Endometrial Cancers Harboring Mutated Fibroblast Growth Factor Receptor 2 Protein Are Successfully Treated With a New Small Tyrosine Kinase Inhibitor in an Orthotopic Mouse Model

Taurin, Sébastien; Yang, Cheng‐Yu; Reyes, Maria R.; Cho, Sungpil; Coombs, Demetrius M.; Jarboe, Elke A.; Werner, Theresa L.; Peterson, C. Matthew; Janát-Amsbury, Margit M.

doi:10.1097/igc.0000000000001129

Cited by 69 publications

(59 citation statements)

References 30 publications

(38 reference statements)

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“…Anlotinib is a novel, small molecule receptor tyrosine kinases (RTKs) and inhibits both tumor proliferation and angiogenesis [174][175][176]. Preclinical studies have shown that anlotinib has emerged much stronger anti-angiogenic activity than other anti-angiogenesis agents [177].…”

Section: Anlotinibmentioning

confidence: 99%

Emerging therapies for non-small cell lung cancer

et al. 2019

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Recent advances in the field of novel anticancer agents prolong patients' survival and show a promising future. Tyrosine kinase inhibitors and immunotherapy for lung cancer are the two major areas undergoing rapid development. Although increasing novel anticancer agents were innovated, how to translate and optimize these novel agents into clinical practice remains to be explored. Besides, toxicities and availability of these drugs in specific regions should also be considered during clinical determination. Herein, we summarize emerging agents including tyrosine kinase inhibitors, checkpoint inhibitors, and other potential immunotherapy such as chimeric antigen receptor T cell for non-small cell lung cancer attempting to provide insights and perspectives of the future in anticancer treatment.

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Section: Anlotinibmentioning

confidence: 99%

Emerging therapies for non-small cell lung cancer

et al. 2019

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“…Anlotinib had approved anti-tumor for several cancers, such as AMTC, MRCC, NSCLC, and ASTS [28,29]. Currently, most researches focus on the anti-angiogenic effect of drugs on tumor cells and the therapeutic effect on non-small cell carcinoma [9,10,26,27]. However, relevant data indicated that the effect of anlotinib on the proliferation and apoptosis of drug-resistant cells in colorectal cancer is still rarely reported.…”

Section: Discussionmentioning

confidence: 99%

“…Anlotinib is a novel small molecule, a multi-target tyrosine kinase inhibitor, that has been used to treat various types of cancers, including CRC, based on its known ability to block angiogenesis [8]. It has proven strong inhibitory activity on many target receptors, for example PDGFR, FGFR and VEGFR [9][10][11]. Recently, it has been shown that many tumor cells are sensitive to anlotinib [8].…”

Section: Introductionmentioning

confidence: 99%

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway

Lan

Zhao

Shang

et al. 2019

Preprint

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Background: Anlotinib is a multi-tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the functional mechanisms whereby anlotinib mediates against deadly drug-resistant colorectal cancer (CRC) has not been fully describedspecifically, the potential mechanisms that inhibit proliferation and induce apoptosis remain largely unknown. Methods:MTT assays were used to detect cell viability and calculate the resistance index. Colony formation was used to evaluate the proliferation of resistant cells. DAPI staining was used to detect cell apoptosis morphologically. Annexin V-FITC with PI staining was used to detect early and late-stage apoptosis of cells. Cell cycle distribution was determined by Flow cytometry. Transwell assays were performed to examine the ability of migration and invasion. Cyclin D1 Survivin, CDK4, Bcl-2, Bax and changes of PI3K/AKT pathway were detected by Western blotting. Compared as a single agent or combined with anlotinib or LY294002, PI3K inhibitor (LY294002) was used to verify whether it inhibited drug-resistant CRC cells by lowering PI3K/AKT. Results: HCT-8/5-FU cells showed multiple drug resistance. Drug resistance index of 5-FU, ADM and DDP were 390.27, 2.55 and 4.57, respectively. Anlotinib was shown to inhibit cell viability on HCT-8/5-FU and HCT-8 cells for 24 h and 48 h in a dosage-and time-dependent pattern. Compared with 48 h, intervened with anlotinib (0 μM, 10 μM, 20 μM and 40 μM) for 24 h, the HCT-8/5-FU cells were sensitive to anlotinib, and their sensitivity was greater than that of the parent cell line (HCT-8) at 24 h. Further, anlotinib inhibited the number of cloned cells significantly and had a significant inhibitory effect on cell cycle, mainly by blocking G1 transferring to S phase. Moreover, anlotinib could down-regulate the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, vimentin, MMP-9, and N-cadherin, while up-regulating cleaved-caspase-3, Bax and E-cadherin. Anlotinib inhibited the activity of the PI3K/AKT pathway and induced apoptosis in HCT-8/5-FU cells. Using LY294002, a specific PI3K inhibitor, our experiment found anlotinib can inhibit drug-resistant CRC cells by reducing PI3K and p-AKT activity-induce apoptosis.Conclusions: Anlotinib inhibited the proliferation , metastasis and induced apoptosis of HCT-8 / 5-FU cells ; and the mechanism could be that anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway .

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“…The vitro studies using recombinant enzymes indicated that the capability of anlotinib to inhibit VEGFR2/KDR and VEGFR3 is approximately 20 and 500 times stronger compared with sunitinib and sorafenib [5]. The dysregulation of fibroblast growth factor (FGF)/FGF receptor axis results in aggressive cancer phenotypes by promoting cancer progression and enhancing the angiogenic potential of tumor microenvironment [6]. FGF/FGFR signaling alterations have also been found to be connected with chemotherapy resistance and poor prognosis.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Liu

Wang

et al. 2020

Cancer Chemother Pharmacol

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Purpose Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. Methods Six male patients were enrolled and divided into two groups. Group A (containing two patients) received 14.15 mg/80 µCi/subject [ 14 C]-anlotinib hydrochloride. Group B (containing four patients) received 14.15 mg/120 µCi/subject [ 14 C]-anlotinib hydrochloride. The blood, urine, and feces of all the six patients after orally administration of [ 14 C]-anlotinib were collected. The absorption, metabolism, and excretion of [ 14 C]-anlotinib were investigated, and the efficacy and safety of anlotinib were evaluated. Results In plasma, the average time to peak concentration (T max) of total radioactivity was 4.42 h and the average peak concentration (C max) of total radioactivity was 18.80 ng Eq./g. The average values of AUC 0-last , AUC 0-∞ , and MRT 0-t were 4071 h.ng Eq./g, 13,555 h.ng Eq./g, and 125 h, respectively. The average recovery of total radioactivity (TRA) in urine and feces was 62.03%, accounting for 48.52% and 13.51% in feces and urine of the total dosage, respectively. The parent drug, a carboxylic metabolite (M30), and mono-oxidation products (M46/M66) were major drug-related components in human plasma. Oxidative metabolism played the major role in drug clearance in human. The major metabolic pathways include oxidative deamination to M2, mono-oxidation to M1, and the formation of M30. Adverse events occurred in five patients and severe adverse events (SAE) occurred in one. Tumor response were evaluated as stable disease (SD) in three, partial response (PR) in one, and progressive disease (PD) in one of the patients, respectively. Conclusions Anlotinib had a good pharmacokinetic profile with rapid absorption, long half-life, and extensive hepatic metabolism. The adverse events and efficacy were as expected.

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Endometrial Cancers Harboring Mutated Fibroblast Growth Factor Receptor 2 Protein Are Successfully Treated With a New Small Tyrosine Kinase Inhibitor in an Orthotopic Mouse Model

Abstract: Supplemental digital content is available in the text.

Cited by 69 publications

References 30 publications

Emerging therapies for non-small cell lung cancer

Emerging therapies for non-small cell lung cancer

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway

A phase I study investigation of metabolism, and disposition of [14C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

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