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Chitoran E, Rotaru V, Ionescu SO, Gelal A, Capsa CM, Bohiltea RE, Mitroiu MN, Serban D, Gullo G, Stefan DC, Simion L. Bevacizumab-Based Therapies in Malignant Tumors-Real-World Data on Effectiveness, Safety, and Cost. Cancers (Basel) 2024; 16:2590. [PMID: 39061228 PMCID: PMC11274419 DOI: 10.3390/cancers16142590] [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: 06/30/2024] [Revised: 07/08/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Overall, it is estimated that more than 3,500,000 patients have received Bevacizumab as part of systemic oncologic treatment. Bevacizumab and its biosimilars are currently marketed in over 130 countries. Given the wide usage of Bevacizumab in current oncological practice, it is very important to compare the "real-world" results to those obtained in controlled clinical trials. This study aims to describe the clinical experience of using Bevacizumab in a large cohort of cancer patients in "non-controlled real-world" conditions with regard to effectiveness, safety, and cost of therapy. METHODS For this purpose, we conducted an open, observational, retrospective study involving all patients treated for solid malignant tumors in the Bucharest Institute of Oncology with "Prof. Dr. Al. Trestioreanu" with Bevacizumab-based systemic therapy, between 2017 and 2021. RESULTS The study consisted of 657 treatment episodes in 625 patients (F/B = 1.62/1, with a median age of 57.6 years) which were treated for malignant tumors (majority colorectal, non-small cell lung, ovarian, and breast cancer). First-line treatment was administered in 229 patients, and the rest received Bevacizumab as second or subsequent lines of treatment. The overall response rate to Bevacizumab-based therapies was around 60-65% across all indication except for subsequent treatment lines in colorectal and ovarian cancers, where lower values were recorded (27.1%, and 31.5% respectively). Median PFS for the entire cohort was 8.2 months (95% CI 6.8-9.6), and the median OS was 13.2 months (95% CI 11.5-14.9). Usual bevacizumab-related toxicities were observed, including bleeding, hypertension, wound-healing complications, gastrointestinal perforation, other types of fistulas, septic complications, and thromboembolic events. Although the clinical benefits are undeniable, the addition of Bevacizumab to standard chemotherapy increased the overall treatment cost by 213%. CONCLUSIONS Bevacizumab remains a high-cost therapy, but it can add to clinical benefits (like overall survival, progression-free survival, and response rate) when used in conjunction with standard chemotherapy. Similar results as those presented in various controlled trials are observable even on unselected cohorts of patients in the uncontrolled conditions of "real-world" oncological practice. Off-label usage is encountered in clinical practice, and this aspect should be monitored given the potential adverse effects of the therapy.
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Affiliation(s)
- Elena Chitoran
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Vlad Rotaru
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Sinziana-Octavia Ionescu
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Aisa Gelal
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Cristina-Mirela Capsa
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Radiology Department, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Roxana-Elena Bohiltea
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Obstetrics and Gynecology Department, “Filantropia” Clinical Hospital, 011132 Bucharest, Romania
| | - Madalina-Nicoleta Mitroiu
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Obstetrics and Gynecology Department, “Filantropia” Clinical Hospital, 011132 Bucharest, Romania
| | - Dragos Serban
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Surgery Department 4, Bucharest University Emergency Hospital, 050098 Bucharest, Romania
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy
| | - Daniela-Cristina Stefan
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laurentiu Simion
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
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Huang H, Zhang H, Cao B. A study protocol for an open-label, single-arm, single-center phase I clinical study on tolerability, safety, and efficacy of dalpiciclib combined with apatinib in the treatment of patients with advanced or metastatic sarcoma. Thorac Cancer 2024; 15:427-433. [PMID: 38211967 PMCID: PMC10864114 DOI: 10.1111/1759-7714.15208] [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: 11/27/2023] [Accepted: 12/12/2023] [Indexed: 01/13/2024] Open
Abstract
INTRODUCTION The prognosis of patients with advanced or metastatic sarcoma is very poor, and a new strategy for patients who fail systemic treatment is urgently required. Apatinib is a small molecule tyrosine kinase inhibitor of VEGFR-2, which can exert an antitumor effect by blocking downstream PI3K/AKT and VEGFR2/STAT3 signaling pathways of sarcoma. Dysregulation of the cyclin D (CCND)-cyclin-dependent kinase 4/6 (CDK4/6)-retinoblastoma 1 (Rb) pathway is highly prevalent in sarcoma. Thus, blocking VEGFR2 and CDK4/6 may exert a synergistic effect. We hypothesize that a combination of apatinib and dalpiciclib, an oral, highly effective, and selective small molecule CDK4/6 inhibitor, may result in higher antitumor efficacy in patients with refractory sarcoma. METHODS In this open-label, single-arm, single-center phase I trial, participants diagnosed with sarcoma who failed standard systemic treatment will be enrolled. Dose escalation will be conducted into three groups according to traditional 3 + 3 principle: dose 1, dalpiciclib 100 mg once daily oral d1-21+ apatinib 250 mg once daily oral d1-28, every 28 days as one cycle; dose 2, dalpiciclib 100 mg d1-21+ apatinib 500 mg d1-28; dose 3, dalpiciclib 150 mg d-21+ apatinib 500 mg d1-28. The primary endpoint is the safety and tolerability of combined treatment. The secondary endpoint is to evaluate the initial efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS). DISCUSSION This trial will provide evidence of the tolerability, safety, and efficacy of dalpiciclib in combination with apatinib in metastatic sarcoma patients who have failed first-line systemic treatment.
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Affiliation(s)
- Huiying Huang
- Department of Medical Oncology and Radiation SicknessPeking University Third HospitalBeijingChina
| | - Hua Zhang
- Research Center of Clinical EpidemiologyPeking University Third HospitalBeijingChina
| | - Baoshan Cao
- Department of Medical Oncology and Radiation SicknessPeking University Third HospitalBeijingChina
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1407-1424. [DOI: 10.3748/wjg.v29.i10.1407] [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] [Indexed: 03/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1551-1568. [PMID: 36970588 PMCID: PMC10037251 DOI: 10.3748/wjg.v29.i10.1551] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/08/2023] [Accepted: 02/22/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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Vimalraj S. A concise review of VEGF, PDGF, FGF, Notch, angiopoietin, and HGF signalling in tumor angiogenesis with a focus on alternative approaches and future directions. Int J Biol Macromol 2022; 221:1428-1438. [PMID: 36122781 DOI: 10.1016/j.ijbiomac.2022.09.129] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/26/2022]
Abstract
Angiogenesis forms new vessels from existing ones. Abnormal angiogenesis, which is what gives tumor microenvironments their distinctive features, is characterised by convoluted, permeable blood vessels with a variety of shapes and high perfusion efficiency. Tumor angiogenesis controls cancer growth by allowing invasion and metastasis and is highly controlled by signalling networks. Therapeutic techniques targeting VEGF, PDGF, FGF Notch, Angiopoietin, and HGF signalling restrict the tumor's vascular supply. Numerous pathways regulate angiogenesis, and when one of those processes is blocked, the other pathways may step in to help. VEGF signalling inhibition alone has limits as an antiangiogenic therapy, and additional angiogenic pathways such as FGF, PDGF, Notch, angiopoietin, and HGF are important. For the treatment of advanced solid tumors, there are also new, emerging medicines that target multiple angiogenic pathways. Recent therapies block numerous signalling channels concurrently. This study focuses on 'alternative' methods to standard antiangiogenic medicines, such as cyclooxygenase-2 blocking, oligonucleotide binding complementary sites to noncoding RNAs to regulate mRNA target, matrix metalloproteinase inhibition and CRISPR/Cas9 based gene edition and dissecting alternative angiogenesis mechanism in tumor microenvironment.
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Feng MY, Chan LL, Chan SL. Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond. Curr Oncol 2022; 29:5489-5507. [PMID: 36005172 PMCID: PMC9406660 DOI: 10.3390/curroncol29080434] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.
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Affiliation(s)
- Maple Ye Feng
- Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Landon L. Chan
- Department of Oncology, Princess Margaret Hospital, Hong Kong, China
| | - Stephen Lam Chan
- Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
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Chen Z, Yuan T, Yan F, Ye S, Xie Q, Zhang B, Lin N, He Q, Yang B, Zhu H. CT-707 overcomes hypoxia-mediated sorafenib resistance in Hepatocellular carcinoma by inhibiting YAP signaling. BMC Cancer 2022; 22:425. [PMID: 35440025 PMCID: PMC9020089 DOI: 10.1186/s12885-022-09520-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 04/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome. MATERIALS AND METHODS The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia. RESULTS Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC. CONCLUSIONS Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.
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Affiliation(s)
- Zibo Chen
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.,Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, USA
| | - Tao Yuan
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Fangjie Yan
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Song Ye
- School of Medicine, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qin Xie
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Zhang
- Cancer Center of Zhejiang University, Hangzhou, China.,Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Nengmin Lin
- Cancer Center of Zhejiang University, Hangzhou, China.,Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.,Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.,School of Medicine, Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China.,Cancer Center of Zhejiang University, Hangzhou, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
| | - Hong Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. .,Cancer Center of Zhejiang University, Hangzhou, China.
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Luo XY, Wu KM, He XX. Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res 2021; 40:172. [PMID: 34006331 PMCID: PMC8130401 DOI: 10.1186/s13046-021-01968-w] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Although hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.
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Affiliation(s)
- Xiang-Yuan Luo
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Kong-Ming Wu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xing-Xing He
- Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Jászai J, Schmidt MHH. Trends and Challenges in Tumor Anti-Angiogenic Therapies. Cells 2019; 8:cells8091102. [PMID: 31540455 PMCID: PMC6770676 DOI: 10.3390/cells8091102] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 01/18/2023] Open
Abstract
Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of “vessel normalization” might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization.
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Affiliation(s)
- József Jászai
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.
| | - Mirko H H Schmidt
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.
- German Cancer Consortium (DKTK), Partner Site Dresden, 01307 Dresden, Germany.
- German Cancer Research Center (DKFZ), 61920 Heidelberg, Germany.
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The Evaluation of Angiogenesis Markers in Hepatocellular Carcinoma and Precursor Lesions in Liver Explants From a Single Institution. Appl Immunohistochem Mol Morphol 2019; 26:330-336. [PMID: 27556821 DOI: 10.1097/pai.0000000000000426] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Precursor lesions are described, and the correct diagnosis of liver nodules is paramount when considering liver transplantation. We evaluated the immunohistochemical expression of vascular endothelial growth factor (VEGF) and angiopoietin-2 in HCC and precursors lesion in a single institution series of whole liver explants between 2013 and 2015, evaluating morphologic and clinical variables. The study comprised 67 patients (32.8% female) and 107 nodules. The mean age of the patients was 52.7 years (29 to 70 y). There were no significant epidemiologic differences among malignant lesions, dysplastic nodules, and regenerative nodules. Angiopoietin-2 expression was significantly more expressed in carcinoma when compared with regenerative lesions (P<0.0001). A statistically significant relationship was noted between the expression of VEGF in hepatocytes and Ang-2 expression in the small vasculature (P=0.006). VEGF expression also correlated significantly with the number of nonpaired arteries (P=0.03), although it was not useful in separating benign from malignant cases. We identified a sensitivity of 54% and a specificity of 96% using angiopoietin-2, and a sensitivity of 68.7% and a specificity of 31.2% when using VEGF for the diagnosis of HCC. There was no significant correlation between the immunohistochemical parameters and the clinical staging, the number of gross lesions, and the histologic grade in cases of HCC. Angiopoietin-2 may be a candidate biomarker in assessing liver nodules in transplant patients, and may assist in the diagnosis of difficult lesions and in small biopsies pretransplant.
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Abstract
Apatinib [Aitan® (brand name in China)], also known as rivoceranib, is a novel, small molecule, selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and is the second anti-angiogenic drug to be approved in China for the treatment of advanced or metastatic gastric cancer. This article summarizes the pharmacological properties of apatinib and reviews its clinical use in chemotherapy-experienced patients with advanced gastric adenocarcinoma, including gastroesophageal adenocarcinoma (GEA), or with other advanced cancers such as non-small cell lung cancer (NSCLC), breast cancer, gynaecological cancers, hepatocellular carcinoma (HCC), thyroid cancer and sarcomas. As third- or subsequent-line therapy, oral apatinib significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared with placebo and had a manageable safety profile in Chinese patients with advanced or metastatic gastric cancer or GEA participating in randomized, double-blind, multicentre, phase 2 and 3 trials. More limited evidence also supports it use as subsequent-line treatment in Chinese patients with other advanced or metastatic solid tumours, including NSCLC, breast cancer and HCC. Further clinical experience and long-term pharmacovigilance data are required to more definitively establish the efficacy and safety profile of apatinib, including its use in combination with other chemotherapy agents and its role in the management of other types of advanced or metastatic solid tumours. In the meantime, given its convenient administration regimen and the limited treatment options and poor prognosis for patients with advanced or metastatic solid tumours, apatinib is an important, emerging treatment option for adult patients with advanced gastric adenocarcinoma or GEA who have progressed or relapsed after chemotherapy.
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Affiliation(s)
- Lesley J Scott
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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Liu T, Liu X, Li W. Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy. Oncotarget 2018; 7:40800-40815. [PMID: 27027348 PMCID: PMC5130046 DOI: 10.18632/oncotarget.8315] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 03/10/2016] [Indexed: 12/19/2022] Open
Abstract
Cancer is a disease caused by the abnormal proliferation and differentiation of cells governed by tumorigenic factors. Chemotherapy is one of the major cancer treatment strategies, and it functions by targeting the physiological capabilities of cancer cells, including sustained proliferation and angiogenesis, the evasion of programmed cell death, tissue invasion and metastasis. Remarkably, natural products have garnered increased attention in the chemotherapy drug discovery field because they are biologically friendly and have high therapeutic effects. Tetrandrine, isolated from the root of Stephania tetrandra S Moore, is a traditional Chinese clinical agent for silicosis, autoimmune disorders, inflammatory pulmonary diseases, cardiovascular diseases and hypertension. Recently, the novel anti-tumor effects of tetrandrine have been widely investigated. More impressive is that tetrandrine affects multiple biological activities of cancer cells, including the inhibition of proliferation, angiogenesis, migration, and invasion; the induction of apoptosis and autophagy; the reversal of multidrug resistance (MDR); and the enhancement of radiation sensitization. This review focuses on introducing the latest information about the anti-tumor effects of tetrandrine on various cancers and its underlying mechanism. Moreover, we discuss the nanoparticle delivery system being developed for tetrandrine and the anti-tumor effects of other bisbenzylisoquinoline alkaloid derivatives on cancer cells. All current evidence demonstrates that tetrandrine is a promising candidate as a cancer chemotherapeutic.
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Affiliation(s)
- Ting Liu
- College of Life Sciences, Wuhan University, Wuhan, P. R. China
| | - Xin Liu
- Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, College of Pharmacy, Wuhan University, Wuhan, P. R. China
| | - Wenhua Li
- College of Life Sciences, Wuhan University, Wuhan, P. R. China
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14
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Fako V, Yu Z, Henrich CJ, Ransom T, Budhu AS, Wang XW. Inhibition of wnt/β-catenin Signaling in Hepatocellular Carcinoma by an Antipsychotic Drug Pimozide. Int J Biol Sci 2016; 12:768-75. [PMID: 27313491 PMCID: PMC4910596 DOI: 10.7150/ijbs.14718] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 03/11/2016] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common forms of malignant cancers in the world, yet very few effective systemic treatments for HCC patients exist. Thus, the development of new treatment modalities presents a great need. The wnt/β-catenin signaling pathway is highly activated in stem cell-like aggressive HCC, which is associated with chemoresistance and poor survival in HCC patients. In a previous study, we found that an FDA-approved psychiatric drug, pimozide (PMZ), has anti-cancer properties in HCC cell lines that express epithelial cell adhesion molecule (EpCAM), a hepatic stem cell marker that is a functional down-stream target of the wnt/β-catenin pathway. In this study, we demonstrate that PMZ effectively inhibits cell growth of HCC cells by disrupting the wnt/β-catenin signaling pathway and reducing EpCAM expression. Thus, PMZ may be a useful molecular entity that could be repurposed as an anti-cancer therapy for treatment of HCC.
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Affiliation(s)
- Valerie Fako
- 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - Zhipeng Yu
- 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - Curtis J. Henrich
- 2. Molecular Targets Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA
- 3. Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21701, USA
| | - Tanya Ransom
- 2. Molecular Targets Laboratory, National Cancer Institute, Frederick, Maryland 21702, USA
| | - Anuradha S. Budhu
- 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
| | - Xin W. Wang
- 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
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15
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Firtina Karagonlar Z, Koc D, Iscan E, Erdal E, Atabey N. Elevated hepatocyte growth factor expression as an autocrine c-Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells. Cancer Sci 2016; 107:407-16. [PMID: 26790028 PMCID: PMC4832867 DOI: 10.1111/cas.12891] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Revised: 12/31/2015] [Accepted: 01/14/2016] [Indexed: 01/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer‐related deaths worldwide. Limitations in HCC treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only FDA approved drug available for advanced HCC patients, and development of second‐line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib‐resistant cells from Huh7 and Mahlavu cell lines by long‐term sorafenib exposure. Sorafenib‐resistant HCC cells acquired spindle‐shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long‐term sorafenib treatment, HCC cells showed induction of hepatocyte growth factor (HGF) synthesis and secretion along with increased levels of c‐Met kinase and its active phosphorylated form, indicating autocrine activation of HGF/c‐Met signaling. Importantly, the combined treatment of the resistant cells with c‐Met kinase inhibitor SU11274 and HGF neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib‐induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of HGF synthesis leading to autocrine activation of HGF/c‐Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with HGF and c‐Met inhibitors comprise promising candidates for overcoming sorafenib resistance.
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Affiliation(s)
- Zeynep Firtina Karagonlar
- Faculty of Engineering and Computer Science, Izmir University of Economics, Izmir.,Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir
| | - Dogukan Koc
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir
| | - Evin Iscan
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir
| | - Esra Erdal
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Neşe Atabey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir.,Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
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16
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Peng WX, Xiong EM, Ge L, Wan YY, Zhang CL, Du FY, Xu M, Bhat RA, Jin J, Gong AH. Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells. Exp Cell Res 2015; 340:62-70. [PMID: 26708617 DOI: 10.1016/j.yexcr.2015.12.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Revised: 12/09/2015] [Accepted: 12/15/2015] [Indexed: 12/12/2022]
Abstract
Previous studies suggest that early growth response gene-1 (Egr-1) plays an important role in hypoxia-induced drug-resistance. However, the mechanism still remains to be clarified. Herein, we investigated the role of Egr-1 in hypoxia-induced autophagy and its resulted hypoxia-driven chemo-resistance in Hepatocellular Carcinoma (HCC) cells. Our data demonstrated that Egr-1 was overexpressed in HCC tissues and cells and conferred them drug resistance under hypoxia. Mechanistically, Egr-1 transcriptionally regulated hypoxia-induced autophagy by binding to LC3 promoter in HCC cells, which resulted in resistance of HCC cells to chemotherapeutic agents; while dominant negative Egr-1 could inhibit autophagy level, and thus enhanced the sensitivity of HCC cells to chemotherapeutic agents, indicating that hypoxia-induced Egr-1 expression enhanced drug resistance of HCC cells likely through autophagy. Accordingly, it is suggested that a mechanism of hypoxia/Egr-1/autophagy axis might be involved in drug resistance in HCC.
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Affiliation(s)
- Wan-Xin Peng
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Er-Meng Xiong
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Lu Ge
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Yan-Ya Wan
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China; Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, PR China
| | - Chun-Li Zhang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Feng-Yi Du
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Min Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, PR China
| | - Reyaz Ahmed Bhat
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, PR China
| | - Jie Jin
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China
| | - Ai-Hua Gong
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, PR China.
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17
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Gao JJ, Shi ZY, Xia JF, Inagaki Y, Tang W. Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. World J Gastroenterol 2015; 21:12059-12070. [PMID: 26576091 PMCID: PMC4641124 DOI: 10.3748/wjg.v21.i42.12059] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
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18
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Han XJ, Su HY, Shao HB, Xu K. Prognostic factors of spontaneously ruptured hepatocellular carcinoma. World J Gastroenterol 2015; 21:7488-7494. [PMID: 26139994 PMCID: PMC4481443 DOI: 10.3748/wjg.v21.i24.7488] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 01/29/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the prognostic factors in patients with spontaneously ruptured hepatocellular carcinoma (HCC).
METHODS: Seventy-nine patients experiencing spontaneous rupture of HCC between April 2004 and August 2014 were enrolled in this study. The clinical features, treatment modalities and outcomes were reviewed. The statistical methods used in this work included univariate analysis, Kaplan-Meier survival analysis with log-rank tests, and multivariate analysis using a Cox regression hazard model.
RESULTS: Of the 79 patients with HCC rupture, 17 (21.5%) underwent surgery, 32 (40.5%) underwent transarterial embolization (TAE), and 30 (38%) received conservative treatment. The median survival time was 125 d, and the mortality rate at 30 d was 27.8%. Multivariate analysis revealed that lesion length (HR = 1.46, P < 0.001), lesion number (HR = 1.37, P = 0.042), treatment before tumor rupture (HR = 4.36, P = 0.019), alanine transaminase levels (HR = 1.0, P = 0.011), bicarbonate levels (HR = 1.18, P < 0.001), age (HR = 0.96, P = 0.026), anti-tumor therapy during the follow-up period (HR = 0.21, P = 0.008), and albumin levels (HR = 0.89, P = 0.010) were independent prognostic factors of survival after HCC rupture. The Barcelona-Clinic Liver Cancer (BCLC) stage was also an important prognostic factor; the median survival times for BCLC stages A, B and C were 251, 175 and 40 d, respectively (P < 0.001).
CONCLUSION: Anti-tumor therapy during the follow-up period, without a history of anti-tumor therapy prior to HCC rupture, small tumor length and number, and early BCLC stage are the most crucial predictors associated with satisfactory overall survival. Other factors play only a small role in overall survival.
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19
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Zhang H, Yao M, Wu W, Qiu L, Sai W, Yang J, Zheng W, Huang J, Yao D. Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma. Tumour Biol 2015; 36:9373-83. [PMID: 26109000 DOI: 10.1007/s13277-015-3678-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 06/15/2015] [Indexed: 12/15/2022] Open
Abstract
Hepatic annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical symptoms and plays a key role in development, metastasis, and drug resistance of lethal hepatocellular carcinoma (HCC). However, the prognostic significance of ANXA2 for HCC has not been elucidated up to now. In this study, ANXA2 was frequently found to be up-regulated in HCC tissues compared with benign liver disease (BLD) tissues, which was consistent with the results in serum samples and tissue specimens of patients with HCC. Furthermore, ANXA2 expression was significantly correlated with differentiated degree, intrahepatic metastasis, portal vein thrombus, and tumor node metastasis (TNM) staging. More importantly, increased ANXA2 level was first confirmed to be closely associated with shortened overall survival of HCC (χ (2) = 12.872, P = 0.005) and identified as an independent prognostic factor (hazard ratio 1.338, 95 % confidence interval (CI) 1.013 ~ 1.766, P = 0.040), suggesting that ANXA2 up-regulation might represent an acquired metastasis phenotype of HCC, help to screen out high-risk population for HCC, or more effectively treat a subset of postsurgical HCC patients positive for ANXA2.
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Affiliation(s)
- Haijian Zhang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China
| | - Min Yao
- Department of Immunology, Medical School of Nantong University, Nantong, China
| | - Wei Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China
| | - Liwei Qiu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China
| | - Wenli Sai
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China
| | - Junling Yang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China
| | - Jianfei Huang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
| | - Dengfu Yao
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 West Temple Road, Jiangsu, 226001, China.
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20
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Zhao Y, Adjei AA. Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. Oncologist 2015; 20:660-73. [PMID: 26001391 DOI: 10.1634/theoncologist.2014-0465] [Citation(s) in RCA: 410] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/06/2015] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR-2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti-VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors. IMPLICATIONS FOR PRACTICE Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF-targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.
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Affiliation(s)
- Yujie Zhao
- Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Alex A Adjei
- Roswell Park Cancer Institute, Buffalo, New York, USA
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