学

Molecular Pathways: Receptor Ectodomain Shedding in Treatment, Resistance, and Monitoring of Cancer

1区 · 医学

Review

作者: Miller, Miles A. ; Lauffenburger, Douglas A. ; Sullivan, Ryan J.

AbstractProteases known as sheddases cleave the extracellular domains of their substrates from the cell surface. The A Disintegrin and Metalloproteinases ADAM10 and ADAM17 are among the most prominent sheddases, being widely expressed in many tissues, frequently overexpressed in cancer, and promiscuously cleaving diverse substrates. It is increasingly clear that the proteolytic shedding of transmembrane receptors impacts pathophysiology and drug response. Receptor substrates of sheddases include the cytokine receptors TNFR1 and IL6R; the Notch receptors; type-I and -III TGFβ receptors; receptor tyrosine kinases (RTK) such as HER2, HER4, and VEGFR2; and, in particular, MET and TAM-family RTKs AXL and Mer (MerTK). Activation of receptor shedding by mechanical cues, hypoxia, radiation, and phosphosignaling offers insight into mechanisms of drug resistance. This particularly holds for kinase inhibitors targeting BRAF (such as vemurafenib and dabrafenib) and MEK (such as trametinib and cobimetinib), along with direct sheddase inhibitors. Receptor proteolysis can be detected in patient fluids and is especially relevant in melanoma, glioblastoma, lung cancer, and triple-negative breast cancer where RTK substrates, MAPK signaling, and ADAMs are frequently dysregulated. Translatable strategies to exploit receptor shedding include combination kinase inhibitor regimens, recombinant decoy receptors based on endogenous counterparts, and, potentially, immunotherapy. Clin Cancer Res; 23(3); 623–9. ©2016 AACR.

Frontiers in Immunology

Preclinical characterization and phase I clinical trial of CT053PTSA targets MET, AXL, and VEGFR2 in patients with advanced solid tumors

Article

作者: Jiang, Ying-Zhi ; Zhang, Yang ; Ma, Yu-Xiang ; Liu, Qian-Wen ; Zhuang, Yu-Lei ; Xi, Ning ; Liu, Fu-Rong ; Kang, Ning ; Huang, Yan ; Chen, Zhi-Qiang ; Chen, Qun ; Zhang, Qi ; Zhao, Hong-Yun ; Yang, Yun-Peng ; Fang, Wen-Feng ; Zhang, Li

BackgroundCT053PTSA is a novel tyrosine kinase inhibitor that targets MET, AXL, VEGFR2, FLT3 and MERTK. Here, we present preclinical data about CT053PTSA, and we conducted the first-in-human (FIH) study to evaluate the use of CT053PTSA in adult patients with pretreated advanced solid tumors.MethodsThe selectivity and antitumor activity of CT053PTSA were assessed in cell lines in vitro through kinase and cellular screening panels and in cell line-derived tumor xenograft (CDX) and patient-derived xenograft (PDX) models in vivo. The FIH, phase I, single-center, single-arm, dose escalation (3 + 3 design) study was conducted, patients received at least one dose of CT053PTSA (15 mg QD, 30 mg QD, 60 mg QD, 100 mg QD, and 150 mg QD). The primary objectives were to assess safety and tolerability, to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended dose of CT053PTSA for further study. Secondary objectives included pharmacokinetics, antitumor activity.ResultsCT053 (free-base form of CT053PTSA) inhibited MET, AXL, VEGFR2, FLT3 and MERTK phosphorylation and suppressed tumor cell angiogenesis by blocking VEGF and HGF, respectively, in vitro. Moreover, cell lines with high MET expression exhibited strong sensitivity to CT053, and CT053 blocked the MET and AXL signaling pathways. In an in vivo study, CT053 significantly inhibited tumor growth in CDX and PDX models. Twenty eligible patients were enrolled in the FIH phase I trial. The most common treatment-related adverse events were transaminase elevation (65%), leukopenia (45%) and neutropenia (35%). DLTs occurred in 3 patients, 1/6 in the 100 mg group and 2/4 in the 150 mg group, so the MTD was set to 100 mg. CT053PTSA was rapidly absorbed after the oral administration of a single dose, and the Cmax and AUC increased proportionally as the dose increased. A total of 17 patients in this trial underwent tumor imaging evaluation, and 29.4% had stable disease.ConclusionsCT053PTSA has potent antitumor and antiangiogenic activity in preclinical models. In this FIH phase I trial, CT053PTSA was well tolerated and had a satisfactory safety profile. Further trials evaluating the clinical activity of CT053PTSA are ongoing.