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Gao C, Chen L, Zhao L, Su Y, Ma M, Zhang W, Hong X, Xiao L, Xu B, Hu T. Apatinib Degrades PD-L1 and Reconstitutes Colon Cancer Microenvironment via the Regulation of Myoferlin. Cancers (Basel) 2025; 17:524. [PMID: 39941891 PMCID: PMC11816266 DOI: 10.3390/cancers17030524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/20/2025] [Accepted: 01/25/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. METHODS Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. RESULTS We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. CONCLUSIONS These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses.
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Affiliation(s)
- Chunyi Gao
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China
| | - Lu Chen
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
| | - Lingying Zhao
- Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen 518038, China;
| | - Yongcheng Su
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
| | - Miaomiao Ma
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
| | - Wenqing Zhang
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
| | - Xiaoting Hong
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
| | - Li Xiao
- Department of Oncology, Zhongshan Hospital of Xiamen University, Xiamen 361004, China;
| | - Beibei Xu
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Tianhui Hu
- Xiamen Key Laboratory for Tumor Metastasis, Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China; (C.G.); (L.C.); (Y.S.); (M.M.); (W.Z.); (X.H.)
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases (Ministry of Education), Gannan Medical University, Ganzhou 341000, China
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Liu ZP, Liu SH, Zhao H, Ruan FY, Zhang DX, Xu B. Pathologically Complete Response to Camrelizumab and Apatinib in Advanced Cervical Cancer with PTEN, PIK3CA, MTOR, and ARID1A Mutations: A Case Report. Case Rep Oncol 2025; 18:480-492. [PMID: 40255685 PMCID: PMC12007909 DOI: 10.1159/000545068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 02/25/2025] [Indexed: 04/22/2025] Open
Abstract
Introduction Limited treatment options are available for residual locally advanced cervical cancer after concurrent radio-chemotherapy. Pembrolizumab has been approved by the US Food and Drug Administration to treat patients with persistent, recurrent, and metastatic cervical cancer. However, it is expensive and not covered by medical insurance in China. Case Description A patient presented with stage IIIC1 cervical cancer characterized by PTEN, PIK3CA, MTOR, and ARID1A mutations, accompanied by low programmed cell death-ligand 1 expression (tumor cell proportion score 1% and combined positive score 1). The patient exhibited a residual cervical lesion after concurrent radio-chemotherapy but eventually achieved a pathologically complete response through a combination of the programmed cell death-1 (PD-1) inhibitor camrelizumab with the antiangiogenic drug apatinib (two medicines produced by Chinese Jiangsu Hengrui Pharmaceutical Co.). Surgical intervention confirmed the lack of residual tumor cells in the cervix. Regular follow-up confirmed that disease-free survival time was 41 months and overall survival time was 51 months. Adverse events, including cutaneous capillary endothelial proliferation, hepatic insufficiency, hemorrhoidal hemorrhage, and neutropenia, were manageable during treatment with camrelizumab and apatinib. Conclusion Our findings suggest that the combination of camrelizumab and apatinib could offer a valuable therapeutic option for residual advanced cervical cancer patients after concurrent radio-chemotherapy. Camrelizumab is affordable, at just 10% of the price of pembrolizumab, although it is similarly not covered by medical insurance for cervical cancer in China. The PTEN, PIK3CA, MTOR, and ARID1A gene mutations hold the potential to serve as predictive biomarkers for cervical cancer patients treated by PD-1 inhibitors.
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Affiliation(s)
- Zhi-Ping Liu
- Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Si-Han Liu
- Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - He Zhao
- Department of Medicine, Zhejiang Shaoxing Topgen Biomedical Technology Co. Ltd., Shaoxing City, China
| | - Fang-Ying Ruan
- Department of Medicine, Zhejiang Shaoxing Topgen Biomedical Technology Co. Ltd., Shaoxing City, China
| | - Da-Xin Zhang
- Department of Oncology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bai Xu
- Department of Gynaecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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Navas Moreno V, Sebastián Valles F, Lahera Vargas M, Hernández Marín B, Carrillo López E, Marazuela M, Muñoz de Nova JL. Neoadjuvant Treatment in Locally Advanced Thyroid Carcinoma. J Clin Med 2024; 13:5769. [PMID: 39407830 PMCID: PMC11477333 DOI: 10.3390/jcm13195769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Although the focus in the last decades has been on the overdiagnosis of incidentally detected thyroid carcinomas in early stages, the other extreme of the disease is represented by locally advanced tumors with the invasion of neighboring structures. These are infrequent tumors, but they have a high complexity and a poor prognosis. In the absence of effective therapies allowing preoperative tumor reduction, in order to achieve a more restricted surgery, treatment was limited to aggressive surgery with resection of the aerodigestive tract and major vascular structures or palliative treatment. However, due to the increased knowledge of tumor biology and the results that tyrosine kinase inhibitors have achieved in the treatment of radioactive iodine-refractory tumors, neoadjuvant therapy with a curative intent has emerged as a reality to be taken into account when dealing with these patients. This paper presents a narrative review of the current scientific evidence regarding neoadjuvant treatment in locally advanced thyroid cancer.
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Affiliation(s)
- Víctor Navas Moreno
- Department of Endocrinology and Nutrition, Hospital Universitario de La Princesa, 28028 Madrid, Spain
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28028 Madrid, Spain
| | - Fernando Sebastián Valles
- Department of Endocrinology and Nutrition, Hospital Universitario de La Princesa, 28028 Madrid, Spain
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28028 Madrid, Spain
| | - Marcos Lahera Vargas
- Department of Endocrinology and Nutrition, Hospital Universitario de La Princesa, 28028 Madrid, Spain
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28028 Madrid, Spain
| | - Berta Hernández Marín
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28028 Madrid, Spain
- Department of Oncology, Hospital Universitario de La Princesa, 28028 Madrid, Spain
- Department of General and Digestive Surgery, Hospital Universitario de La Princesa, 28028 Madrid, Spain
| | - Elena Carrillo López
- Department of Endocrinology and Nutrition, Hospital Universitario de La Princesa, 28028 Madrid, Spain
| | - Mónica Marazuela
- Department of Endocrinology and Nutrition, Hospital Universitario de La Princesa, 28028 Madrid, Spain
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28028 Madrid, Spain
- Department of Oncology, Hospital Universitario de La Princesa, 28028 Madrid, Spain
| | - José Luis Muñoz de Nova
- Instituto de Investigación Sanitaria Princesa (IIS-IP), 28028 Madrid, Spain
- Department of General and Digestive Surgery, Hospital Universitario de La Princesa, 28028 Madrid, Spain
- Department of Surgery, Universidad Autónoma de Madrid, 28029 Madrid, Spain
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Chang L, Zhang X, Ma Q, Kong L, Yu Y, Tao J, Li Q. Safety and efficacy of apatinib in combination with chemotherapy with or without immunotherapy versus chemotherapy alone as first-line treatment for advanced gastric cancer. Invest New Drugs 2024; 42:161-170. [PMID: 38367168 PMCID: PMC10944401 DOI: 10.1007/s10637-024-01423-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 01/22/2024] [Indexed: 02/19/2024]
Abstract
The specific first-line regimen for advanced gastric cancer (GC) is still controversial. The benefit of apatinib for first-line treatment of advanced GC remains unknown and needs to be further explored. Eighty-two patients with advanced GC treated in our institution from October 2017 to March 2023 were retrospectively reviewed. All individuals had her-2 negative GC and had received at least two cycles of first-line treatment, including 44 patients in the combination treatment group (apatinib in combination with chemotherapy with or without immunotherapy) and 38 patients in the simple chemotherapy group. We evaluated the efficacy and safety of apatinib in combination with chemotherapy with or without immunotherapy in the first-line treatment of advanced GC by comparing the efficacy, progression-free survival (PFS), and adverse events in two groups of patients. The median PFS of the simple chemotherapy group was 9.25 months (95% confidence interval (CI), 6.1-11.2 months), and that of the combination treatment group was 10.9 months (95% CI, 7.9-15.8 months), which was 1.65 months longer than the simple chemotherapy group. Statistically significant differences are shown (P = 0.022). The objective response rate (ORR) of the combination treatment group was 65.9%, and 36.8% in the simple chemotherapy group. Statistically significant differences are shown (P = 0.014). No serious (Grade IV) adverse events occurred in either group. Our study indicates that apatinib in combination with chemotherapy with or without immunotherapy as first-line treatment for advanced GC exhibits good anti-tumor activity and is well tolerated by patients.
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Affiliation(s)
- Lele Chang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang Province 150001, China
| | - Xuemei Zhang
- Department of Radiation Oncology, Quzhou People's Hospital, Quzhou, China
| | - Qian Ma
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang Province 150001, China
| | - Lingyang Kong
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang Province 150001, China
| | - Yang Yu
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Ji Tao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang Province 150001, China
| | - Qingwei Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang Province 150001, China.
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Chen M, Li Y, Cheng M. Efficacy and safety of the combination of camrelizumab and apatinib in the treatment of liver cancer: a systematic review and single-arm meta-analysis. BMC Gastroenterol 2024; 24:55. [PMID: 38297195 PMCID: PMC10829166 DOI: 10.1186/s12876-024-03144-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/23/2024] [Indexed: 02/02/2024] Open
Abstract
OBJECTIVE To evaluate the efficacy and safety of the combination of camrelizumab and apatinib in the treatment of liver cancer and to furnish clinical recommendations for pharmacological interventions. METHODS PubMed, Embase, Web of Science and the Cochrane Library were scrutinized for research publications from their inception to 22 December 2023. Bibliographic perusal and data procurement were executed. The quality of the included studies was evaluated employing the MINORS tool. Meta-analysis was conducted utilizing Stata 15.0 software. RESULTS A total of 10 studies involving 849 patients were included in the meta-analysis. The study revealed that the objective response rate (ORR) of the combined therapy was 28% (95% CI: 23%-34%), the disease control rate (DCR) was 69% (95% CI: 64%-73%), the median progression-free survival (mPFS) was 5.87 months (95% CI: 4.96-6.78), the median overall survival (mOS) was 19.35 months (95% CI: 17.53-21.17), the incidence of any grade adverse events was 90% (95% CI: 85%-95%), and the occurrence of grade 3 or higher adverse events was 49% (95% CI: 27%-71%). CONCLUSION The combination of camrelizumab and apatinib exhibits commendable effectiveness in the management of liver cancer; nevertheless, vigilance should be exercised concerning potential adverse reactions in clinical applications to enhance the safety of pharmacological interventions.
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Affiliation(s)
- Min Chen
- Department of Pharmacy, Zhejiang Hospital, No.12 Ling Yin Road, Hangzhou, 310013, Zhejiang, China.
| | - Yanglei Li
- Department of Pharmacy, Zhejiang Hospital, No.12 Ling Yin Road, Hangzhou, 310013, Zhejiang, China
| | - Minyu Cheng
- Department of Pharmacy, Zhejiang Hospital, No.12 Ling Yin Road, Hangzhou, 310013, Zhejiang, China.
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Wang L, Li J, Chen H. Efficacy and Safety of Low-Dose Apatinib Combined with Chemotherapy as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis. Chemotherapy 2023; 69:11-22. [PMID: 37339610 DOI: 10.1159/000531524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 06/07/2023] [Indexed: 06/22/2023]
Abstract
INTRODUCTION At present, there are several studies on low-dose apatinib combined with chemotherapy as a second-line treatment of advanced gastric cancer (AGC), but the conclusions are controversial. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of low-dose apatinib combined with chemotherapy as a second-line treatment of AGC. METHODS Nine databases were searched for records on apatinib combined with chemotherapy in treating AGC from inception to June 2022. The observation group received low-dose apatinib combined with chemotherapy, while the controls received chemotherapy alone or other non-placebo treatments. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. The relative risk (RR) and weighted mean difference (WMD) were used as effect sizes. RESULTS Eight studies involving 679 patients were included in this meta-analysis. The results of the meta-analysis showed that the observation group was superior to the controls in terms of ORR (RR = 1.38, 95% confidence interval [CI]: 1.05-1.81, p = 0.02), DCR (RR = 1.35, 95% CI: 1.20-1.53, p < 0.001), OS (WMD = 4.72, 95% CI: 0.71-8.72, p < 0.001), and PFS (WMD = 2.67, 95% CI: 1.7-3.63, p < 0.001). There were no significant differences between the two groups in adverse events of any grade except hypertension (RR = 2.82, 95% CI: 2.07-3.84, p < 0.001), hand-mouth syndrome (RR = 1.84, 95% CI: 1.84-2.48, p < 0.001), and proteinuria (RR = 3.63, 95% CI: 2.31-5.7, p < 0.001). CONCLUSION Low-dose apatinib combined with chemotherapy as a second-line therapy is more effective in improving the efficacy of AGC compared to chemotherapy alone. However, this option has the potential to increase the risk of hypertension, hand-mouth syndrome, and proteinuria.
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Affiliation(s)
- Liang Wang
- Department of Radiotherapy, Hainan Cancer Hospital, Haikou, China
| | - Juyuan Li
- Department of Gastroenterology, Hainan West Central Hospital, Danzhou, China
| | - Huamin Chen
- Department of Gastrointestinal Oncology Surgery, The Second Affiliated Hospital of Hainan Medical College, Haikou, China
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Shi B, Chang J, Sun X, Ma X, Zhao P, Zhou C, Wang Y, Yang Y. A meta-analysis: the clinical value of PD-1 inhibitor or protein tyrosine kinase inhibitors in the treatment of advanced osteosarcoma. Front Oncol 2023; 13:1148735. [PMID: 37377920 PMCID: PMC10291171 DOI: 10.3389/fonc.2023.1148735] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Backgrounds PD-1 inhibitors and TKIs have been used to treat advanced osteosarcoma, but there is still a lack of intuitive data for the comparison of their efficacy. We conducted a meta-analysis to evaluate their therapeutic benefits. Methods A systematic methodological search of five primary electronic databases was performed. Studies with a randomized design of any type about PD-1 inhibitors or TKIs for the treatment of advanced osteosarcoma were included. The primary outcomes mainly included CBR, PFS, OS and ORR, The CR, PR, SD and AEs were the secondary outcomes. The survival period (months) of patients was taken as the main analysis data. Random-effects models were used for meta-analysis. Results Eight immunocheckpoint inhibitors in 327 patients from 10 clinical trials were finally evaluated. For OS, TKIs [11.67 months (95% CI, 9.32-14.01)] show more obvious advantages than PD-1 inhibitors [6.37 months (95% CI, 3.96-8.78)]. For PFS, TKIs [4.79 months (95% CI, 3.33-6.24)] are longer than PD-1 inhibitors [1.46 months (95% CI, 1.23-1.69)]. Although there was no fatal event, attention should still be paid, especially during the combined application of PD-1 inhibitors with TKIs since their obvious AEs. Conclusions The findings of this study suggest that patients with advanced osteosarcoma, TKIs may be more beneficial than PD-1 inhibitors. TKIs combined with PD-1 inhibitors has a bright future in the treatment of advanced osteosarcoma, but we should always pay attention to the strong side effects.
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Affiliation(s)
- Binhao Shi
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Junli Chang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Xingyuan Sun
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Xiaoping Ma
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Peng Zhao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Chujie Zhou
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Yongjun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
| | - Yanping Yang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Theory and Therapy of Muscles and Bones, Ministry of Education, Shanghai, China
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Kang R, Song M, Fang Z, Liu K. Nano-composite hydrogels of Cu-Apa micelles for anti-vasculogenic mimicry. J Drug Target 2023; 31:166-178. [PMID: 35993258 DOI: 10.1080/1061186x.2022.2115047] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Vasculogenic mimicry (VM) describes the phenomenon whereby fluid-conducting vessels are formed by highly invasive tumour cells, which supply blood to tumours during their early growth stages. Single antiangiogenic agents have limited inhibitory effects on VM, therefore, a multi-pathway anti-VM strategy is required. In this study, Apatinib (Apa) was coordinated with Cu2+ to form a Cu-Apa copper complex. The latter was loaded into oligo-hyaluronic acid (HA) polymeric micelles (HA-Chol) and subsequently embedded in Astragalus polysaccharide-based in situ hydrogels (APsGels) to generate Cu-Apa/HA-Chol@APsGels. In this system, Cu-Apa exerts the combined effects of Cu2+ and Apa to inhibit VM; HA-Chol micelles achieve targeted drug delivery and enhance endocytosis efficiency; APsGels realise sustained release of the drugs to ensure an anti-VM effect. This system demonstrated improved VM inhibition with low cytotoxicity and high biocompatibility, wound healing, and transwell invasion in three-dimensional cell cultured VM. Moreover, this system significantly inhibited VM formation and melanoma growth in a mouse tumour transplantation model. This study provides an effective strategy for inhibiting VM.
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Affiliation(s)
- Rui Kang
- Department of Biopharmaceutics, College of Food Science and Technology, Shanghai Ocean University, Shanghai, PR China
| | - Mengdi Song
- Department of Biopharmaceutics, College of Food Science and Technology, Shanghai Ocean University, Shanghai, PR China
| | - Zhou Fang
- Department of Biopharmaceutics, College of Food Science and Technology, Shanghai Ocean University, Shanghai, PR China
| | - Kehai Liu
- Department of Biopharmaceutics, College of Food Science and Technology, Shanghai Ocean University, Shanghai, PR China
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Xiang Z, Deng X, He W, Yang Q, Ni L, Dehghan Shasaltaneh M, Maghsoudloo M, Yang G, Wu J, Imani S, Wen Q. Treatment of malignant pleural effusion in non-small cell lung cancer with VEGF-directed therapy. Ann Med 2022; 54:1357-1371. [PMID: 35543207 PMCID: PMC9103356 DOI: 10.1080/07853890.2022.2071977] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is a critical regulator of malignant pleural effusion (MPE) in non-small-cell lung cancer (NSCLC). Bevacizumab (BEV) and apatinib (APA) are novel VEGF blockers that inhibit lung cancer cell proliferation and the development of pleural effusion. METHODS In this study, we established Lewis lung cancer (LLC) xenograft mouse models to compare the therapeutic effect of APA and BEV in combination with cisplatin (CDDP) against MPE. The anti-tumour and anti-angiogenic effects of this combination therapy were evaluated by 18F-FDG PET/CT imaging, TUNEL assay and Immunohistochemistry. RESULTS The triple drug combination significantly prolonged the overall survival of the tumour-bearing mice by reducing MPE and glucose metabolism and was more effective in lowering VEGF/soluble VEGFR-2 levels in the serum and pleural exudates compared to either of the monotherapies. Furthermore, CDDP + APA + BEV promoted in vivo apoptosis and decreased microvessel density. CONCLUSIONS Mechanistically, LLC-induced MPE was inhibited by targeting the VEGF-MEK/ERK pathways. Further studies are needed to establish the synergistic therapeutic effect of these drugs in NSCLC patients with MPE.KEY MESSAGESCombined treatment of MPE with apatinib, bevacizumab and cisplatin can prolong the survival time of mice, reduce the content of MPE, decrease the SUVmax of thoracic tumour tissue, down-regulate the content of VEGF and sVEGFR-2 in serum and pleural fluid, and promote the apoptosis of tumour cells. Angiogenesis and MPE formation can be inhibited by down-regulation of HIF-1α, VEGF, VEGFR-2, MEK1 and MMP-2 molecular signalling pathway proteins.
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Affiliation(s)
- Zhangqiang Xiang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Phase 1 Clinical Trial Center, Deyang People's Hospital, Deyang, China
| | - Xiangyu Deng
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenfeng He
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qian Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Laichao Ni
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | | | - Mazaher Maghsoudloo
- Laboratory of Systems Biology and Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.,Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Gang Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Department of Oncology, Anyue Hospital of Traditional Chinese Medicine, Second Ziyang Hospital of Traditional Chinese Medicine, Ziyang, China
| | - Jingbo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China. The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Saber Imani
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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11
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Yu L, Wang Y, He Y, Zhong H, Ge S, Zou Y, Lai Y, Xu Q, Gao J, Liu W, Guo W. Combination of apatinib with apo-IDO1 inhibitor for the treatment of colorectal cancer. Int Immunopharmacol 2022; 112:109233. [PMID: 36126409 DOI: 10.1016/j.intimp.2022.109233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/03/2022] [Accepted: 09/02/2022] [Indexed: 11/05/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world. Recently, many clinical studies have demonstrated the therapeutic potential of immune checkpoint therapy combined with inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) in colon cancer. Compound B37, identified in our previous experiment, is an apo-form indoleamine-2,3-dioxygenase 1 inhibitor (apo-IDO1 inhibitor), which has been shown to significantly suppress tumor growth combined with an anti-PD1 antibody. We speculated whether this apo-IDO inhibitor (B37) combined with a VEGFR2 inhibitor (apatinib) would further improve its anti-tumor activity. Therefore, a syngeneic mouse colon cancer model (mouse colon cancer cell line CT26) was established to investigate the anti-tumor activity of B37 combined with apatinib. As expected, the combination of B37 and apatinib (VEGFR2 inhibitor) improved the therapeutic effect compared with apo-IDO1 inhibitor and apatinib monotherapy, as shown by the reduced growth of transplanted tumors, weakened proliferation, and increased apoptosis of cancer cells. Specifically, there was a 24.8% reduction in tumor volume using apatinib and 31.3% reduction using B37. The combination-treated group showed remarkable inhibition of tumor growth (52.2%). For tumor weight, there was a 29.2% reduction in the apatinib-treated group and 35.0% reduction in the B37-treated group. The combination-treated group showed a 56.3% reduction. Moreover, the combination therapy reprogrammed the immune microenvironment by increasing infiltration of CD4+ and CD8+ T cells, decreasing the ratio of regulatory T cells, and promoting the killing ability of T cells manifested by elevated expression of IFN-γ and granzyme B in the combination-treated group. Our study indicates that the combination of apo-IDO1 inhibitor and apatinib is a promising strategy for CRC therapy.
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Affiliation(s)
- Longbo Yu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Yuanyuan Wang
- The First People's Hospital of Lianyungang, Lianyungang, PR China
| | - Yingxue He
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Haiqing Zhong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Shushan Ge
- China State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yi Zou
- China State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yisheng Lai
- China State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
| | - Jian Gao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
| | - Wen Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210093, PR China.
| | - Wenjie Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
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12
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Yu W, Zhang H, Chen J, Zhang X, Chen Y, Qu G, Huang G, Zhou Y, Ye T, Fan Z, Yao Y. Efficacy and safety of apatinib in patients with untreated or chemotherapy-refractory soft tissue sarcoma: a multicenter, phase 2 trial. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:981. [PMID: 36267741 PMCID: PMC9577792 DOI: 10.21037/atm-22-4229] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/13/2022] [Indexed: 11/06/2022]
Abstract
Background Anti-angiogenic agents have been reported to exert promising clinical activity for advanced soft tissue sarcoma (STS). Apatinib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is effective and safe for various solid tumors, but its role in STS remains unclear. The aim of this study was to explore the efficacy and safety of apatinib in patients with untreated or chemotherapy-refractory STS. Methods In this multicenter, single-arm, phase 2 trial, patients aged 18-70 years with untreated or chemotherapy-refractory STS were enrolled and received 500 mg apatinib per day. During treatment, patients were followed up with imaging every 8 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), overall survival (OS), and adverse events (AEs), which were graded following the National Cancer Institute common terminology criteria for AEs version 4.03. Results From June 2017 to October 2018, 53 patients were enrolled, 51 of whom received at least one dose of apatinib. Of the 53 patients, 41 (77.4%) had chemotherapy-refractory disease. The median follow-up was 13.3 months. The 6- and 12-month PFS rates were 46.8% and 25.2%, respectively, with a median PFS of 5.6 months [95% confidence interval (CI): 3.8-9.2 months]. The median PFS was 5.5 months for chemotherapy-refractory patients, 9.1 months for untreated patients, 13.9 months for patients with alveolar soft part sarcoma (ASPS), and 3.7 months for patients with clear cell sarcoma (CCS). The 12- and 24-month OS rates were 58.6% and 44.9%, respectively, with a median OS of 20.0 months (95% CI: 9.2-31.1 months). The median OS was 10.7 months for chemotherapy-refractory patients and not estimated for untreated, ASPS, nor CCS patients. In 50 evaluable patients, the ORR was 18.0% and the disease control rate was 86.0%. These results were similar to those of the per-protocol set. The most common grade 3 or 4 AEs included hypertension [30 (58.8%) of 51 patients], leukopenia [12 (23.5%)], proteinuria [8 (15.69%)], and hematuria [8 (15.69%)]. One patient died of unknown cause. Conclusions This study suggested that apatinib might be effective and tolerable in patients with untreated or chemotherapy-refractory STS (NCT03064243).
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Affiliation(s)
- Wenxi Yu
- Department of Oncology, Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hongmei Zhang
- Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, Xi’an, China
| | - Jing Chen
- Department of Bone Soft Tissue Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing Zhang
- Department of Medical Melanoma and Sarcoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yong Chen
- Department of Orthopaedic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Guofan Qu
- Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin, China
| | - Gang Huang
- Department of Bone Neoplasms, Hunan Provincial Tumor Hospital, Changsha, China
| | - Yuhong Zhou
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ting Ye
- Department of Bone Soft Tissue Oncology, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhengfu Fan
- Department of Orthopaedic Oncology, Beijing Cancer Hospital, Beijing, China
| | - Yang Yao
- Department of Oncology, Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, China
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Solid Tumors and Kinase Inhibition: Management and Therapy Efficacy Evolution. Int J Mol Sci 2022; 23:ijms23073830. [PMID: 35409190 PMCID: PMC8998551 DOI: 10.3390/ijms23073830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 02/01/2023] Open
Abstract
The increasing numbers of cancer cases worldwide and the exceedingly high mortality rates of some tumor subtypes raise the question about if the current protocols for cancer management are effective and what has been done to improve upon oncologic patients’ prognoses. The traditional chemo-immunotherapy options for cancer treatment focus on the use of cytotoxic agents that are able to overcome neoplastic clones’ survival mechanisms and induce apoptosis, as well as on the ability to capacitate the host’s immune system to hinder the continuous growth of malignant cells. The need to avert the highly toxic profiles of conventional chemo-immunotherapy and to overcome the emerging cases of tumor multidrug resistance has fueled a growing interest in the field of precision medicine and targeted molecular therapies in the last couple of decades, although relatively new alternatives in oncologic practices, the increased specificity, and the positive clinical outcomes achieved through targeted molecular therapies have already consolidated them as promising prospects for the future of cancer management. In recent years, the development and application of targeted drugs as tyrosine kinase inhibitors have enabled cancer treatment to enter the era of specificity. In addition, the combined use of targeted therapy, immunotherapy, and traditional chemotherapy has innovated the standard treatment for many malignancies, bringing new light to patients with recurrent tumors. This article comprises a series of clinical trials that, in the past 5 years, utilized kinase inhibitors (KIs) as a monotherapy or in combination with other cytotoxic agents to treat patients afflicted with solid tumors. The results, with varying degrees of efficacy, are reported.
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14
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Apatinib and Ginsenoside-Rb1 Synergetically Control the Growth of Hypopharyngeal Carcinoma Cells. DISEASE MARKERS 2022; 2022:3833489. [PMID: 35069931 PMCID: PMC8776476 DOI: 10.1155/2022/3833489] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/06/2021] [Accepted: 12/14/2021] [Indexed: 02/07/2023]
Abstract
Background Apatinib is an anticancer drug known to inhibit the vascular endothelial growth factor receptor-2 (VEGFR-2) through regulating tyrosine kinases. Drug resistance and reduced activity in various cancers is the matter of great concern; thus, researchers opt to use combination of the two or more drugs. So far, its gynergetic anticancer role with a traditional Chinese drug Ginsenoside-Rb1 (G-Rb1) has not been studied in cancers including hypopharyngeal carcinoma. Objective The current study is aimed at investigating the anticancer synergetic effects of G-Rb1 and apatinib in hypopharyngeal carcinoma. Methods The synergetic effects of both drugs on cell proliferation, wound healing and cell migration, and cell apoptosis were studied in hypopharyngeal carcinoma cells. Furthermore, the xenograft rat model was generated, and tumor inhibition was monitored after treating rats with both drugs as mono- and combination therapy. In addition, protein expression and localization were performed by western blotting and immunofluorescent staining, respectively. Results The analyses of the data showed that combination therapy of apatinib and G-Rb1 significantly inhibited the proliferation, migration, and wound healing capability of hypopharyngeal carcinoma cells. Moreover, the glycolysis rate of the cells in the combination therapy (apatinib and G-Rb1) group was significantly decreased as compared to that in the monotherapy group or no treatment group, suggesting that the glycolysis inhibition led to the inhibition of tumor growth. Moreover, the combination therapy on xenograft rats dramatically reduced the tumor size. Furthermore, combination therapy also exhibited an increased count of CD3+ and CD4+ T cells, as well as the ratio between CD4+ and CD8+ T cells. Conclusion Interestingly, a combination of apatinib and G-Rb1 induced more tumor cell apoptosis and reduced cell proliferation than the individual drug treatment and promote antitumor immunity by enhancing immunomodulatory molecules. Thus, we believe that this study could serve as a valuable platform to assess the synergetic anticancer effects of the herbal as well as synthetic medicines.
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15
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Emerging Therapeutic Agents for Colorectal Cancer. Molecules 2021; 26:molecules26247463. [PMID: 34946546 PMCID: PMC8707340 DOI: 10.3390/molecules26247463] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023] Open
Abstract
There are promising new therapeutic agents for CRC patients, including novel small-molecule inhibitors and immune checkpoint blockers. We focused on emerging CRC’s therapeutic agents that have shown the potential for progress in clinical practice. This review provides an overview of tyrosine kinase inhibitors targeting VEGF and KIT, BRAF and MEK inhibitors, TLR9 agonist, STAT3 inhibitors, and immune checkpoint blockers (PD1/PDL-1 inhibitors), for which recent advances have been reported. These new agents have the potential to provide benefits to CRC patients with unmet medical needs.
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16
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Tian Z, Niu X, Yao W. Efficacy and Response Biomarkers of Apatinib in the Treatment of Malignancies in China: A Review. Front Oncol 2021; 11:749083. [PMID: 34676173 PMCID: PMC8525889 DOI: 10.3389/fonc.2021.749083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/21/2021] [Indexed: 02/03/2023] Open
Abstract
Apatinib is a multitarget tyrosine kinase inhibitor marketed in China for the treatment of advanced gastric cancer (GC) and hepatocellular carcinoma (HCC). It has also been used off-label for the treatment of many other malignancies. To comprehensively evaluate the efficacy of apatinib as a targeted therapy in the treatment of malignancies, we conducted systematic online and manual searches of the literature on apatinib in the treatment of malignancies. In this review, we first summarized the efficacy of apatinib against various malignancies based on clinical trials where results have been reported. In prospectively registered trials, apatinib has been proven to be effective against GC, HCC, lung cancer, breast cancer, sarcoma, esophageal cancer, colorectal cancer, ovarian cancer, cervical cancer, cholangiocarcinoma, diffuse large B-cell lymphoma, nasopharyngeal carcinoma, and differentiated thyroid cancer. The response biomarkers for apatinib were also reviewed. This review will serve as a good reference for the application of apatinib in clinical studies and the design of clinical trials.
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Affiliation(s)
- Zhichao Tian
- Department of Orthopedics, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xiaohui Niu
- Department of Orthopedic Oncology, Beijing Jishuitan Hospital, Beijing, China
| | - Weitao Yao
- Department of Orthopedics, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
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17
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Wang L, Zhao L, Zhang L, Jing X, Zhang Y, Shao S, Zhao X, Luo M. [Vascular endothelial growth factor promotes cancer stemness of triple-negative breast cancer via MAPK/ERK pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:1484-1491. [PMID: 34755663 DOI: 10.12122/j.issn.1673-4254.2021.10.06] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To investigate the role of vascular endothelial growth factor (VEGF) in regulating triple-negative breast cancer (TNBC) stem cells and the possible pathways involved in this regulatory mechanism. METHODS The Oncomine database, UALCAN database and Human Protein Atlas (HPA) database were used to analyze the expression of VEGF in breast cancer and its association with the molecular subtypes and prognosis of breast cancer. Sphere formation assay was carried out to examine the effects of hVEGF165 on sphere formation ability of TNBC MDA-MB-231 cell line; Western blotting and RT-qPCR were performed to detect the expression of the tumor stem cell markers including CD44, c-Myc, Nanog, and ALDH1 and the activation of the related pathways. RESULTS Data from the online databases all showed a significant increase of VEGF expression in breast cancer tissues than in the adjacent tissues (P < 0.0001), and its expression level was associated with the molecular subtypes of breast cancer. Specifically, the expression of VEGF was markedly higher in TNBC than in other subtypes of breast cancer. Survival analysis showed that breast cancer patients with a high VEGF expression had a significantly shortened overall survival (P < 0.0001). In the cell experiments, the sphere formation ability of MDA-MB-231 cells was significantly enhanced after treatment with hVEGF165 (P=0.0029). Compared with the monolayer cells, MDA-MB-231 spheres showed significantly increased expressions of VEGF, NRP-1, CD44, Nanog and c-Myc. Treatment with hVEGF165 resulted in significant time-dependent up-regulation of the expressions of CD44, c-Myc, Nanog and ALDH1 and down-regulation of CD24 expression in the cells. The results of Western blotting demonstrated that treatment with hVEGF165 caused significant activation of the ERK/MAPK pathway in MDA-MB-231 cells. CONCLUSION VEGF promotes cancer stemness of triple-negative breast cancer possibly through the ERK/MAPK pathway.
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Affiliation(s)
- L Wang
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - L Zhao
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - L Zhang
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - X Jing
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Y Zhang
- Department of Respiratory, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - S Shao
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - X Zhao
- Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - M Luo
- Department of Hematology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
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18
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Zhong N, Zhuang W, Huang Q, Wang Q, Jin W. Apatinib inhibits the growth of small cell lung cancer via a mechanism mediated by VEGF, PI3K/Akt and Ki-67/CD31. J Cell Mol Med 2021; 25:10039-10048. [PMID: 34590406 PMCID: PMC8572765 DOI: 10.1111/jcmm.16926] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/24/2021] [Accepted: 08/29/2021] [Indexed: 12/01/2022] Open
Abstract
This study aimed to investigate the anti‐tumour effect of apatinib on extensive‐stage small cell lung cancer (SCLC) and elucidate the associated mechanisms. NCI‐H345 cells were selected as model cells because of high expression of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2) and phosphorylated‐VEGFR2 (pVEGFR2). Cells were exposed to recombinant human VEGF (rhVEGF) and apatinib. Cells were then divided into eight groups, namely, control, rhVEGF, apatinib, rhVEGF+apatinib, serum‐free medium (SM), SM+rhVEGF, SM+apatinib and SM+rhVEGF+apatinib. In comparison with the control group, cell proliferation in vitro in apatinib, SM, SM+apatinib and SM+rhVEGF+apatinib groups was inhibited, particularly in SM+apatinib group. The effect of apatinib on tumour growth in vivo was investigated using a mouse xenograft tumour model. In comparison with the control group, tumour sizes were reduced in apatinib‐treated group on days 34 and 37. Immunohistochemical and immunofluorescence staining revealed that VEGF, pVEGFR2, PI3K, AKT, p‐ERK1/2, Ki‐67 and CD31 in the tumour cells of apatinib‐treated group were downregulated compared with control group. Haematoxylin and eosin staining revealed that apatinib promoted the necrosis of SCLC cells in vivo. In conclusion, apatinib inhibited the growth of SCLC cells by downregulating the expression of VEGF, pVEGFR2, p‐PI3K, p‐AKT, p‐ERK1/2, Ki‐67 and CD31.
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Affiliation(s)
- Ning Zhong
- Department of Geriatric Oncology, Jiangxi Provincial Tumor Hospital, Nanchang, China
| | - Wei Zhuang
- Jiangxi Health Vocational College, Nanchang, China
| | - Qian Huang
- Department of Abdominal Surgery, Jiangxi Provincial Tumor Hospital, Nanchang, China
| | - Qiang Wang
- Department of Oncology, the People's Hospital of Ruijin City, Ruijin, China
| | - Wenjian Jin
- Department of Geriatric Oncology, Jiangxi Provincial Tumor Hospital, Nanchang, China
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Chen TL, Patel AS, Jain V, Kuppusamy R, Lin YW, Hou MH, Su TL, Lee TC. Discovery of Oral Anticancer 1,2-Bis(hydroxymethyl)benzo[ g]pyrrolo[2,1- a]phthalazine Hybrids That Inhibit Angiogenesis and Induce DNA Cross-Links. J Med Chem 2021; 64:12469-12486. [PMID: 34459195 DOI: 10.1021/acs.jmedchem.0c01733] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Designing hybrid molecules with dual functions is one approach to improve the therapeutic efficacy of combination treatment. We have previously conjugated phthalazine and bis(hydroxymethyl)pyrrole pharmacophores to form hybrids bearing antiangiogenesis and DNA interstrand cross-linking activities. To improve the bioavailability, we adopted a benzology approach to design and synthesize a new series of 1,2-bis(hydroxymethyl)benzo[g]pyrrolo[2,1-a]phthalazines. These new hybrids retained the dual functions and could be formulated into vehicles for intravenous and oral administration. Among them, we demonstrated that compound 19a with dimethylamine at the C6 position markedly suppressed the tumor growth of human small cell lung cancer cell line H526, squamous lung cancer cell line H520, and renal cancer cell line 786-O in nude mice, implying that compound 19a is a broad-spectrum anticancer agent. Our results implicated that the conjugation of antiangiogenic and DNA cross-linking is likely to be a helpful approach to improving the efficacy of combination therapy.
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Affiliation(s)
- Tai-Lin Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.,School of Pharmacy, China Medical University, Taichung 40400, Taiwan
| | - Anilkumar S Patel
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.,Department of Chemistry, Atmiya University, Rajkot 360005, Gujarat, India
| | - Vicky Jain
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.,Department of Chemistry, Marwadi University, Rajkot 360003, Gujarat, India
| | | | - Yi-Wen Lin
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
| | - Ming-Hon Hou
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40227, Taiwan
| | - Tsann-Long Su
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
| | - Te-Chang Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
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20
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Shi Q, Lu Y, Huang S, Zhou C, Yang C, Liu J, Ma J, Xiong B. Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro, pharmacokinetics and tumor response in vivo. Drug Deliv 2021; 27:1301-1307. [PMID: 32924634 PMCID: PMC7534301 DOI: 10.1080/10717544.2020.1818881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Apatinib mesylate is an oral antiangiogenic agent that can inhibit activation of vascular endothelial growth factor receptor-2 tyrosine kinase. However, its therapeutic use in liver cancer is restricted due to severe systemic toxicity. Our work aimed to construct apatinib-loaded CalliSpheres Beads (CBAPA) and investigate its application in transarterial chemoembolization (TACE) of liver cancer. The established stock solution containing 20, 40 or 60 mg apatinib were fully mixed with 100-300 μm CalliSpheres Beads (CB) for 2 hours, respectively. The highest loading efficiency at 30 min after combination in 20 mg group (maximum 70.7%). Further, apatinib can be steadily released from CBAPA in vitro release test. For pharmacokinetics and tumor response in vivo, sixty New Zealand white rabbits with VX2 liver tumor were assigned into four groups: sham (NS) group, apatinib solution alone (APA) group, CB group and CBAPA group. Apatinib was measured in plasma and liver tissue by high performance liquid chromatography-tandem mass spectrometry. Compared to APA group, the administration of apatinib by TACE with CBAPA resulted in low systemic concentration. In addition, intratumoural apatinib concentration was higher than adjacent hepatic parenchyma in the CBAPA group. Compared to other three groups, CBAPA group achieved lower tumor growth rate and improved survival time. In conclusion, these findings provide a basis for the potential application of apatinib-loaded CalliSpheres Beads in liver cancer.
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Affiliation(s)
- Qin Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yongning Lu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Jinqiang Ma
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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21
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Hu W, Li B, Geng N, He X, Ge H, Wang P, Ding C. Association Between PDL1 Genetic Variation and Efficacy of Apatinib Monotherapy in Patients with Previously Treated Advanced NSCLC: A Real-World Retrospective Study. Int J Gen Med 2021; 14:2703-2714. [PMID: 34188525 PMCID: PMC8232958 DOI: 10.2147/ijgm.s303717] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
Background This study aimed to explore associations between PDL1 polymorphisms and efficacy of apatinib for patients with previously treated advanced non-small cell lung cancer (NSCLC) in a real-world setting. Methods We retrospectively recruited 148 patients with previously treated advanced NSCLC from January 2015 to December 2019 continuously. Clinical efficacy in patients receiving apatinib treatment was evaluated. Adverse reactions were documented during treatment. Biological specimens of peripheral blood and cancer tissue biopsies were obtained for the genotyping of genetic variations in PDL1 and corresponding gene-mRNA expression, respectively. Univariate association analysis between the status of PDL1 genetic variations and survival was performed with Kaplan-Meier survival analysis. Results The objective response rate of the 148 patients was 17.6% and disease-control rate 68.9%. Prognostic data suggested that median progression-free survival (PFS) was 3.8 (95% CI 3.13-4.47) months and median overall survival (OS) 10.5 (95% CI 9.06-11.95) months. Regarding PDL1 genetic variation, only rs2297136 was of clinical significance. Prognosis analysis revealed that PFS and OS for the rs2297136 genotype were significantly different. Median PFS of patients with TC/CC and TT genotypes was 3 and 4.5 months, respectively (P=0.006). Median OS of the two genotypes was 9 and 11.6 months, respectively (P=0.04). Furthermore, the safety profile suggested that the most common adverse reactions were hypertension, dermal toxicity, fatigue, and oral toxicity. This study failed to find any significant association between adverse reactions and rs2297136. Interestingly, mRNA-expression analysis demonstrated that mRNA expression of PDL1 in biopsy cancer-tissue specimens was significantly different based on rs2297136-genotype status (P<0.001). Conclusion The PDL1 polymorphism rs2297136 could be used as a potential biomarker for the prognosis of patients with NSCLC receiving apatinib monotherapy.
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Affiliation(s)
- Wenxia Hu
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
| | - Bin Li
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
| | - Nan Geng
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
| | - Xin He
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
| | - Hui Ge
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
| | - Ping Wang
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
| | - Cuimin Ding
- Department of Respiratory Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, People's Republic of China
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Li S. Anlotinib: A Novel Targeted Drug for Bone and Soft Tissue Sarcoma. Front Oncol 2021; 11:664853. [PMID: 34094958 PMCID: PMC8173120 DOI: 10.3389/fonc.2021.664853] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/22/2021] [Indexed: 12/13/2022] Open
Abstract
Bone and soft tissue sarcomas account for approximately 15% of pediatric solid malignant tumors and 1% of adult solid malignant tumors. There are over 50 subtypes of sarcomas, each of which is notably heterogeneous and manifested by remarkable phenotypic and morphological variability. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) targeting c-kit, platelet-derived growth factor receptors, fibroblast growth factor receptor, and vascular endothelial growth factor receptor. In comparison with the placebo, anlotinib was associated with better overall survival and progression-free survival (PFS) in a phase III trial of patients with advanced non-small cell lung cancer (NSCLC), albeit with cancer progression after two previous lines of treatment. Recently, the National Medical Products Administration approved anlotinib monotherapy as a third-line treatment for patients with advanced NSCLC. Additionally, a phase IIB randomized trial substantiated that anlotinib is associated with a significant longer median PFS in patients with advanced soft tissue sarcoma. Moreover, anlotinib is also effective in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma. Anlotinib has similar tolerability to other TKIs targeting vascular endothelial growth factor receptors and other tyrosine kinase-mediated pathways. However, anlotinib has a notably lower rate of side effects ≥grade 3 relative to sunitinib. This review discussed the remarkable characteristics and major dilemmas of anlotinib as a targeted therapy for sarcomas.
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Affiliation(s)
- Shenglong Li
- Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.,Department of Tissue Engineering, Center of 3D Printing & Organ Manufacturing, School of Fundamental Sciences, China Medical University (CMU), Shenyang, China
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Li X, Wang L, Wang L, Yu J, Lu G, Zhao W, Miao C, Zou C, Wu J. Overcoming therapeutic failure in osteosarcoma via Apatinib-encapsulated hydrophobic poly(ester amide) nanoparticles. Biomater Sci 2021; 8:5888-5899. [PMID: 33001086 DOI: 10.1039/d0bm01296c] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Anti-angiogenic tyrosine kinase inhibitors (TKIs) have been proved to be effective in prolonging progression-free survival in advanced osteosarcoma. However, osteosarcoma stem-like cells persist for a long time and ultimately cause disease recurrence and therapy resistance. Here, we reveal that inefficient accumulation of Apatinib, an anti-angiogenic TKI, induces the expression of ribosome-associated genes in osteosarcoma, and confers apoptosis resistance. An engineered nanoscale delivery system based on hydrophobic poly(ester amide) has been established to effectively deliver Apatinib to improve the treatment. Notably, the considerable uptake by osteosarcoma cells enables this nanodrug to distribute increasingly inside the tumor. Furthermore, the delivered nano-Apatinib can suppress osteosarcoma stemness and enhance osteosarcoma stem-like cell apoptosis, and overcomes the crucial bottleneck of the unfavorable stem-like cell residue for TKI therapy. Importantly, nano-Apatinib significantly inhibits the osteosarcoma stem-like cell-derived tumor growth in contrast with free Apatinib, with minimal side effects. These results suggest that this Apatinib-loaded nano delivery system may serve as a promising strategy to solve the issue of TKI therapeutic resistance existing in advanced osteosarcoma.
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Affiliation(s)
- Xiangyu Li
- The Stem Cell and Tissue Engineering Research Center, Changzhi Medical College, Changzhi, Shanxi 046000, P. R. China.
| | - Liying Wang
- School of Biomedical Engineering, Sun Yat-Sen University, Guangzhou 510006, China.
| | - Li Wang
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - Jiaming Yu
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - Guohao Lu
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - Wei Zhao
- Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou 510080, China
| | - Congxiu Miao
- The Stem Cell and Tissue Engineering Research Center, Changzhi Medical College, Changzhi, Shanxi 046000, P. R. China.
| | - Changye Zou
- Musculoskeletal Oncology Center, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China.
| | - Jun Wu
- The Stem Cell and Tissue Engineering Research Center, Changzhi Medical College, Changzhi, Shanxi 046000, P. R. China. and School of Biomedical Engineering, Sun Yat-Sen University, Guangzhou 510006, China.
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Lengyel CG, Hussain S, Trapani D, El Bairi K, Altuna SC, Seeber A, Odhiambo A, Habeeb BS, Seid F. The Emerging Role of Liquid Biopsy in Gastric Cancer. J Clin Med 2021; 10:2108. [PMID: 34068319 PMCID: PMC8153353 DOI: 10.3390/jcm10102108] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
(1) Background: Liquid biopsy (LB) is a novel diagnostic method with the potential of revolutionizing the prevention, diagnosis, and treatment of several solid tumors. The present paper aims to summarize the current knowledge and explore future possibilities of LB in the management of metastatic gastric cancer. (2) Methods: This narrative review examined the most recent literature on the use of LB-based techniques in metastatic gastric cancer and the current LB-related clinical trial landscape. (3) Results: In gastric cancer, the detection of circulating cancer cells (CTCs) has been recognized to have a prognostic role in all the disease stages. In the setting of localized disease, cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) qualitative and quantitative detection have the potential to inform on the risk of cancer recurrence and metastatic dissemination. In addition, gastric cancer-released exosomes may play an essential part in metastasis formation. In the metastatic setting, the levels of cfDNA show a positive correlation with tumor burden. There is evidence that circulating tumor microemboli (CTM) in the blood of metastatic patients is an independent prognostic factor for shorter overall survival. Gastric cancer-derived exosomal microRNAs or clonal mutations and copy number variations detectable in ctDNA may contribute resistance to chemotherapy or targeted therapies, respectively. There is conflicting and limited data on CTC-based PD-L1 verification and cfDNA-based Epstein-Barr virus detection to predict or monitor immunotherapy responses. (4) Conclusions: Although preliminary studies analyzing LBs in patients with advanced gastric cancer appear promising, more research is required to obtain better insights into the molecular mechanisms underlying resistance to systemic therapies. Moreover, validation and standardization of LB methods are crucial before introducing them in clinical practice. The feasibility of repeatable, minimally invasive sampling opens up the possibility of selecting or dynamically changing therapies based on prognostic risk or predictive biomarkers, such as resistance markers. Research is warranted to exploit a possible transforming area of cancer care.
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Affiliation(s)
| | - Sadaqat Hussain
- North West Cancer Center, Altnagelvin Hospital, Londonderry BT47 6SB, UK;
| | - Dario Trapani
- European Institute of Oncology, IRCCS, 20141 Milan, Italy;
| | | | | | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Andrew Odhiambo
- Unit of Medical Oncology, Department of Clinical Medicine, University of Nairobi, Nairobi 30197, Kenya;
| | - Baker Shalal Habeeb
- Department of Medical Oncology, Shaqlawa Teaching Hospital, Shaqlawa, Erbil 44005, Iraq;
| | - Fahmi Seid
- School of Medicine and Health Sciences, Hawassa University, Hawassa 1560, Ethiopia;
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Zhao L, Peng Y, He S, Li R, Wang Z, Huang J, Lei X, Li G, Ma Q. Apatinib induced ferroptosis by lipid peroxidation in gastric cancer. Gastric Cancer 2021; 24:642-654. [PMID: 33544270 DOI: 10.1007/s10120-021-01159-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Apatinib, a competitive inhibitor of VEGFR2, has anti-angiogenesis and anticancer activities through different mechanisms, but it still cannot fully explain the drug efficacy of apatinib. Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in cancer biology, however, the exact role of ferroptosis in apatinib-mediating anticancer treatment are still not clear. METHODS The effects of (1S, 3R)-RSL3 and apatinib were evaluated in different GC cell lines and in normal human gastric epithelial cells. Further, the effects of apatinib and inhibition of antioxidant defense enzyme glutathione peroxidase (GPX4) on cell viability, cell death, glutathione (GSH) levels, lipid ROS production, cellular malondialdehyde (MDA) levels and protein expression were evaluated in vitro as well as in a mouse tumor xenograft model. The expression level of GPX4 in GC tissues and paracancerous tissues was measured by immunohistochemistry. RESULTS (1S, 3R)-RSL3 selectively killed GC cells, but not normal cells. Apatinib induced ferroptosis in GC cells by decreasing cellular GSH levels and increasing lipid peroxidation levels. This effect was blocked by co-incubation with ferrostatin-1, liproxstatin-1, GSH, or vitamin E. Further investigation revealed that apatinib down-regulated GPX4 expression via inhibition of the transcription factors Sterol regulatory element-binding protein-1a (SREBP-1a). Besides, we found that multi-drug resistant GC cells were vulnerable to apatinib-induced GPX4 inhibition. CONCLUSIONS In summary, we show that apatinib could induce the lipid peroxidation through GPX4 mediated by SREBP-1a, then negatively regulate the GC cell, even the multi-drug-resistant GC cell, ferroptosis.
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Affiliation(s)
- Liying Zhao
- Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Yanmei Peng
- Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Sixiao He
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Ru Li
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Ziqing Wang
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Junhao Huang
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Xuetao Lei
- Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
| | - Qiang Ma
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
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Zhang Y, Deng X, Ding Z, Kang J, Wu B, Guo B, Fan Y. Preoperative neoadjuvant targeted therapy with apatinib for inoperable differentiated thyroid cancer: A case report. Medicine (Baltimore) 2021; 100:e25191. [PMID: 33761701 PMCID: PMC9281949 DOI: 10.1097/md.0000000000025191] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/25/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Though the majority of differentiated thyroid cancer (DTC) patients have a good prognosis after careful and standardized therapy, approximately 13% to 15% of DTC cases show surprisingly aggressive behavior and invasion of the surrounding structures, and a few progress to unresectable diseases. In this study, we report a case of an inoperable locally advanced DTC patient who underwent a curative operation after treatment of preoperative monotherapy of apatinib in a short time. PATIENT CONCERNS A 64-year-old woman complained of dysphagia due to large cervical mass, which severely invaded the left esophagus at the junction of the neck and thorax. DIAGNOSES The female patient was diagnosed with locally advanced papillary thyroid cancer (PTC) by cytopathology and it was difficult to perform a safe and complete removal. INTERVENTIONS Apatinib (500 mg orally once a day) was initially used to treat this patient as a neoadjuvant therapy. OUTCOMES Six weeks later, the tumor dramatically shrunk from 56 × 37 mm to 29 × 26 mm with well-controlled mild hypertension. After a 10-day interval of apatinib withdrawal, complete tumor excision was accomplished through cervical incision without esophageal fistula. Postoperative thyroid stimulating hormone suppression and radioiodine 131I ablation therapy were performed. At the 1-year follow-up evaluation, no tumor recurrence or metastasis was observed. LESSONS Preoperative short term targeted treatment with apatinib for locally advanced inoperable DTC may become a promising neoadjuvant therapy that, can reduce the tumor size and decrease stage, thus making the complete and safe removal of the lesion feasible.
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Affiliation(s)
- Yingchao Zhang
- Center of Thyroid and Parathyroid, Department of Thyroid-breast-hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Xianzhao Deng
- Center of Thyroid and Parathyroid, Department of Thyroid-breast-hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Zheng Ding
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Kang
- Center of Thyroid and Parathyroid, Department of Thyroid-breast-hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Bo Wu
- Center of Thyroid and Parathyroid, Department of Thyroid-breast-hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Bomin Guo
- Center of Thyroid and Parathyroid, Department of Thyroid-breast-hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
| | - Youben Fan
- Center of Thyroid and Parathyroid, Department of Thyroid-breast-hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital
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Chi D, Chen B, Guo S, Bai K, Ma H, Hu Y, Li Q, Zhu Y. Oral maintenance therapy using apatinib combined with S-1/capecitabine for esophageal squamous cell carcinoma with residual disease after definitive chemoradiotherapy. Aging (Albany NY) 2021; 13:8408-8420. [PMID: 33713398 PMCID: PMC8034932 DOI: 10.18632/aging.202652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/21/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND A substantial number of patients with esophageal squamous cell carcinoma (ESCC) do not achieve complete remission after definitive concurrent chemoradiotherapy (dCRT). We performed this retrospective study to evaluate the efficacy and safety of apatinib combined with S-1/capecitabine as the oral maintenance therapy for these patients. METHODS Thirty-nine ESCC patients with residual disease after dCRT were included. Patients were treated with apatinib combined with S-1 /capecitabine after dCRT. Efficacy, toxicity, and survival were analyzed. RESULTS Of the 39 patients, 5 (12.8%) achieved a partial response and 29 (74.4%) achieved stable disease, yielding a disease control rate of 87.2%. The median progression-free survival (PFS) and overall survival (OS) were 27.5 (95%CI: 14.9 - 40.1) and 38.1 (95%CI: 31.3 - 44.8) months. Most frequent adverse events were of grade 1 to 2. Multivariate analysis revealed the occurrence of any adverse events (HR = 0.274, 95%[CI] = 0.119 - 0.630) correlated to better PFS and occurrence of proteinuria (HR = 0.108, 95%[CI] = 0.025 - 0.456) predicted better OS. CONCLUSION The oral combination therapy consisting of apatinib and S-1/capecitabine showed a tolerable toxicity profile and achieved satisfactory disease control in ESCC patients with residual disease after dCRT.
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Affiliation(s)
- Dongmei Chi
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
- Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
- Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Baoqing Chen
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
- Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Suping Guo
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
- Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Kunhao Bai
- Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Huali Ma
- Department of Radiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
| | - Yonghong Hu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
- Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Qiaoqiao Li
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
- Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
| | - Yujia Zhu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, P.R. China
- Guangdong Esophageal Cancer Research Institute, Guangzhou, Guangdong, P. R. China
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Efficacy and safety of apatinib in advanced sarcoma: an open-label, nonrandomized, single-center study of 45 patients. Anticancer Drugs 2020; 30:e0778. [PMID: 31305297 DOI: 10.1097/cad.0000000000000778] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Sarcoma is a rare tumor with more than 50 histologic subtypes. Patients with advanced sarcoma have a poor prognosis. The aim of this study was to evaluate the efficacy and safety of apatinib, an oral vascular endothelial growth factor receptor-2 inhibitor, as salvage treatment for advanced bone and soft tissue sarcomas. From May 2017 to July 2018, a prospective, open-label, nonrandomized, clinical trial of apatinib was carried out in selected patients with advanced sarcoma. After apatinib dosing, progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate, and treatment-related adverse events (AEs) were reviewed and evaluated. Patients were administered apatinib for at least 1 month. Median follow-up time was 6.00 months (1-13 months). The median PFS was 7.88 months, with the longest PFS of 13 months observed in a patient with epithelial sarcoma. The 3-month PFS rate was 66.44%. The median OS was 11.64 months with significant differences observed based on disease subtypes. Four patients achieved a partial response, and 36 patients achieved stable disease. The objective response rate was 8.88% (4/45), and the disease control rate was 88.89% (40/45). The most common grade 3/4 treatment-related AEs were hypertension (12.50%), hand-foot syndrome (6.67%), diarrhea (12.50%), fatigue (6.25%), and proteinuria (14.29%). One drug-related severe AE of thrombocytopenia (21×10/l) occurred 2 months after therapy. Apatinib treatment in our study exhibited objective efficacy in PFS, OS, and manageable toxicity in patients with advanced sarcoma. This result supports future randomized controlled trials to further define apatinib activity in stage IV sarcomas.
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Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma. Cancers (Basel) 2020; 12:cancers12082116. [PMID: 32751679 PMCID: PMC7463778 DOI: 10.3390/cancers12082116] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC.
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Wang Q, Peng H, Qi X, Wu M, Zhao X. Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence. Signal Transduct Target Ther 2020; 5:137. [PMID: 32728057 PMCID: PMC7391668 DOI: 10.1038/s41392-020-0199-6] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/12/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022] Open
Abstract
Advanced and recurrent gynecological cancers are associated with poor prognosis and lack of effective treatment. The developments of the molecular mechanisms on cancer progression provide insight into novel targeted therapies, which are emerging as groundbreaking and promising cancer treatment strategies. In gynecologic malignancies, potential therapeutic targeted agents include antiangiogenic agents, poly (ADP-ribose) polymerase (PARP) inhibitors, tumor-intrinsic signaling pathway inhibitors, selective estrogen receptor downregulators, and immune checkpoint inhibitors. In this article, we provide a comprehensive review of the clinical evidence of targeted agents in gynecological cancers and discuss the future implication.
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Affiliation(s)
- Qiao Wang
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Hongling Peng
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Xiaorong Qi
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China
| | - Min Wu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, 58203, USA
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, P.R. China.
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Yan Z, Gu YY, Hu XD, Zhao Q, Kang HL, Wang M, Duan W, Guan Y. Clinical outcomes and safety of apatinib monotherapy in the treatment of patients with advanced epithelial ovarian carcinoma who progressed after standard regimens and the analysis of the VEGFR2 polymorphism. Oncol Lett 2020; 20:3035-3045. [PMID: 32782621 DOI: 10.3892/ol.2020.11857] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 06/05/2020] [Indexed: 12/30/2022] Open
Abstract
The aims of the present study were to investigate the clinical outcomes and safety of apatinib monotherapy in the treatment of patients with advanced epithelial ovarian carcinoma (EOC) who have progressed after standard regimens, and to analyze the vascular endothelial growth factor receptor 2 (VEGFR2) rs2071559 polymorphism. A total of 118 patients with advanced EOC who received apatinib treatment were included in the study. Tumor response was evaluated using progression-free survival (PFS) and overall survival (OS) time, and safety data were documented. Additionally, peripheral blood and peripheral blood mononuclear cell (PBMC) specimens from the patients with EOC were collected to perform the genotyping of genetic polymorphism and assess the mRNA expression of VEGFR2, respectively. The objective response rate across the 118 patients with advanced EOC was 38.98%, the disease control rate was 63.56%, the median PFS time was 4.65 months and the median OS time was 15.10 months. Regarding the polymorphism analysis, the prevalence of rs2071559 in VEGFR2 among the 118 patients with advanced EOC was recorded as the TT genotype in 72 cases (61.02%), TC genotype in 41 cases (34.75%) and CC genotype in 5 cases (4.23%), and the minor allele frequency of rs2071559 was 0.22. The distribution of the three genotypes was in accordance with the Hardy-Weinberg equilibrium (P=0.781). TC and CC genotypes were merged in the subsequent analysis. The prognosis analyses suggested that the median PFS time of patients with the TC/CC genotype and the TT genotype was 3.10 and 5.40 months, respectively (P=0.015). Moreover, the median OS time of the two genotypes was 12.60 and 17.50 months, respectively (P=0.009). However, no association was noted between genotype status of the polymorphism and adverse reactions. Additionally, the mRNA expression analysis indicated that the mRNA expression levels of VEGFR2 in PBMC specimens were significantly different between TT and TC/CC genotypes (P<0.001). The present study suggested that the clinical outcomes of patients with advanced EOC, who progressed after standard regimens and received apatinib treatment, might be influenced by the VEGFR2 rs2071559 polymorphism.
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Affiliation(s)
- Zhen Yan
- Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Yuan-Yuan Gu
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
| | - Xiao-Di Hu
- Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Qun Zhao
- Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Hai-Li Kang
- Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Miao Wang
- Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Wei Duan
- Department of Gynecological Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, P.R. China
| | - Yin Guan
- Department of Oncology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
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An Oral Small Molecule VEGFR2 Inhibitor, Apatinib, in Patients with Recurrent or Refractory Cervical Cancer: A Real World Study. JOURNAL OF ONCOLOGY 2020; 2020:3852373. [PMID: 32655637 PMCID: PMC7327550 DOI: 10.1155/2020/3852373] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/25/2020] [Accepted: 06/03/2020] [Indexed: 12/31/2022]
Abstract
To evaluate the efficacy and safety of apatinib, an oral antiangiogenic drug, in patients with recurrent or refractory cervical cancer as salvage treatment, we retrospectively analyzed the medical records of recurrent or refractory cervical cancer patients admitted to the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Hunan Cancer Hospital, from October 1, 2016, to December 31, 2017. Patients who progressed within 6 months after the last treatment were given apatinib orally at a dose of 250 mg daily until disease progression or unacceptable toxicity. Twenty-nine patients were enrolled in our retrospective study. Up to February 1, 2019, the median follow-up time was 18 months. The median progression-free survival was 128 days (95% confidence interval (CI): 20–540 days), and the median overall survival was 9 months (95% CI: 4–23 months). The longest period of apatinib administration was 540 days. No complete response was observed, 5 (17.2%) patients achieved partial response, and 11 (37.9%) achieved stable disease. The objective response rate and disease control rate were 17.2% and 55.1%, respectively. The most common adverse events were hypertension (G1, 65.5%, 19/29), mucositis (G1, 55.2%, 16/29), hand-foot syndrome (G1-2, 44.8%, 13/29), and proteinuria (G1-2, 20.7%, 6/29). Grade 3 proteinuria occurred in only one patient (3.4%, 1/29). Apatinib single-agent use might be an effective and tolerable choice as salvage therapy for patients with recurrent or refractory cervical cancer.
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Yanwei L, Feng H, Ren P, Yue J, Zhang W, Tang P, Shang X, Pang Q, Liu D, Chen C, Pan Z, Tao YZ. Safety and Efficacy of Apatinib Monotherapy for Unresectable, Metastatic Esophageal Cancer: A Single-Arm, Open-Label, Phase II Study. Oncologist 2020; 25:e1464-e1472. [PMID: 32342599 DOI: 10.1634/theoncologist.2020-0310] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 04/06/2020] [Indexed: 12/31/2022] Open
Abstract
LESSONS LEARNED Patient compliance with the oral dosage treatment was good, with no need for hospitalization. Patients with tracheal and esophageal fistulas can take crushed apatinib by nutrient tube, with the same bioavailability and efficacy. Apatinib may be an effective and safe second- or further-line treatment for advanced esophageal cancer. BACKGROUND Apatinib is an inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2), which is thought to play a role in esophageal cancer progression. Our goal was to evaluate the efficacy and safety of apatinib in patients with unresectable esophageal cancer and to examine whether VEGFR2 expression influenced the clinical response. METHODS This single-arm, open-label, investigator-initiated phase II study enrolled patients with advanced squamous cell carcinoma (SCC) or adenocarcinoma of the esophagus or esophagogastric junction who were admitted to Tianjin Medical University Cancer Institute and Hospital between August 2017 and January 2019. Apatinib monotherapy (500 mg/day) was given orally or via an enteral tube until disease progression, unacceptable toxicity, withdrawal, or death. Patients were followed until treatment was discontinued or death. The main endpoints were tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS Among 32 patients screened for inclusion, 30 were included in the safety and survival analyses (i.e., received apatinib), and 26 were included in the efficacy analysis (at least one imaging follow-up). Median follow-up time and exposure to apatinib were 5.34 months and 72 days, respectively. Among 26 patients included in the efficacy analysis, 2 had a partial response (PR; 7.7%) and 14 had stable disease (SD; 53.8%). The overall response rate (ORR) was 7.7%, and the disease control rate (DCR) was 61.5%. Median PFS and OS were 4.63 months (95% confidence interval, 2.11-7.16 months) and 6.57 months (4.90 months to not estimable), respectively. Fifteen patients (50.0%) experienced treatment-related AEs, most commonly hypertension (26.7%), diarrhea (20.0%), and hand-foot-skin reaction (10.0%). No patients had grade ≥4 treatment-related AEs. CONCLUSION Apatinib was effective as second- or further-line treatment for advanced esophageal cancer.
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Affiliation(s)
- Li Yanwei
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, People's Republic of China
- Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin, People's Republic of China
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - He Feng
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, People's Republic of China
- Tianjin Key Laboratory of Brain Science and Neural Engineering, Tianjin University, Tianjin, People's Republic of China
| | - Peng Ren
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Jie Yue
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Wencheng Zhang
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Peng Tang
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Xiaobin Shang
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Qingsong Pang
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Dongying Liu
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Chuangui Chen
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Zhanyu Pan
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
| | - Yu Zhen Tao
- Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China
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Wei B, Wang Y, Wang J, Cai X, Xu L, Wu J, Wang Y, Liu W, Gu Y, Guo W, Xu Q. Apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer via the Akt/β-catenin pathway. Cancer Cell Int 2020; 20:198. [PMID: 32514243 PMCID: PMC7254695 DOI: 10.1186/s12935-020-01290-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 05/22/2020] [Indexed: 02/08/2023] Open
Abstract
Background Esophageal cancer is the sixth leading cause of cancer-related mortality worldwide, which is partially due to limited progress of therapy. Apatinib, an inhibitor of VEGFR2, has a promising antitumor effect on malignancies. However, the underlying mechanism of its antitumor effect on esophageal cancer remains poorly understood. Materials and methods Eighteen pairs of frozen esophageal cancer and their para-cancer samples and 25 paraffin specimens from advanced esophageal cancer patients treated with cisplatin-based regimen were collected. The effects of apatinib on cell growth, cell apoptosis, cell cycle and invasion/migration of esophageal cancer cells were assessed. Bioinformatics, luciferase reporter, immunoprecipitation and immunofluorescence assays were conducted for mechanic investigation. Quantitative RT-PCR, western blotting and immunohistochemistry were used to measure the expression of functional genes. Xenograft tumor growth of mice was performed. Results We found that VEGFR2 was highly expressed in esophageal cancer and associated with poor efficacy of cisplatin-based treatment. Apatinib displayed profound actions against tumor cell growth of human esophageal cancer via promoting cell apoptosis and cell cycle arrest. Also, apatinib displayed the inhibitory effects on cell migration and invasion. Moreover, apatinib strongly suppressed the growth of esophageal cancer xenografts in mice. The effects of apatinib on esophageal cancer were partially dependent on its block of the VEGFR2/Akt/β-catenin pathway. Specifically, apatinib induced the degradation of β-catenin and decreased its transcriptional activity through Akt/GSK-3β repression. Further in vitro and in vivo studies revealed that low dose apatinib had a synergistic antitumor effect with cisplatin on esophageal cancer. Conclusion Our study indicates that apatinib suppresses tumor progression and enhances cisplatin sensitivity in esophageal cancer by deactivating the Akt/β-catenin pathway. These findings provide a theoretical foundation for using apatinib as an effective therapeutic drug for esophageal cancer.
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Affiliation(s)
- Bin Wei
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China.,Department of Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Yuanyuan Wang
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China
| | - Jiawei Wang
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China
| | - Xiaomin Cai
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China
| | - Lingyan Xu
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China
| | - Jingjing Wu
- Department of Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Ying Wang
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China
| | - Wen Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, 210093 China
| | - Yanhong Gu
- Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029 China
| | - Wenjie Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, 210093 China
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, 210093 China
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Nogués A, Gallardo-Vara E, Zafra MP, Mate P, Marijuan JL, Alonso A, Botella LM, Prieto MI. Endoglin (CD105) and VEGF as potential angiogenic and dissemination markers for colorectal cancer. World J Surg Oncol 2020; 18:99. [PMID: 32434528 PMCID: PMC7240983 DOI: 10.1186/s12957-020-01871-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 05/06/2020] [Indexed: 12/31/2022] Open
Abstract
Background Colorectal cancer (CRC) is an important current problem concerning public health due to its high incidence and mortality. Advances in molecular and cellular knowledge and the detection of new disease biomarkers are very important to improve prognosis, prediction, and early diagnosis. In this study, we aimed to analyze the gene and protein expression levels of two angiogenic markers, VEGF and soluble Endoglin, during different tumor stages as well as at different stages of cancer treatment, to predict the diagnosis and evolution of colon and rectal cancer. Material and methods This study includes 133 CRC patients (93 with colon cancer and 40 with rectal cancer) on which the gene and protein expression of Endoglin (membrane and soluble form) and VEGF were analyzed by molecular and immunohistochemical techniques on different tumor stage samples and plasma obtained preoperatively as well as 3, 6, and 9 months after resection of the tumor. Results VEGF and Endoglin gene expressions were higher in tumor tissue than in surrounding non-tumoral tissue for both types of cancer. The VEGF levels in plasma were found to decrease in less aggressive tumors, whereas soluble Endoglin was increased in preoperative samples of patients with metastasis. Membrane Endoglin expression was higher on the vascular endothelium of more aggressive tumors. In contrast, Endoglin expression was mainly in the colon epithelium in less aggressive stage tumors. Conclusion Endoglin and VEGF are proteins with a major role in the tumor angiogenesis process. This study performed with a wide cohort of human samples shows that both proteins seem to be valuable biomarkers in the diagnosis and prognosis of CRC.
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Affiliation(s)
- Ana Nogués
- Department of General Surgery, Hospital Universitario La Paz, 28046, Madrid, Spain.
| | - Eunate Gallardo-Vara
- Centro de Investigaciones Biológicas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
| | - Mª Paz Zafra
- Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10021, USA
| | - Paloma Mate
- Department of General Surgery, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - Jose Luis Marijuan
- Department of General Surgery, Hospital Universitario La Paz, 28046, Madrid, Spain
| | - Alfredo Alonso
- Department of General Surgery, Hospital Universitario del Sureste de Madrid, Arganda del Rey, Madrid, Spain
| | - Luisa Mª Botella
- Centro de Investigaciones Biológicas (CIB), Consejo Superior de Investigaciones Científicas (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain
| | - Mª Isabel Prieto
- Department of General Surgery, Hospital Universitario La Paz, 28046, Madrid, Spain
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Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3145182. [PMID: 32509141 PMCID: PMC7244982 DOI: 10.1155/2020/3145182] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/09/2020] [Accepted: 04/20/2020] [Indexed: 12/19/2022]
Abstract
Apatinib, a new-generation oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway, shows favorable therapeutic effects in various malignant tumors. However, its effect on ovarian cancer has not yet been characterized. Here, we demonstrated that apatinib inhibited ovarian cancer cell growth and migration in a concentration-dependent manner. Further, we found that apatinib could directly act on tumor cells and promote ROS-dependent apoptosis and autophagy. Mechanistically, we showed that apatinib suppressed glutathione to generate ROS via the downregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and maintained an antitumor effect at a low level of VEGFR2 in ovarian cancer, suggesting that combination of apatinib with Nrf2 inhibitor may be a promising therapy strategy for patients with ovarian cancer.
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Li L, Kong F, Zhang L, Li X, Fu X, Wang X, Wu J, Zhang F, Ren L, Zhang M. Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study. Invest New Drugs 2020; 38:1847-1853. [PMID: 32363427 PMCID: PMC7575486 DOI: 10.1007/s10637-020-00925-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 03/16/2020] [Indexed: 11/16/2022]
Abstract
Purpose Apatinib, a new tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has shown promising efficacy against several solid cancers, but evidence of its efficacy against relapsed and refractory nasopharyngeal carcinoma is limited. We investigated the efficacy and safety of apatinib for relapsed and refractory nasopharyngeal carcinoma in an open-label, single-arm, phase II clinical trial. Fifty-one patients with relapsed and refractory nasopharyngeal carcinoma in the First Affiliated Hospital, Zhengzhou University, who met the inclusion criteria were enrolled in the study. All patients received apatinib at an initial dose of 500 mg daily (1 cycle = 28 days). The primary and secondary endpoints were overall response rate, progression-free survival, and overall survival. We evaluated treatment effects and recorded apatinib-related adverse events by performing regular follow-ups and workup. The overall response rate (complete and partial responses) was 31.37% (16/51). The median overall survival and progression-free survival were 16 (95% CI, 9.32–22.68) and 9 months (95% CI, 5.24–12.76), respectively. Most patients tolerated treatment-related adverse events of grades 1 and 2; hypertension (29, 56.86%), proteinuria (25, 49.02%), and hand–foot syndrome (27, 52.94%) were the most common adverse events. There were no treatment-related deaths. Apatinib showed good efficacy and safety in patients with relapsed and refractory NPC.
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Affiliation(s)
- Ling Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. .,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China.
| | - Fei Kong
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Lei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Xin Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Xiaorui Fu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Xinhua Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Jingjing Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Fangwen Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Liangliang Ren
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. .,Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, 450052, Henan, China.
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Guo JH, Wang YY, Zhang JW, Liu PM, Hao YJ, Duan HR. Clinical effects of apatinib mesylate for treatment of multiple brain micrometastases: Two case reports. World J Clin Cases 2020; 8:1326-1336. [PMID: 32337210 PMCID: PMC7176611 DOI: 10.12998/wjcc.v8.i7.1326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Apatinib is a small-molecule multitargeted tyrosine kinase inhibitor. Apatinib has demonstrated encouraging antitumor activities. This study aimed to observe the efficacy and safety of apatinib for the treatment of multiple brain micrometastases.
CASE SUMMARY We report two patients with multiple brain micrometastases after failure of second-line treatment. Both patients had extracerebral metastases. When the patients took 250 mg/d apatinib orally, the intracerebral lesions disappeared. The extracerebral lesions were partially alleviated. Both patients had a progression-free survival of more than 12 mo and were still stable. The safety was good. The main adverse events (AEs) were mild hypertension and proteinuria, which could be controlled.
CONCLUSION Apatinib has clear efficacy and good tolerance in patients with multiple brain micrometastases after failure of second-line treatment.
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Affiliation(s)
- Jun-Hui Guo
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Province Hospital of TCM, Zhengzhou 450002, Henan Province, China
| | - Yuan-Yuan Wang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Province Hospital of TCM, Zhengzhou 450002, Henan Province, China
| | - Jiang-Wei Zhang
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Province Hospital of TCM, Zhengzhou 450002, Henan Province, China
| | - Pei-Min Liu
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Province Hospital of TCM, Zhengzhou 450002, Henan Province, China
| | - Yan-Jun Hao
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Province Hospital of TCM, Zhengzhou 450002, Henan Province, China
| | - Hai-Rui Duan
- Department of Oncology, The Second Affiliated Hospital of Henan University of Chinese Medicine, Henan Province Hospital of TCM, Zhengzhou 450002, Henan Province, China
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Zhou L, Lin J, Wu G, Chen J, Huang X, Zhang S. Safety and Feasibility of Low-Dose Apatinib Combined with S-1 as the Second-Line Therapy or Beyond in Chinese Patients with Pulmonary and Hepatic Metastasis of Nasopharyngeal Carcinoma. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1257-1262. [PMID: 32280197 PMCID: PMC7125328 DOI: 10.2147/dddt.s244102] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Accepted: 03/18/2020] [Indexed: 12/21/2022]
Abstract
Introduction The purpose of this study was to analyze the safety and feasibility of low-dose apatinib combined with S-1 as a second-line therapy or beyond in Chinese patients with pulmonary and/or hepatic metastases of nasopharyngeal carcinoma (NPC). Methods Forty-one Chinese NPC patients with pulmonary and hepatic metastases were treated with low-dose apatinib plus S-1. The S-1 dose was determined according to each patient’s body surface area (BSA): 40 mg twice a day for BSA <1.25 m2; 50 mg twice a day for 1.25 m2≤BSA <1.5 m2; and 60 mg twice a day for BSA ≥1.5 m2. S-1 was received for 14 days, after stopping for 7 days, given 3 weeks apart. Apatinib, 125 mg was orally administered daily on days 1 through 28 of each 4-week cycle. If the toxicity was not tolerable, the dose of apatinib was reduced to 125 mg every other day. Results Treatment efficacy was evaluated in all 41 patients after four courses of chemotherapy. The objective response rate was 34.1%, and the disease control rate was 80.4%. The median progression-free survival was 9.7 months (95% confidence interval, 6.2–13.8 months), and the median overall survival was 22.1 months (95% confidence interval, 15.1–28.9 months). The 2-year survival rate was 41.5%. The most common toxicities included loss of appetite in 39.0% of patients, dyslipidemia in 34.1%, hypertension in 31.7%, myelosuppression in 24.4%, fatigue in 21.9%, and hand-foot syndrome in 17.1%. Seven patients received dose adjustment of apatinib due to side effects. Conclusion In patients with pulmonary and/or hepatic metastases of NPC, low-dose apatinib plus S-1 yielded an excellent survival benefit, and the toxicities were mild and tolerable.
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Affiliation(s)
- Liya Zhou
- Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China
| | - Jie Lin
- Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China
| | - Gang Wu
- Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China
| | - Jiawei Chen
- Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China
| | - Xiaopeng Huang
- Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China
| | - Shuai Zhang
- Department of Radiation Oncology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province 570311, People's Republic of China
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Liu JY, Zhu BR, Wang YD, Sun X. The efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis. Int J Clin Oncol 2020; 25:1195-1205. [PMID: 32215805 DOI: 10.1007/s10147-020-01644-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 02/28/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis. METHODS Designed as a retrospective study, a total of 105 metastatic osteosarcoma patients who progressed after standard therapy were included in this study. The metastatic osteosarcoma patients received 500-750 mg Apatinib mesylate according to body surface area until disease progression or unacceptable toxicity with 28 days one cycle. Overall response was evaluated after two cycles Apatinib treatment, then progression-free survival (PFS) and overall survival (OS) were evaluated, and safety data were recorded. Additionally. peripheral blood and peripheral blood mononuclear cell (PBMC) specimens in the osteosarcoma patients were collected for the genotyping of VEGFR2 genetic variation and mRNA expression, respectively. Analysis on the association between genotype and baseline characteristics and VEGFR2 gene mRNA expression was analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis was adjusted by Cox regression analysis. RESULTS The objective response rate (ORR) of the 105 metastatic osteosarcoma patients was 37.14%, disease control rate (DCR) was 77.14%, median PFS was 4.1 months, and median OS was 9.0 months. Regarding the VEGFR2 gene polymorphisms analysis, only - 906 T > C was of clinical significance. The prevalence of - 906 T > C in VEGFR2 among the study population was as follows: TT genotype 62 cases (59.05%), TC genotype 36 cases (34.29%) and CC genotype 7 cases (6.66%), minor allele frequency of - 906 T > C was 0.24. Compared with patients with TC/CC genotype, patients with TT genotype showed longer median PFS (5.0 versus 3.1 months, P = 0.011) and median OS (9.8 versus 7.6 months, P = 0.032). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression in 69 randomly selected sample indicated that the mRNA expression of VEGFR2 of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P < 0.001). CONCLUSION Apatinib was safe and effective in the treatment of metastatic osteosarcoma patients who progressed after standard therapy. The clinical outcomes of Apatinib may be influenced by the polymorphism - 906 T > C of VEGFR2 through mediating the mRNA expression of VEGFR2.
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Affiliation(s)
- Jia-Yong Liu
- Department of Bone and Soft Tissue Tumor, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, P. R. China.
| | - Bao-Rang Zhu
- Department of Tumor Minimally Invasive Treatment, The Fifth Medical Centre, Chinese PLA General Hospital (Former 307th Hospital of the PLA), Beijing, 100071, P. R. China
| | - Yu-Dong Wang
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, P. R. China
| | - Xin Sun
- Department of Orthopedic Oncology, Peking University People's Hospital, Beijing, 100044, P. R. China.
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Wang X, Zhang R, Du N, Yang M, Zang A, Liu L, Yu J, Gao J, Zhang J, Fu Z, Ren Y, Ma L, Guo J, Li Q, Li X, Fan Z, Song X, Liu Z, Zhang Y, Li G, Yu Z, Diao J, Jia J, Liang F, Wang H, Sun J, Gao Y, Yang P, Bai C, Ren X, Zhong D. An open label, multicenter, noninterventional study of apatinib in advanced gastric cancer patients (AHEAD-G202). Ther Adv Med Oncol 2020; 12:1758835920905424. [PMID: 32218807 PMCID: PMC7082876 DOI: 10.1177/1758835920905424] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/14/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Apatinib has been proved to be effective and well tolerated among patients in
phase II and III studies. Here, we evaluated the safety and effectiveness of
apatinib in advanced gastric cancer patients in a real-world setting. Methods: This study enrolled advanced gastric cancer patients who had progressed or
relapsed despite systemic chemotherapy. The primary outcome was safety and
the secondary outcomes included overall survival (OS) and progression-free
survival (PFS). Results: A total of 337 patients were included. In total, 62 (18.4%), 102 (30.3%), and
173 (51.3%) patients received first, second, and third or higher line
apatinib therapy, respectively. Grade 3/4 treatment-emergent adverse events
(AEs) were infrequent (<5%), with hypertension (6.8%) being the only
grade 3/4 AE occurring in more than 5% of the patients and across the
low-dose (250 mg, 7.3%), mid-dose (425–500 mg, 6.1%), and high-dose group
(675–850 mg, 2/15, 13.3%). The median OS and PFS were 7.13 months (95% CI,
6.17–7.93) and 4.20 months (95% CI, 4.60–4.77), respectively, and were
comparable among the low-, mid-, and high-dose groups. Conclusion: Lower daily doses of apatinib achieved comparable OS and PFS
versus higher daily doses of apatinib while maintaining
a more benign safety profile in advanced gastric cancer patients. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02668380.
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Affiliation(s)
- Xiang Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ruixing Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Nan Du
- Department of Medical Oncology, Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Mudan Yang
- Digestive Department of Oncology, Shanxi Tumor Hospital, Taiyuan, China
| | - Aimin Zang
- Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, China
| | - Likun Liu
- Oncology Department, Shanxi Provincial Hospital of Traditional Chinese Medicine, Taiyuan, China
| | - Junyan Yu
- Department of Oncology, Peace Hospital of Changzhi Medical College, Changzhi, China
| | - Jinghua Gao
- Department of Medical Oncology, Cangzhou Central Hospital, Cangzhou, China
| | - Junping Zhang
- Department of Medical Oncology, Shanxi Academy of Medical Sciences, Shanxi Dayi Hospital, Taiyuan, China
| | - Zhanzhao Fu
- Department of Medical Oncology, First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Yuchuan Ren
- Oncology Department, Yangquan First People's Hospital, Yangquan, China
| | - Liwen Ma
- Department of Tumor Chemotherapy and Radiology, Peking University Third Hospital, Beijing, China
| | - Jun Guo
- Department of Medical Oncology, Xingtai People's Hospital, Hebei Medical University Affiliated Hospital, Xingtai, China
| | - Qingshan Li
- Department of Medical Oncology, Affiliated Hospital of Chengde Medical University, Chengde, China
| | - Xiaomei Li
- Department of Medical Oncology, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China
| | - Zaiwen Fan
- Department of Medical Oncology, Air Force General Hospital, PLA, Beijing, China
| | - Xiang Song
- Department of Medical Oncology, Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zheng Liu
- Department of Radiology, Handan Central Hospital, Handan, China
| | - Yan Zhang
- Department of Medical Oncology, Shijiazhuang People's Hospital, Shijiazhuang, China
| | - Guozhong Li
- Department of Medical Oncology, Peking University Binhai Hospital, Tianjin, China
| | - Zhonghe Yu
- Department of Medical Oncology, Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Jianfeng Diao
- Department of Medical Oncology, Datong Second People's Hospital, Datong, China
| | - Junmei Jia
- Department of Medical Oncology, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Feng Liang
- Department of General Surgery, Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Huaqing Wang
- Department of Medical Oncology, Tianjin People's Hospital, Tianjin, China
| | - Junzhong Sun
- Department of Medical Oncology, Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Yunge Gao
- Department of Hematology and Oncology, Strategic Support Force Characteristic Medical Center/Former The 306 Hospital of PLA, Beijing, China
| | - Ping Yang
- Department of Medical Oncology, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100032, China
| | - Xiubao Ren
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
| | - Diansheng Zhong
- Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Song ZZ, Zhao LF, Zuo J, Fan ZS, Wang L, Wang YD. Clinical Outcomes and Safety of Apatinib Mesylate in the Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer in Patients Who Progressed After Standard Therapy and Analysis of the KDR Gene Polymorphism. Onco Targets Ther 2020; 13:603-613. [PMID: 32021302 PMCID: PMC6982468 DOI: 10.2147/ott.s222985] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 12/17/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose This study investigated the clinical outcomes and safety of apatinib mesylate in the treatment of advanced non-squamous non-small cell lung cancer (NSCLC) in patients who progressed after standard therapy, and analyzed the kinase insert domain receptor (KDR) gene polymorphism. Methods A total of 135 patients with advanced non-squamous NSCLC who received apatinib mesylate were included. Objective response rates were evaluated. Subsequently, progression-free survival (PFS) and overall survival (OS) were assessed and safety data were recorded. Additionally, peripheral blood and biopsy cancer tissue specimens were collected from the patients with NSCLC for the genotyping of the genetic polymorphism and mRNA expression of the KDR gene, respectively. Analysis on the association between genotypes and prognosis was conducted. Results The objective response rate of the 135 patients with NSCLC was 18.52%, disease control rate was 65.19%, median PFS was 3.95 months, and median OS was 10.05 months. Regarding the KDR gene polymorphism analysis, the distribution of the 4397T>C polymorphism genotypes was in accordance with the Hardy–Weinberg Equilibrium (P=0.868). Moreover, the prognosis analysis indicated that the median PFS of patients with the CC/TC and TT genotypes was 2.80 and 4.80 months, respectively (P=0.002). Furthermore, the median OS of patients with the two genotypes was 9.10 and 10.56 months, respectively (P=0.041). The multivariate Cox regression analysis showed that the TC/CC genotypes were an independent factor for PFS (odds ratio: 1.72, P=0.009). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression analysis suggested that the mRNA levels of KDR in cancer tissues were significantly different between the TT and TC/CC genotypes (P<0.001). Conclusion The clinical outcomes of treatment with apatinib mesylate for advanced non-squamous NSCLC in patients who progressed after standard therapy may be influenced by the KDR 4397T>C polymorphism through mediation of the mRNA expression of KDR.
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Affiliation(s)
- Zi-Zheng Song
- Department of Medical Oncology, The Affiliated Hospital of Hebei University, Baoding, People's Republic of China
| | - Li-Fen Zhao
- Department of Respiratory and Critical Care Medicine, The Shanxi Dayi Hospital, Taiyuan, People's Republic of China
| | - Jing Zuo
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Zhi-Song Fan
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Long Wang
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
| | - Yu-Dong Wang
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China
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Fathi Maroufi N, Rashidi MR, Vahedian V, Akbarzadeh M, Fattahi A, Nouri M. Therapeutic potentials of Apatinib in cancer treatment: Possible mechanisms and clinical relevance. Life Sci 2020; 241:117106. [DOI: 10.1016/j.lfs.2019.117106] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 11/15/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023]
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Guan J, Luo Z, Xiao Z, Xie Y, Lin L. Treatment of consistent BRAF/HRAS gene mutation and MYC amplification radiation-induced abdominal wall angiosarcoma with low-dose apatinib: a case report. BMC Cancer 2019; 19:1188. [PMID: 31805975 PMCID: PMC6896664 DOI: 10.1186/s12885-019-6351-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/11/2019] [Indexed: 12/31/2022] Open
Abstract
Background An extremely rare condition, radiation-induced angiosarcoma is characterized by a poor prognosis, high recurrence rate and lack of effective treatment. Herein, we present a case report of a 48-year-old female patient with radiation-induced abdominal wall angiosarcoma who showed a dramatic response to low-dose apatinib. Case presentation The patient, who was diagnosed with cervical squamous cell carcinoma 20 years ago, had received radiotherapy and chemotherapy after operation. Angiosarcomas of the abdominal wall appeared 9 years later. After repeated surgical operations and intravenous chemotherapy for the angiosarcomas, the patient developed tumor recurrence and pulmonary metastasis. The abdominal wall tumors showed repeated rupture and bleeding, with poor wound healing. On evaluation, laboratory findings detected the negative serum tumor markers CEA, CA 125, CA 15–3 and CA 19–9. Imaging showed multiple subcutaneous nodules and masses in the abdominal wall, accompanied by suspected small subpleural nodule at the lower lobe of the right lung. Immunohistochemistry of previous surgical pathology indicated that CD31, ERG and Vim were positive. The result of whole exome sequencing suggested the mutations of BRAF and HRAS, and the amplification of MYC. Based on the above results, the patient was clinically diagnosed with radiation-induced angiosarcoma of the abdominal wall with pulmonary metastasis. The patient was treated with low-dose apatinib and rejected reoperation or chemotherapy. Results At the 6-month follow-up visit, the abdominal wall lesions that had previously ruptured stopped bleeding and showed significant shrinkage. Imaging showed that most of the abdominal wall lesions had partially regressed, and some of the lesions on the abdominal wall and the suspected lesion of subpleural nodule at the lower lobe of the right lung had disappeared. Conclusions We described this case and reviewed the literature on radiation-related angiosarcoma. Importantly, this case suggests that apatinib may be an effective and sensitive treatment for radiation-induced angiosarcoma even at the lowest dosage, without aggravating the bleeding of lesions.
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Affiliation(s)
- Jieshan Guan
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 510405, Guangzhou, Guangdong, People's Republic of China
| | - Zhijie Luo
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 510405, Guangzhou, Guangdong, People's Republic of China
| | - Zhiwei Xiao
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 510405, Guangzhou, Guangdong, People's Republic of China
| | - Yubin Xie
- The First Clinical Medical College, Guangzhou University of Chinese Medicine, 510405, Guangzhou, Guangdong, People's Republic of China
| | - Lizhu Lin
- Cancer Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 510405, Guangzhou, Guangdong, People's Republic of China.
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Su M, Gao Y, Ye X, Zhou Q, Zhao L, Cai X, Chen D, Su H, Zhang X, Xie C. Clinical Value Of Apatinib As A Salvage Treatment In Patients With Chemo-Refractory Advanced Cervical Cancer. Onco Targets Ther 2019; 12:9707-9713. [PMID: 32009803 PMCID: PMC6859957 DOI: 10.2147/ott.s230406] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 10/30/2019] [Indexed: 12/19/2022] Open
Abstract
Purpose Apatinib is effective and safe for several advanced or metastatic cancers, but its therapeutic value in cervical cancer is still unknown. The aim of the study was to assess the therapeutic value of apatinib in patients with chemo-refractory advanced cervical cancer. Patients and methods This was a retrospective study of patients with advanced cervical cancer treated with apatinib between April 2015 and December 2018 at the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Patients had to have failed at least 2 lines of chemotherapy prior to receiving apatinib. The clinical tumor response was evaluated after 4 weeks of apatinib treatment, and then every 8 weeks (two cycles). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events were evaluated. Results Twenty-five patients were included in this study. The median PFS was 5.8 months (95% CI, 4.65–6.95), and the median OS was 12.2 months (95% CI, 8.99–15.41). ORR was 48% and DCR was 96%. Complete response was not observed. The most common adverse events in this study (all grades) were hand-foot syndrome (48%), hypertension (20%), and mouth mucositis (20%). Conclusion Apatinib monotherapy showed good therapeutic value with tolerable adverse events for patients with chemo-refractory advanced cervical cancer.
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Affiliation(s)
- Meng Su
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Ya Gao
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - XuXue Ye
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - QingYu Zhou
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - LiHao Zhao
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaona Cai
- Derpartment of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Didi Chen
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Huafang Su
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Xiaohua Zhang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Congying Xie
- Department of Radiotherapy and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
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Comparison of the Therapeutic Efficacies of Topical Rivoceranib and Topical Bevacizumab in a Murine Model of Corneal Neovascularization. ACTA ACUST UNITED AC 2019; 55:medicina55110729. [PMID: 31703332 PMCID: PMC6915418 DOI: 10.3390/medicina55110729] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/01/2019] [Accepted: 11/06/2019] [Indexed: 12/14/2022]
Abstract
Background and Objectives: Corneal neovasculariziation (CNV) is a serious vision-threatening complication; however, all therapeutics have their clinical limitations. The aim of this study is to investigate the efficacy of topical rivoceranib compared with topical bevacizumab in a murine model of corneal neovascularization (CNV). Materials and Methods: Murine CNV was induced by means of total de-epithelization and alkali burn. Mice were divided into five groups according to topical treatment: untreated control, phosphate-buffered saline (PBS), 0.1% and 0.5% rivoceranib, and 0.5% bevacizumab. CNV area and index were measured 7 and 14 days after treatment. After corneal tissues were excised at day 14, the blood and lymphatic vessels were quantified by cluster of differentiation 31 (CD31) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) immunofluorescence, respectively. Results: After 14 days, treatment groups with 0.1% and 0.5% rivoceranib and 0.5% bevacizumab showed a decrease in CNV area and index compared with the untreated and PBS groups (all p < 0.01). Blood and lymphatic vascularization significantly decreased in the 0.5% rivoceranib and 0.5% bevacizumab groups, as measured by CD31 and LYVE1 immunofluorescence. There was no significant difference of vascularization between the 0.5% rivoceranib and bevacizumab groups. Conclusions: Topical application of rivoceranib could effectively decrease CNV equivalent to topical bevacizumab in a murine model.
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Zhao Y, Liu F, He G, Li K, Zhu C, Yu W, Zhang C, Xie M, Lin J, Zhang J, Jin Y. Discovery of arylamide-5-anilinoquinazoline-8-nitro derivatives as VEGFR-2 kinase inhibitors: Synthesis, in vitro biological evaluation and molecular docking. Bioorg Med Chem Lett 2019; 29:126711. [PMID: 31668972 DOI: 10.1016/j.bmcl.2019.126711] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/23/2019] [Accepted: 09/19/2019] [Indexed: 01/07/2023]
Abstract
Herein, we embarked on a structural optimization campaign aiming at the discovery of novel anticancer agents with our previously reported XL-6f as a lead compound. A library of 23 compounds has been synthesized based on the highly conserved active site of VEGFR-2. Several title compounds exhibited selective inhibitory activities against VEGFR-2, which also displayed selective anti-proliferation potency against HepG2 cell. All synthesized compounds were evaluated for anti-angiogenesis capability. Compound 7o showed the most potent anti-angiogenesis ability, the efficient cytotoxic activities (in vitro against HUVEC and HepG2 cell lines with IC50 values of 0.58 and 0.23 µM, respectively). The molecular docking analysis revealed 7o is a Type-II inhibitor of VEGFR-2 kinase. In general, these results indicated these arylamide-5-anilinoquinazoline-8-nitro derivatives are promising inhibitors of VEGFR-2 for the potential treatment of anti-angiogenesis.
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Affiliation(s)
- Yongqiang Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Feifei Liu
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China
| | - Guojing He
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Ke Li
- Biomedical Department, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming 650118, PR China.
| | - Changcheng Zhu
- Institute of Drug Research and Development, Kunming Pharmaceutical Corporation, Kunming 650100, PR China
| | - Wei Yu
- Pharmaceutical Department, Kunming General Hospital of Chengdu Military Command, Kunming 650118, PR China
| | - Conghai Zhang
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Mingjin Xie
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China
| | - Jun Lin
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
| | - Jihong Zhang
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, PR China.
| | - Yi Jin
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, PR China.
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Apatinib Mesylate in the treatment of advanced progressed lung adenocarcinoma patients with EGFR-TKI resistance -A Multicenter Randomized Trial. Sci Rep 2019; 9:14013. [PMID: 31570733 PMCID: PMC6768876 DOI: 10.1038/s41598-019-50350-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/05/2019] [Indexed: 12/15/2022] Open
Abstract
Few pieces of evidence have been published on the use of Apatinib Mesylate (AM) against EGFR-TKI resistance in lung adenocarcinoma (LA) patients. Here, we investigate the clinical efficacy and safety of AM in the treatment of advanced progressed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) resistant LA patients. We conducted a double-blind, randomized controlled trial in 68 patients admitted to 18 hospitals of Anhui province in China. The efficacy and safety of AM treatment were evaluated in terms of progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), as well as related adverse events (AE). A literature knowledge database analysis and a pathway model reconstruction were performed to decipher the relevant mechanism may be involved. Our results showed that, compared to the control group, AM presented improved efficacy in PFS (P = 0.033), ORR (P < 0.001), and DCR (P < 0.001). No significant difference was observed between case and control group in terms of AE, and no drug-related death occurred. Pathway analysis supports that Apatinib can be repurposed for the treatment of LA. Our results suggested that AM could be a potential option for advanced progressed LA patients to combat EGFR-TKI resistance.
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Zuo W, Zhao L. Recent advances and application of PD-1 blockade in sarcoma. Onco Targets Ther 2019; 12:6887-6896. [PMID: 31692518 PMCID: PMC6711553 DOI: 10.2147/ott.s220045] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 07/31/2019] [Indexed: 12/23/2022] Open
Abstract
The role of the programmed death-1 (PD-1) signaling pathway in tumor immunotherapy is becoming increasingly important, and several PD-1-blocking agents have been approved by the US Food and Drug Administration. PD-1-blocking therapy alone or in combination with other therapeutic modalities has become a standard treatment for several kinds of solid tumors. However, sarcomas are not indications for anti-PD-1 therapy. Sarcomas are a group of heterogeneous diseases that can currently only be cured by surgery at the early stage. No effective treatments exist for sarcoma patients in advanced stages. Owning to the diversity of sarcomas, it is very difficult to conduct randomized controlled clinical studies on specific subtypes of sarcomas. Although clinical studies of sarcomas continue, few breakthroughs in the treatment of sarcomas have been achieved over the past decades. This review summarizes recent progress in anti-PD-1 therapy for sarcomas. Based on the published data, PD-1 blockade may be more effective in combination with other modalities for the treatment of sarcomas. In addition, biomarkers may be used to ascertain sensitivity to PD-1 blockade in sarcoma patients.
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Affiliation(s)
- Wenli Zuo
- Hematology Department, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou City 450008, People's Republic of China
| | - Lingdi Zhao
- Hematology Department, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou City 450008, People's Republic of China
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Zhang Y, Zou JY, Wang Z, Wang Y. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag Res 2019; 11:7787-7803. [PMID: 31496821 PMCID: PMC6701622 DOI: 10.2147/cmar.s215533] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/28/2019] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis plays a critical role in the neoplastic growth, progression, and metastasis of colorectal cancer (CRC) in a process regulated by vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR). Several small-molecule anti-VEGFR tyrosine kinase inhibitors (TKIs), such as regorafenib, famitinib, axitinib and apatinib, have been shown to be effective in treating metastatic colorectal cancer (mCRC). Fruquintinib (ELUNATE®) is a novel oral anti-VEGFR TKI, originated and developed by Hutchison MediPharma. Fruquintinib is a potent and highly selective small-molecule inhibitor of VEGFR-1, -2 and -3. In the Phase 3 FRESCO trial, fruquintinib improved both overall survival (OS) and progression-free survival (PFS) in patients with mCRC, compared with placebo. Fruquintinib also showed an acceptable safety and tolerability profile. Based on the data from this trial, fruquintinib was approved by the China Food and Drug Administration (CFDA) in 2018, for the treatment of patients with mCRC who had undergone at least two prior standard anticancer therapies. The existing clinical trials and future prospects of fruquintinib in mCRC will be discussed in this article. In addition, to better understand the role of fruquintinib in this setting, recent advances in other anti-VEGFR TKIs for mCRC treatment are also reviewed herein.
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Affiliation(s)
- Ying Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Jia-Yun Zou
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Ying Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
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