Figure - available from: Frontiers in Oncology
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Representative images of changes in the number of vessels showed that the four treatment groups showed different numbers of vessels in which anlotinib combined with chemoradiation-treated group was the lowest compared with the control group. The figure provided is a representative image, and other images are provided in the Supplementary Files. RT, radiation therapy; DDP, cisplatin.
Source publication
Objective: The aim of this study was to evaluate the safety and efficacy of anlotinib combined with chemoradiotherapy for treating esophageal squamous cell carcinoma (ESCC) using patient-derived xenografts (PDXs).
Methods: PDX-bearing mice were randomly divided into five groups, as follows: control group receiving normal saline, the group receiving...
Citations
... Current studies on anlotinib have mostly focused on its anticancer activity against advanced non-small-cell lung cancer [7]. Jingzhen Shi combined anlotinib with chemoradiotherapy to treat EC with good achievements [16]. These results have inspired us to investigate the underlying mechanisms behind anlotinib's effects on EC. ...
Anlotinib is effective in treatment of many kinds of malignant cancer, but its antineoplastic effects on esophageal cancer remains unclear. This study aims to investigate its impact on esophageal cancer and the underlying mechanisms. Anlotiniband 5-fluorouracil + cisplatin (5-FU + DDP) was administered separately to human esophageal cancer TE- 1 cells tumor xenograft mouse models every 3 days. Tumor size and body weight were measured before each treatment and at the end of the experiment. In vitro studies were conducted using TE- 1 cells to examine the effects of Anlotinib. Cell viability, migration, proliferation, apoptosis, cell cycle, their regulatory proteins and the transcriptomic changes were analyzed. Anlotinib reduced tumor size, tumor weight, and the ratio of tumor weight to body weight in vivo. It decreased the viability of TE- 1 cells, with a 50% growth-inhibitory concentration of 9.454 μM for 24 h, induced apoptosis, and arrested TE- 1 cell cycle in the S phase. It inhibited migration and proliferation while negatively regulating the PI3K/Akt signaling pathway. Enhanced expressions of P21, Bax, and lowered expressions of cyclin A1, cyclin B1, CDK1, PI3K, Akt, p-Akt, and Bcl-2 were observed after Anlotinib treatment. Anlotinib exhibits antineoplastic activity against human esophageal cancer TE- 1 cells by negatively regulating the PI3K/Akt signaling pathway, consequently altering the expressions of proteins related to proliferation, apoptosis, and the cell cycle.
... By inhibiting the expression of PD-L1 on endothelial cells, anlotinib can promote the entry of CD8 + T cells, increase the secretion of cytokines such as tumor necrosis factor ␣ in the microenvironment, inhibit the secretion of interleukin, and increase the local immune response. 17,25 HIF-1␣ is a factor closely associated with oxygenation in the local microenvironment. HIF-1␣ can enable hypopharyngeal cancer tumor cells to tolerate the hypoxia microenvironment and can improve the ability of tumor metastasis by regulating local glucose metabolism, angiogenesis tumor invasion, and other activities. ...
Objective
The purpose of this study is to study the in-vitro effects of multitarget inhibitor anlotinib on hypopharyngeal cancer cell proliferation and cell migration, and the underlying mechanism, which will provide new drug choices for hypopharyngeal cancer treatment.
Methods
The Hypopharyngeal cancer Fadu cells were treated with anlotinib at a concentration of 0, 5, and 10 μmoL/L, respectively. Cell counting kit-8 and the colony-forming assay were used to detect the inhibition of cell proliferation. Wound-healing assay and transwell assay were used to detect the migration and invasion ability of cells. Flow cytometry was used to detect the effects of anlotinib on cell cycle and apoptosis. RT-qPCR and Western blot were used to measure gene expression levels.
Results
CCK-8 and colony-forming assay showed that anlotinib could significantly inhibit cell proliferative activity. Wound-healing assay and transwell assay showed that anlotinib could inhibit cell migration and scratch. These results showed that anlotinib has obvious antitumor activity. Flow cell cycle experiment showed that anlotinib could promote Fadu cell apoptosis and block the G2/M phase for inhibiting cell proliferation. In addition, anlotinib decreased the expression of HIF-1α.
Conclusions
Anlotinib has an excellent suppressing effect on the proliferation, migration, and invasion of hypopharyngeal cancer Fadu cells in-vitro. Moreover, it can play an anti-tumor role through blocking cell cycle G2/M and promoting apoptosis, which may be related to the decrease of HIF-1a expression. Our study would provide a potential treatment method for patients with hypopharyngeal cancer.
Level of evidence
Level 3.
... Anlotinib selectively inhibits VEGFR and contributes to the inhibition of tumor growth and metastasis, significantly improving PFS and disease control rate (DCR) in patients with advanced ESCC, and is now entering second-line and further-line treatment in ESCC [119]. Cisplatinbased CCRT toxicity is difficult to tolerate in patients with unresectable advanced ESCC, and RT combined with cisplatin and anlotinib or RT combined with paclitaxel and erlotinib can achieve better anti-esophageal cancer outcomes [110,120]. As a novel selective inhibitor of VEGFR-2, apatinib has previously entered secondor third-line therapy for advanced ESCC. ...
Esophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-related mortality worldwide, with more than half of them occurred in China. Radiotherapy (RT) has been widely used for treating ESCC. However, radiation-induced DNA damage response (DDR) can promote the release of cytokines and chemokines, and triggers inflammatory reactions and changes in the tumor microenvironment (TME), thereby inhibiting the immune function and causing the invasion and metastasis of ESCC. Radioresistance is the major cause of disease progression and mortality in cancer, and it is associated with heterogeneity. Therefore, a better understanding of the radioresistance mechanisms may generate more reversal strategies to improve the cure rates and survival periods of ESCC patients. We mainly summarized the possible mechanisms of radioresistance in order to reveal new targets for ESCC therapy. Then we summarized and compared the current strategies to reverse radioresistance.
... Anlotinib, as a novel oral small-molecule multi-target tyrosine kinase inhibitor, has been demonstrated to inhibit tumor growth and exert anti-tumor angiogenesis effects, effectively inhibiting PDGFR, C-KIT, FGFR, VEGFR, and other kinases that are critical to cancer progression (15,16). In recent years, the Chinese National Medical Products Administration (NMPA) approved anlotinib for the treatment of small cell lung cancer(SCLC) (17), advanced nonsmall cell lung cancer (NSCLC) (16,18), thyroid cancer (19), soft tissue sarcoma (20), and esophageal cancer (21). Many clinical trials in liver cancer, gastric cancer, colorectal cancer, kidney cancer, breast cancer, endometrial cancer, ovarian cancer, NK/T cell lymphoma, Ewing's sarcoma, diffuse large B cell lymphoma, and other cancers are currently underway. ...
Background
Anlotinib may boost the efficacy of pancreatic cancer (PC) treatment if timely added to the GS regimen (Gemcitabine, Tegafur-gimeracil-oteracil potassium); however, no data has been published. This study evaluated the safety and efficacy of anlotinib in combination with the GS regimen(hereafter referred to as the A+GS regimen) in the first-line treatment of patients with unresectable or metastatic PC.Methods
Patients with unresectable or metastatic PC treated at Yueyang Central Hospital and Yueyang People’s Hospital between October 2018 and June 2022 were enrolled in this retrospective real-world investigation. Treatment efficacy was evaluated based on the overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and objective response rate (ORR), while the treatment safety was assessed by the frequency of major adverse events (AEs).ResultsSeventy-one patients were included in this study, 41 in the GS group and 30 in the A+GS group. The A+GS group had a longer mPFS than the GS group (12.0 months (95% CI, 6.0–18.0) and 6.0 months (95% CI, 3.0–8.1)), respectively (P = 0.005). mOS was longer in the GS+A group) when compared with the GS group (17.0 months (95%CI, 14.0–20.0) and 10.0 months (95% CI, 7.5–12.5)), respectively (P = 0.018). The GS+A group had higher ORR (50.0% vs 26.8%, P = 0.045) and DCR (83.3% vs 58.5%, P = 0.026). Furthermore, there were no grade 4-5 AEs and no treatment-related deaths, and no discernible increase in AEs in the GS+A group when compared with the GS group.Conclusion
The A+GS regimen therapy holds great promise in managing treatment-naive advanced PC, except that future prospective studies with larger sample sizes and multiple centers are required to determine its efficacy and safety.
... [27] More importantly, clinical studies have provided strong evidence that the use of anti-angiogenic agents, and particularly anlotinib, can promote tumor vascular normalization, thereby improving the delivery and efficacy of chemotherapy drugs in many solid tumors. [28][29][30] In our case, 6 courses of treatment with anlotinib combined with chemotherapy significantly reduced the tumor size, providing an opportunity for surgical resection of the tumor, suggesting that anlotinib combined with chemotherapy may be useful in the treatment of recurrent CCSK. ...
Rationale:
Renal clear cell sarcoma is a rare and highly invasive malignant renal tumor that easily relapses after treatment. Recurrent recurrent clear cell carcinoma (CCSK) responds poorly to chemotherapy and has no established standardized treatment, and need to be explored potentially useful treatments.
Patient concerns:
A 18-years-old patient with renal clear cell sarcoma recurrence after open radical nephrectomy.
Diagnosis:
Recurrent clear cell sarcoma.
Interventions:
After chemotherapy alone failed, the patient received 6 courses of anlotinib combined with chemotherapy. The tumor had significantly reduced in size and the recurrent tumor and part of the liver were resected.
Outcomes:
No tumor recurrence or metastasis was detected during the follow-up 8 months after the operation.
Lessons:
This is the first report describing the use of anlotinib in treating CCSK. We believe that anlotinib combined with chemotherapy may be a useful treatment option for patients with recurrent CCSK.
... It can mainly target vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR) and c-kit [13]. Previously, it has been shown that anlotinib is safe and highly effective for the treatment of various solid tumors, including lung cancer [14], esophageal squamous cell carcinoma [15], STS [16,17], etc. In addition, a previous study investigated the potential anti-tumor effects of anlotinib in SS [18], which demonstrated that the anti-tumor properties of anlotinib is mediated through the downregulation of GINS complex subunit 1 expression downstream. ...
Objective:
To identify potential biomarkers, key pathways and modules following the exposure of synovial sarcoma (SS) cells to anlotinib.
Methods:
In the current study, we integrated multiple bioinformatics methods to identify the hub genes and key pathways associated with the effects of anlotinib treatment in SS cells. In addition, we used reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) to validate the expression levels of the identified hub genes in SS cells treated with anlotinib.
Results:
In total, 183 differentially expressed genes (DEGs) were identified, of which 47 were upregulated and 136 were downregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the DEGs were predominantly involved in cell division and cell cycle progression. A total of two modules were identified from the protein-protein interaction network using the MCODE plugin in Cytoscape, where module 1 was the most significant. By combining the results of CytoHubba analysis based on the module 1 and The Cancer Genome Atlas database, six real hub genes, cyclin (CCN) A2, kinesin family member 2C, cell division cycle 20, CCNB2, aurora kinase B and CCNB1, were identified. Subsequent GO and KEGG pathway analysis revealed that these six real hub genes were significantly associated with the cell cycle and mitosis. Finally, RT-qPCR verified that the mRNA expression levels of these six real hub genes were significantly decreased in SS cells treated with anlotinib compared with those in the control group. Altogether, our study identified biomarkers and key pathways associated with the effects of anlotinib treatment in SS cells, which may provide novel insights into the underlying mechanism of anlotinib treatment in SS.
... In fact, anlotinib has great therapeutic efficacy in treating cancers, such as advanced nonsmall cell lung cancer (NSCLC), advanced soft tissue sarcoma, and metastatic renal cell carcinoma [9]. In ESCC, it has been reported that anlotinib combined with radiotherapy and chemotherapy has strong antitumor effects on patient-derivedxenografts-bearing mice [10]. In a clinical trial, it has been found that anlotinib combined with chemotherapy could improve the survival of patients with advanced ESCC [11]. ...
... In another clinical trial, it has been noticed that combined administration of nivolumab and anlotinib as a second-line therapy could improve the physical condition of the patient with advanced ESCC [20]. In addition to that, a recent report has highlighted that anlotinib and chemoradiotherapy in combination have the ideal antitumor effect to suppress the process of ESCC in mice [10]. Besides, a double-blind randomized phase 2 trial has mentioned that the use of anlotinib has a great advantage in improving progression-free survival (PFS) of patients within recurrent and metastatic ESCC [21]. ...
Background:
Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and has antitumor activity in a variety of solid tumors. Given that, our study was designed to unearth the mechanism of anlotinib in radioresistant esophageal cancer (EC) cells.
Methods:
Radioresistant EC cell lines TE-1R and KYSE-150R were established by multiple fractionated irradiation. Detection of cell proliferation was governed by the MTT assay, angiogenesis by the tube formation assay, and cell migration and invasion by the transwell assay. Lastly, RT-qPCR Western blotting was employed to detect the expression of related genes. Cancerous cells showing tumor growth were then detected by tumor xenografts in mice.
Results:
Radioresistant EC cell lines TE-1R and KYSE-150R were successfully established. Anlotinib downregulated EphA2 inhibited proliferation, angiogenesis, migration, and invasion of radioresistant EC cells in vitro. The up-regulated expression of EphA2 in both EC cell lines and radioresistant EC cells, along with anlotinib, in turn, inhibited the expression of EphA2 in radioresistant EC cells. Inhibiting EphA2 also enhanced anlotinib-mediated effects on radioresistant EC cells, so as to restrain cell proliferation, angiogenesis, migration, and invasion. Correspondingly, overexpression of EphA2 is capable of reversing the therapeutic effect of anlotinib on radioresistant EC cells. Also, anlotinib enhances the inhibitory effect of irradiation on mice.
Conclusion:
It is concluded that anlotinib inhibits EphA2 expression, thereby suppressing angiogenesis and resensitizing EC cells to radiotherapy, providing another perspective to overcome radioresistance in EC.
... Besides, the phase II study of neoadjuvant Anlotinib yielded an objective response rate (ORR) of 76.9% in patients with locally advanced thyroid cancer (17). A preclinical study has demonstrated that combination therapy with Anlotinib and chemoradiotherapy exhibits the strongest antitumor response in patient-derived xenografts (PDXs) mouse models of ESCC compared with other treatment groups (radiotherapy only, chemoradiotherapy, and Anlotinib combined with radiotherapy) (18). A randomized phase II trial demonstrated that Anlotinib significantly prolonged progression-free survival (PFS) in patients with chemotherapy-refractory metastatic ESCC compared to placebo, with a manageable safety profile (19). ...
Background
Clinical benefits of neoadjuvant Anlotinib for locally advanced esophageal squamous cell carcinoma (ESCC) remains unclear. This study evaluated the efficacy and safety of neoadjuvant Anlotinib plus chemotherapy followed by minimally invasive esophagectomy (MIE) for the treatment of patients with locally advanced ESCC.
Methods
Patients with locally advanced ESCC were randomly assigned to neoadjuvant Anlotinib combined with chemotherapy (Anlotinib group) or neoadjuvant chemoradiotherapy alone (nCRT group) with an allocation ratio of 1:1. The primary endpoint was the R0 surgical resection rate. Secondary endpoints included postoperative pathologic stage, complete response (CR) rate, and safety. Safety was assessed by adverse events (AEs) and postoperative complications.
Results
From August 2019 to August 2021, 93 patients were assigned to the nCRT or Anlotinib group. Of the 93 patients, 79 underwent MIE and were finally included in the per-protocol set (nCRT group: n=39; Anlotinib group: n=40). The R0 resection rate was 97.4% for nCRT versus 100.0% for Anlotinib group (p>0.05). Compared with the nCRT group, patients in the Anlotinib group had shorter total operation duration (262.2 ± 39.0 vs. 200.7 ± 25.5 min, p=0.010) and less blood loss (161.3 ± 126.7 vs. 52.4 ± 39.3 mL, p<0.001). No significant differences were found in the postoperative pathologic stage between the Anlotinib group and nCRT group (all p>0.05). Besides, the incidences of AEs (80.0% vs. 92.3%) and postoperative complications (22.5% vs. 30.8%) were similar between the two groups (all p>0.05).
Conclusions
Neoadjuvant Anlotinib plus chemotherapy had a similar safety profile and pathologic response, but better surgical outcomes than nCRT for locally advanced ESCC.
... Chemotherapy and anti-angiogenesis play a crucial role in advanced malignant tumors. Increasing studies (17)(18)(19)(20) have shown that anti-angiogenesis in combination with chemotherapy yielded synergetic effects in several malignancies including breast cancer, lung cancer, and sarcomas. Preclinical studies (21,22) showed that anti-angiogenesis therapy not only induced tumor cell apoptosis but also induced tumor vascular normalization, improved hypoxia, and increased the delivery of chemotherapy drugs. ...
Objective
The aim of this study is to compare gemcitabine (G) plus docetaxel (D) versus G plus anlotinib (A) for advanced soft tissue sarcoma (STS).
Methods
We retrospectively investigated 122 patients with locally advanced or metastatic STS who were treated with either G+D or G+A between July 2016 and October 2021 and compared the efficacy and toxicity of G+D and G+A. The primary endpoints were median progression-free survival (PFS) and the proportion of patients with grade ≥3 adverse events. We also analyzed differences in the clinical efficacy of G+D and G+A in leiomyosarcoma, and the differences in the clinical efficacy of G+D and G+A as first-line therapy.
Results
Overall, 122 patients were included (81 patients receiving G+D and 41 patients receiving G+A) with a median age of 55 years. The main histological types are leiomyosarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma. After a median follow-up of 25 months, PFS did not differ between patients treated with G+D and those treated with G+A (median PFS: 5.8 months and 6.8 months, p = 0.39), and overall survival (OS) was similar (median OS: 14.7 vs. 13.3 months, p = 0.75) with a similar objective response rate (18.5% vs. 14.6%, p = 0.17), whereas the proportion of patients with grade ≥3 adverse events treated with G+D was significantly higher than those treated with G+A (68% vs. 44%, p < 0.05). Subgroup analysis of leiomyosarcoma patients (47.5% of the patients) and first-line treatment patients (46.7% of the patients) shows that PFS was not significantly different between the two groups (LMS: median PFS: 6.5 months vs. 7.5 months, p = 0.08; first-line treatment: median PFS: 6.2 months vs. 7.1 months, p = 0.51).
Conclusion
Compared with gemcitabine plus docetaxel for advanced STS, gemcitabine plus anlotinib achieved a similar response rate on median PFS and OS, but lower toxicity. These results suggest that gemcitabine plus anlotinib may be an effective and safe strategy for advanced STS.
... Hu et al. (Hu et al. 2020) found that the combined use of apatinib in patients with ESCC undergoing radiotherapy and chemotherapy can significantly improve the median survival time of patients, but not the total survival rate. Shi et al. (Shi et al. 2020) also have similar results. Radiotherapy for EC combined with anlotinib can achieve better anti-tumor effect than single drug and radiotherapy alone. ...
Vascular endothelial growth factor (VEGF) is related to the radiation resistance of tumors, resulting in the failure of tumor radiotherapy. The purpose of this study was to discuss the role of VEGF in radiotherapy resistance of esophageal squamous cell carcinoma (ESCC). We used the VEGF kit by ELISA to detect the serum VEGF level of ESCC patients who only received radiotherapy. The expression of VEGF in ESCC cells after siRNA treatment was verified by Western blot. The sensitivity of ESCC cells to radiation after knocking down VEGF was analyzed by Clonogenic assay and Cell counting kit (CCK-8). The results showed that the level of serum VEGF in patients with ESCC before and after radiotherapy was related to the clinical response, and it was confirmed that knocking down the expression of VEGF in ESCC cells improved the sensitivity to radiation.
