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Li Q, Zhou X, Yang Y, Zhang Q, Li Z, Han H, Yuan F, Deng H, Lei H, Duan Y. Nintedanib abrogates patient vitreous-induced Akt activation and tube formation of human retinal microvascular endothelial cells. Tissue Cell 2025; 94:102817. [PMID: 40043340 DOI: 10.1016/j.tice.2025.102817] [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: 09/27/2024] [Revised: 01/16/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025]
Abstract
Growth factors and cytokines in the vitreous are critical drivers of proliferative diabetic retinopathy (PDR), a condition in which many patients exhibit resistance to current therapies. PDR is characterized by the formation of fibrovascular membranes on the vitreous side of the retina, which, if untreated, can lead to retinal detachment. Nintedanib, a clinically approved drug for idiopathic pulmonary fibrosis, targets multiple tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and fibroblast growth factor receptors (FGFRs). In this study, we demonstrate that nintedanib effectively inhibits PDR vitreous-induced signaling molecules-namely, phosphorylation of VEGFR2, Akt, and Erk1/2-as well as cellular responses, including proliferation, migration, and tube formation in primary human retinal microvascular endothelial cells, at a non-toxic concentration of 1 μM. These findings suggest that nintedanib holds potential as a novel therapeutic option for the treatment of PDR.
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Affiliation(s)
- Qiang Li
- Department of Ophthalmology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Xiaoping Zhou
- Department of Ophthalmology, the First People's Hospital of Chenzhou, Chenzhou 423000, China
| | - Yanhui Yang
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, The School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750001, China
| | - Qing Zhang
- Department of Ophthalmology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, China
| | - Zhiyuan Li
- Department of Ophthalmology, the First People's Hospital of Chenzhou, Chenzhou 423000, China
| | - Haote Han
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Fang Yuan
- Department of Ophthalmology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China
| | - Hongwei Deng
- Shenzhen Eye Hospital, Shenzhen Eye Medical Center, Southern Medical University, Shenzhen 518000, China.
| | - Hetian Lei
- Department of Ophthalmology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, China.
| | - Yajian Duan
- Department of Ophthalmology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China.
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Duan H, Shao C, Luo Z, Wang T, Tong L, Liu H, Yao X, Lei J, Zhao J, Gao Y, Jiang T, Yan X. Perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy for resectable non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 2 trial (TD-NeoFOUR trial). Signal Transduct Target Ther 2024; 9:296. [PMID: 39465257 PMCID: PMC11514280 DOI: 10.1038/s41392-024-01992-0] [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: 03/06/2024] [Revised: 09/10/2024] [Accepted: 09/26/2024] [Indexed: 10/29/2024] Open
Abstract
This open-label, single-arm, phase 2 trial evaluated the efficacy and safety of neoadjuvant sintilimab combined with anlotinib and chemotherapy, followed by adjuvant sintilimab, for resectable NSCLC. Forty-five patients received anlotinib (10 mg, QD, PO, days 1-14), sintilimab (200 mg, day 1), and platinum-based chemotherapy of each three-week cycle for 3 cycles, followed by surgery within 4-6 weeks. Adjuvant sintilimab (200 mg) was administered every 3 weeks. The primary endpoint was achieving a pathological complete response (pCR). From June 10, 2021 through October 10, 2023, 45 patients were enrolled and composed the intention-to-treat population. Twenty-six patients (57.8%) achieved pCR, and 30 (66.7%) achieved major pathological response (MPR). Forty-one patients underwent surgery. In the per-protocol set (PP set), 63.4% (26/41) achieved pCR, and 73.2% achieved MPR. The median event-free survival was not attained (95% CI, 25.1-NE). During the neoadjuvant treatment phase, grade 3 or 4 treatment-related adverse events were observed in 25 patients (55.6%), while immune-related adverse events were reported in 7 patients (15.6%). We assessed vascular normalization and infiltration of immune-related cells by detecting the expression of relevant cell markers in NSCLC tissues with mIHC. Significant tumor microenvironment changes were observed in pCR patients, including reduced VEGF+ cells and CD4+Foxp3+ Treg cells, and increased perivascular CD4+ T cells, CD39+CD8+ T cells, and M1 macrophages. In conclusion, perioperative sintilimab and neoadjuvant anlotinib plus chemotherapy achieved pCR in a notable proportion of patients with resectable NSCLC and were associated with profound changes in the tumour microenvironment (ClinicalTrials.gov NCT05400070).
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Affiliation(s)
- Hongtao Duan
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Changjian Shao
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Zhilin Luo
- Department of Thoracic Surgery, Third Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Tianhu Wang
- Department of Thoracic Surgery, Third Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Liping Tong
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Honggang Liu
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Xin Yao
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Jie Lei
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China
| | - Yuan Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, Air Force Medical University, No. 169, Changle West Road, Xi'an, Shaanxi, China.
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China.
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical University, No. 1, Xinsi Road, Xi'an, Shaanxi, China.
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Ackermann M, Werlein C, Plucinski E, Leypold S, Kühnel MP, Verleden SE, Khalil HA, Länger F, Welte T, Mentzer SJ, Jonigk DD. The role of vasculature and angiogenesis in respiratory diseases. Angiogenesis 2024; 27:293-310. [PMID: 38580869 PMCID: PMC11303512 DOI: 10.1007/s10456-024-09910-2] [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: 12/20/2023] [Accepted: 02/11/2024] [Indexed: 04/07/2024]
Abstract
In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.
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Affiliation(s)
- Maximilian Ackermann
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany.
- Institute of Pathology and Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Witten, Germany.
- Institute of Anatomy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
| | | | - Edith Plucinski
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Sophie Leypold
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
| | - Mark P Kühnel
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
| | - Stijn E Verleden
- Antwerp Surgical Training, Anatomy and Research Centre (ASTARC), University of Antwerp, Antwerp, Belgium
| | - Hassan A Khalil
- Division of Thoracic and Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, USA
- Laboratory of Adaptive and Regenerative Biology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Florian Länger
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
| | - Tobias Welte
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Steven J Mentzer
- Division of Thoracic and Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, USA
- Laboratory of Adaptive and Regenerative Biology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Danny D Jonigk
- Institute of Pathology, University Clinics of RWTH University, Aachen, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
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Auberle C, Gao F, Sloan M, Morgensztern D, Winkler L, Ward JP, Devarakonda S, Rearden TP, Govindan R, Waqar SN. A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer. J Thorac Dis 2024; 16:3782-3793. [PMID: 38983151 PMCID: PMC11228753 DOI: 10.21037/jtd-23-1717] [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: 01/17/2024] [Accepted: 05/10/2024] [Indexed: 07/11/2024]
Abstract
Background Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open-label, single-arm pilot study. Methods Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with the above mutations were enrolled. Exclusion criteria included necrotic tumors with invasion of blood vessels, history of recent thromboembolic events, increased risk of bleeding or thrombosis, myocardial infarction, and weight loss >10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. This study was registered with ClinicalTrials.gov, number NCT02299141. Results Between 2015 and 2019, 20 patients were enrolled with a median age was 66 years, 15 (75%) were females, 15 (75%) had adenocarcinoma, and 17 patients had a TP53 mutation (85%). Seventeen (85%) had received prior immunotherapy and 11 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with three partial responses (PR), while 12 patients had stable disease (SD), with disease control rate (DCR) consisting of a PR and SD greater than or equal to 16 weeks of 65% (n=13). Median PFS was 4.3 months [95% confidence interval (CI): 1.8-7.9] and median overall survival (OS) was 11.3 months (95% CI: 3.5-44.2). Three patients experienced prolonged clinical benefit from nintedanib, remaining on treatment for over 1 year and all three had a TP53 mutation and received prior immunotherapy. The most common adverse events of any grade included nausea (80%), fatigue (70%), diarrhea (60%), and anorexia (60%). Conclusions In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity.
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Affiliation(s)
- Christine Auberle
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Feng Gao
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Mark Sloan
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Daniel Morgensztern
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Linda Winkler
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Jeffrey P Ward
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | | | - Timothy P Rearden
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Ramaswamy Govindan
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Saiama N Waqar
- Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
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Senchukova MA, Kalinin EA, Volchenko NN. Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance. World J Clin Oncol 2024; 15:614-634. [PMID: 38835849 PMCID: PMC11145955 DOI: 10.5306/wjco.v15.i5.614] [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: 12/27/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. AIM To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). METHODS A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. RESULTS Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). CONCLUSION The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.
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Affiliation(s)
- Marina A Senchukova
- Department of Oncology, Orenburg State Medical University, Orenburg 460000, Russia
| | - Evgeniy A Kalinin
- Department of Thoracic Surgery, Orenburg Regional Cancer Clinic, Orenburg 460021, Russia
| | - Nadezhda N Volchenko
- Department of Pathology, PA Hertzen Moscow Oncology Research Centre, Branch of National Medical Research Radiological Center, Moscow 125284, Russia
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Schindler H, Lusky F, Daniello L, Elshiaty M, Gaissmaier L, Benesova K, Souto-Carneiro M, Angeles AK, Janke F, Eichhorn F, Kazdal D, Schneider M, Liersch S, Klemm S, Schnitzler P, Stenzinger A, Sültmann H, Thomas M, Christopoulos P. Serum cytokines predict efficacy and toxicity, but are not useful for disease monitoring in lung cancer treated with PD-(L)1 inhibitors. Front Oncol 2022; 12:1010660. [PMID: 36387148 PMCID: PMC9662790 DOI: 10.3389/fonc.2022.1010660] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/14/2022] [Indexed: 01/09/2023] Open
Abstract
Introduction PD-(L)1 inhibitors (IO) have improved the prognosis of non-small-cell lung cancer (NSCLC), but more reliable predictors of efficacy and immune-related adverse events (irAE) are urgently needed. Cytokines are important effector molecules of the immune system, whose potential clinical utility as biomarkers remains unclear. Methods Serum samples from patients with advanced NSCLC receiving IO either alone in the first (1L, n=46) and subsequent lines (n=50), or combined with chemotherapy (ICT, n=108) were analyzed along with age-matched healthy controls (n=15) at baseline, after 1 and 4 therapy cycles, and at disease progression (PD). Patients were stratified in rapid progressors (RP, progression-free survival [PFS] <120 days), and long-term responders (LR, PFS >200 days). Cytometric bead arrays were used for high-throughput quantification of 20 cytokines and other promising serum markers based on extensive search of the current literature. Results Untreated NSCLC patients had increased levels of various cytokines and chemokines, like IL-6, IL-8, IL-10, CCL5, G-CSF, ICAM-1, TNF-RI and VEGF (fold change [FC]=1.4-261, p=0.026-9x10-7) compared to age-matched controls, many of which fell under ICT (FC=0.2-0.6, p=0.014-0.002), but not under IO monotherapy. Lower baseline levels of TNF-RI were associated with longer PFS (hazard ratio [HR]= 0.42-0.54; p=0.014-0.009) and overall survival (HR=0.28-0.34, p=0.004-0.001) after both ICT and IO monotherapy. Development of irAE was associated with higher baseline levels of several cytokines, in particular of IL-1β and angiogenin (FC=7-9, p=0.009-0.0002). In contrast, changes under treatment were very subtle, there were no serum correlates of radiologic PD, and no association between dynamic changes in cytokine concentrations and clinical outcome. No relationship was noted between the patients' serologic CMV status and serum cytokine levels. Conclusions Untreated NSCLC is characterized by increased blood levels of several pro-inflammatory and angiogenic effectors, which decrease under ICT. Baseline serum cytokine levels could be exploited for improved prediction of subsequent IO benefit (in particular TNF-RI) and development of irAE (e.g. IL-1β or angiogenin), but they are not suitable for longitudinal disease monitoring. The potential utility of IL-1/IL-1β inhibitors in the management and/or prevention of irAE in NSCLC warrants investigation.
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Affiliation(s)
- Hannah Schindler
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany
| | - Fabienne Lusky
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany
| | - Lea Daniello
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany
| | - Mariam Elshiaty
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany
| | - Lena Gaissmaier
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany
| | - Karolina Benesova
- Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Margarida Souto-Carneiro
- Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Arlou Kristina Angeles
- Division of Cancer Genome Research (B063), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Florian Janke
- Division of Cancer Genome Research (B063), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Florian Eichhorn
- Department of Thoracic Surgery, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Daniel Kazdal
- Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany,Department of Molecular Pathology Institute of Pathology Heidelberg, Heidelberg, Germany
| | - Marc Schneider
- Translational Research Unit, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
| | - Stephan Liersch
- Department of Pharmacy, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany
| | - Sarah Klemm
- Center for Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Paul Schnitzler
- Center for Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Albrecht Stenzinger
- Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany,Department of Molecular Pathology Institute of Pathology Heidelberg, Heidelberg, Germany
| | - Holger Sültmann
- Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany,Division of Cancer Genome Research (B063), German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Michael Thomas
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, Heidelberg, Germany,Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center of Lung Research (DZL), Heidelberg, Germany,*Correspondence: Petros Christopoulos,
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Shi Y, Lei K, Jia Y, Ni B, He Z, Bi M, Wang X, Shi J, Zhou M, Sun Q, Wang G, Chen D, Shu Y, Liu L, Guo Z, Liu Y, Yang J, Wang K, Xiao K, Wu L, Yi T, Sun D, Kang M, Ma T, Mao Y, Shi J, Tang T, Wang Y, Xing P, Lv D, Liao W, Luo Z, Wang B, Wu X, Zhu X, Han S, Guo Q, Liu R, Lu Z, Zhang J, Fang J, Hu C, Ji Y, Liu G, Lu H, Wu D, Zhang J, Zhu S, Liu Z, Qiu W, Ye F, Yu Y, Zhao Y, Zheng Q, Chen J, Pan Z, Zhang Y, Lian W, Jiang B, Qiu B, Zhang G, Zhang H, Chen Y, Chen Y, Duan H, Li M, Liu S, Ma L, Pan H, Yuan X, Yuan X, Zheng Y, Gao E, Zhao L, Wang S, Wu C. Bevacizumab biosimilar LY01008 compared with bevacizumab (Avastin) as first-line treatment for Chinese patients with unresectable, metastatic, or recurrent non-squamous non-small-cell lung cancer: A multicenter, randomized, double-blinded, phase III trial. Cancer Commun (Lond) 2021; 41:889-903. [PMID: 34184418 PMCID: PMC8441057 DOI: 10.1002/cac2.12179] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 04/25/2021] [Accepted: 05/31/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC). METHODS Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). RESULTS Between December 15th , 2017, and May 15th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. CONCLUSIONS LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting.
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8
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Tan HW, Xu YM, Qin SH, Chen GF, Lau ATY. Epigenetic regulation of angiogenesis in lung cancer. J Cell Physiol 2021; 236:3194-3206. [PMID: 33078404 DOI: 10.1002/jcp.30104] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/08/2020] [Accepted: 09/30/2020] [Indexed: 02/05/2023]
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, in which angiogenesis is highly required for lung cancer cell growth and metastasis. Genetic regulation of this multistep process is being studied extensively, however, relatively less is known about the epigenetic regulation of angiogenesis in lung cancer. Several epigenetic alterations contribute to regulating angiogenesis, such as epimodifications of DNA, posttranslational modification of histones, and expression of noncoding RNAs. Here, we review the current knowledge of the epigenetic regulation of angiogenesis and discuss the potential clinical applications of epigenetic-based anticancer therapy in lung cancer. Overall, epigenetic-based therapy will likely emerge as a prominent approach to treat lung cancer in the future.
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Affiliation(s)
- Heng Wee Tan
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
| | - Yan-Ming Xu
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
| | - San-Hai Qin
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
| | - Guo-Feng Chen
- Department of Hepatobiliary Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, People's Republic of China
| | - Andy T Y Lau
- Laboratory of Cancer Biology and Epigenetics, Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, Guangdong, People's Republic of China
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9
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Ma J, Tang W, Gu R, Hu F, Zhang L, Wu J, Xu G. SHP-2-Induced Activation of c-Myc Is Involved in PDGF-B-Regulated Cell Proliferation and Angiogenesis in RMECs. Front Physiol 2020; 11:555006. [PMID: 33329018 PMCID: PMC7719712 DOI: 10.3389/fphys.2020.555006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 11/03/2020] [Indexed: 12/02/2022] Open
Abstract
Background: Aberrant neovascularization resulting from inappropriate angiogenic signaling is closely related to many diseases, such as cancer, cardiovascular disease, and proliferative retinopathy. Although some factors involved in regulating pathogenic angiogenesis have been identified, the molecular mechanisms of proliferative retinopathy remain largely unknown. In the present study, we determined the role of platelet-derived growth factor-B (PDGF-B), one of the HIF-1-responsive gene products, in cell proliferation and angiogenesis in retinal microvascular endothelial cells (RMECs) and explored its regulatory mechanism. Methods: Cell counting kit-8 (CCK-8), bromodeoxyuridine (BrdU) incorporation, tube formation, cell migration, and Western blot assays were used in our study. Results: Our results showed that PDGF-B promoted cell proliferation and angiogenesis by increasing the activity of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) in RMECs, which was attenuated by the inhibition of PDGF receptor (PDGFR) or SHP-2 knockdown. Moreover, activation of c-Myc was involved in the processes of PDGF-B/SHP-2-driven cell proliferation in RMECs. The promoting effects of PDGF-B/SHP-2 on c-Myc expression were mediated by the Erk pathway. Conclusion: These results indicate that PDGF-B facilitates cell proliferation and angiogenesis, at least in part, via the SHP-2/Erk/c-Myc pathway in RMECs, implying new potential treatment candidates for retinal microangiopathy.
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Affiliation(s)
- Jun Ma
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Wenyi Tang
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Ruiping Gu
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Fangyuan Hu
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Lei Zhang
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jihong Wu
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Gezhi Xu
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China.,Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
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10
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Wright JW, Church KJ, Harding JW. Hepatocyte Growth Factor and Macrophage-stimulating Protein "Hinge" Analogs to Treat Pancreatic Cancer. Curr Cancer Drug Targets 2020; 19:782-795. [PMID: 30914029 DOI: 10.2174/1568009619666190326130008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 03/18/2019] [Accepted: 03/20/2019] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the "hinge regions" of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model.
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Affiliation(s)
- John W Wright
- Department of Psychology, Washington State University, Pullman, WA, United States.,Department of Integrative Physiology and Neuroscience, and Program in Biotechnology, Washington State University, Pullman, WA, United States
| | - Kevin J Church
- Department of Integrative Physiology and Neuroscience, and Program in Biotechnology, Washington State University, Pullman, WA, United States
| | - Joseph W Harding
- Department of Psychology, Washington State University, Pullman, WA, United States.,Department of Integrative Physiology and Neuroscience, and Program in Biotechnology, Washington State University, Pullman, WA, United States
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11
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Sobierajska K, Ciszewski WM, Sacewicz-Hofman I, Niewiarowska J. Endothelial Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1234:71-86. [PMID: 32040856 DOI: 10.1007/978-3-030-37184-5_6] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Angiogenesis is a critical process required for tumor progression. Newly formed blood vessels provide nutrition and oxygen to the tumor contributing to its growth and development. However, endothelium also plays other functions that promote tumor metastasis. It is involved in intravasation, which allows invasive cancer cells to translocate into the blood vessel lumen. This phenomenon is an important stage for cancer metastasis. Besides direct association with cancer development, endothelial cells are one of the main sources of cancer-associated fibroblasts (CAFs). The heterogeneous group of CAFs is the main inductor of migration and invasion abilities of cancer cells. Therefore, the endothelium is also indirectly responsible for metastasis. Considering the above, the endothelium is one of the important targets of anticancer therapy. In the chapter, we will present mechanisms regulating endothelial function, dependent on cancer and cancer niche cells. We will focus on possibilities of suppressing pro-metastatic endothelial functions, applied in anti-cancer therapies.
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Affiliation(s)
| | | | | | - Jolanta Niewiarowska
- Department of Molecular Cell Mechanisms, Medical University of Lodz, Lodz, Poland
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12
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Wang L, He Z, Yang S, Tang H, Wu Y, Li S, Han B, Li K, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Chen W, Luo Y, Wu L, Wang X, Nan K, Jin F, Dong J, Li B, Sun Y, Wang Q. The impact of previous therapy strategy on the efficiency of anlotinib hydrochloride as a third-line treatment on patients with advanced non-small cell lung cancer (NSCLC): a subgroup analysis of ALTER0303 trial. Transl Lung Cancer Res 2019; 8:575-583. [PMID: 31737494 DOI: 10.21037/tlcr.2019.09.21] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Background Lung cancer remains one of the deadliest cancers worldwide. The ALTER0303 trial revealed that anlotinib might be used as a third-line or further treatment in non-small cell lung cancer (NSCLC) patients. Meanwhile, the impact of previous therapy strategies on the efficiency of anlotinib still remains unknown. Methods The subgroup of patients in ALTER0303 were analyzed by using Kaplan-Meier estimates, Pearson χ2, or Fisher's exact test. Results There was no statistical significance on progression-free survival (PFS) and overall survival (OS) among patients in different previous antiangiogenic treatments groups. Patients in the chest radiotherapy (CRT) group had longer median PFS than the non-CRT group (5.93 vs. 4.63 m, P=0.027). Regardless of what kind of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) and chemotherapy regimens were used previously, all patients gained longer PFS in the anlotinib group, while only patients treated with vinorelbine/platinum in the EGFR wild type group, pemetrexed/platinum, vinorelbine/platinum, and gefitinib in the EGFR mutation group, and EGFR TKI used as the first line group could benefit from anlotinib on OS. When the OS was calculated from the time of diagnosis to the death, anlotinib could have increased median OS about 6 months (33.8 vs. 27.8 m, P<0.001) compared to the placebo with a hazard ratio (HR) (95% CI): 0.77 (0.60, 1.00). Conclusions This study indicated that previous bevacizumab or endostatin treatments had no impact on the efficiency of anlotinib. Patients with CRT history benefited more from anlotinib on PFS. EGFR TKI and chemotherapy treatment history had more impact on OS than PFS in patients treated with anlotinib compared to placebo.
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Affiliation(s)
- Lili Wang
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Zhen He
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Sen Yang
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Hong Tang
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yufeng Wu
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Shaomei Li
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai 200030, China
| | - Kai Li
- Department of Thoracic Oncology, Tianjin Medical University Cancer Hospital, Tianjin 300060, China
| | - Li Zhang
- Department of Respiratory Diseases, Peking Union Medical College Hospital, Beijing 100032, China
| | - Jianhua Shi
- Department of Oncology, Linyi Cancer Hospital, Linyi 276001, China
| | - Zhehai Wang
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital, Jinan 250117, China
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun 130012, China
| | - Jianxing He
- Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Yuankai Shi
- Cancer Hospital Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Weiqiang Chen
- Department of Pulmonary Medicine, Lanzhou Military General Hospital, Lanzhou 730050, China
| | - Yi Luo
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha 410006, China
| | - Lin Wu
- Department of Medical Oncology, Hunan Cancer Hospital, Changsha 410006, China
| | - Xiuwen Wang
- Department of Chemotherapy, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Kejun Nan
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Faguang Jin
- Department of Respiratory Diseases, Tang Du Hospital, Xi'an 710038, China
| | - Jian Dong
- First Department of Medical Oncology, Yunnan Cancer Hospital, Kunming 650118, China
| | - Baolan Li
- Department of General Medicine, Capital Medical University, Beijing Chest Hospital, Beijing 101149, China
| | - Yan Sun
- Cancer Hospital Chinese Academy of Medical Sciences, Beijing 100021, China
| | - Qiming Wang
- Oncology Department, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou 450008, China.,Oncology Department, Henan Cancer Hospital, Zhengzhou 450008, China
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13
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Charpidou A, Kotteas E, Gaga M. Towards precision medicine: CCL2, another brick in the wall? Eur Respir J 2019; 53:53/3/1802327. [PMID: 30846448 DOI: 10.1183/13993003.02327-2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 12/11/2018] [Indexed: 11/05/2022]
Affiliation(s)
- Andriani Charpidou
- Oncology Unit, 3rd Internal Medicine Dept, Medical School, National Kapodistrian University of Athens, Athens Chest Hospital Sotiria, Athens, Greece
| | - Elias Kotteas
- Oncology Unit, 3rd Internal Medicine Dept, Medical School, National Kapodistrian University of Athens, Athens Chest Hospital Sotiria, Athens, Greece
| | - Mina Gaga
- 7th Respiratory Medicine Dept, Athens Chest Hospital Sotiria, Athens, Greece
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14
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Chen X, Zheng Q, Li W, Lu Y, Ni Y, Ma L, Fu Y. SOX5 induces lung adenocarcinoma angiogenesis by inducing the expression of VEGF through STAT3 signaling. Onco Targets Ther 2018; 11:5733-5741. [PMID: 30254466 PMCID: PMC6140741 DOI: 10.2147/ott.s176533] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background and objectives Angiogenesis is the main cause of lung adenocarcinoma (LAC) poor prognosis. This study aimed to investigate the effect of sex-determining region Y-box protein 5 (SOX5) expression on angiogenesis of LAC and explore its possible mechanism. Patients and methods The effect on angiogenesis was tested by tube formation assays using human umbilical vein endothelial cells cocultured with A549 cells. Lentivirus shRNA of SOX5 and lentivirus of SOX5 overexpression system were used to establish LAC cell lines, which expressed SOX5 of different levels. SOX5 downstream signaling targets were analyzed by real-time qPCR and Western blot. We collected 90 LAC cases and the tissues were examined by immunohistochemistry for SOX5 and vascular endothelial growth factor (VEGF). Results We found that SOX5 overexpression in A549 cells significantly promoted tube formation capacity of the cocultured human umbilical vein endothelial cells. SOX5 increased VEGF expression and signal transducer activator of transcription 3 phosphorylation; however, SOX5 had no effect on extracellular signal-regulated kinase and protein kinase B pathway. Furthermore, the expression of SOX5 and VEGF had a significantly positive correlation (r=0.399, P=0.001) according to the tissue microarray data. Conclusion These findings suggest that SOX5 induces angiogenesis by activating signal transducer activator of transcription 3/VEGF signaling and confer its candidacy as a potential therapeutic target in LAC.
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Affiliation(s)
- Xin Chen
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China,
| | - Qi Zheng
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China,
| | - Weidong Li
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China,
| | - Yuan Lu
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China,
| | - Yiming Ni
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China,
| | - Liang Ma
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China,
| | - Yufei Fu
- Zhejiang Key Laboratory of Gastro-Intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P. R. China,
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15
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da Silva RF, Dhar D, Raina K, Kumar D, Kant R, Cagnon VHA, Agarwal C, Agarwal R. Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators. Sci Rep 2018; 8:9540. [PMID: 29934570 PMCID: PMC6014981 DOI: 10.1038/s41598-018-27831-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/11/2018] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer (PCa) is the most common malignancy and second leading cause of cancer-related deaths in American men. Proliferating cells have higher need for nutrients and oxygen, triggering angiogenesis that plays a critical role in tumor growth, progression and metastasis. Consequently, immense focus has converged onto inhibitors of angiogenesis in cancer treatment, such as Nintedanib, which has shown exceptional antitumor activity via inhibiting cell proliferation and the resulting tumor growth, primarily due to its combined action on tumor cells, endothelial cells and pericytes. Accordingly, here we assessed both in vitro and in vivo efficacy of Nintedanib in PCa. The results showed that Nintedanib decreased cell viability in both androgen dependent- and -independent PCa cells, together with a decrease in cell motility and invasiveness. Nintedanib also reduced the expression of significant genes responsible for cell cycle progression. PCa PC3 xenograft-carrying nude mice treated with Nintedanib showed significantly decreased tumor volume and cell proliferation alongside diminished levels of pro-angiogenic molecules and blood vessel densities. In conclusion, we report that Nintedanib has strong efficacy against PCa in pre-clinical models via modulation of various pathways, and that it could be employed as a promising new strategy to manage PCa clinically.
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Affiliation(s)
- Raquel Frenedoso da Silva
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.,Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Sao Paulo, Brazil
| | - Deepanshi Dhar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA
| | - Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Dileep Kumar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA
| | - Rama Kant
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA
| | - Valeria Helena Alves Cagnon
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Sao Paulo, Brazil
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA. .,University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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16
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Forster M, Hackshaw A, De Pas T, Cobo M, Garrido P, Summers Y, Dingemans AMC, Flynn M, Schnell D, von Wangenheim U, Loembé AB, Kaiser R, Lee SM. A phase I study of nintedanib combined with cisplatin/gemcitabine as first-line therapy for advanced squamous non-small cell lung cancer (LUME-Lung 3). Lung Cancer 2018; 120:27-33. [DOI: 10.1016/j.lungcan.2018.03.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 03/02/2018] [Accepted: 03/08/2018] [Indexed: 11/30/2022]
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17
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Coelho AL, Gomes MP, Catarino RJ, Rolfo C, Lopes AM, Medeiros RM, Araújo AM. Angiogenesis in NSCLC: is vessel co-option the trunk that sustains the branches? Oncotarget 2018; 8:39795-39804. [PMID: 26950275 PMCID: PMC5503654 DOI: 10.18632/oncotarget.7794] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 02/09/2016] [Indexed: 12/21/2022] Open
Abstract
The critical role of angiogenesis in tumor development makes its inhibition a valuable new approach in therapy, rapidly making anti-angiogenesis a major focus in research. While the VEGF/VEGFR pathway is the main target of the approved anti-angiogenic molecules in NSCLC treatment, the results obtained are still modest, especially due to resistance mechanisms. Accumulating scientific data show that vessel co-option is an alternative mechanism to angiogenesis during tumor development in well-vascularized organs such as the lungs, where tumor cells highjack the existing vasculature to obtain its blood supply in a non-angiogenic fashion. This can explain the low/lack of response to current anti-angiogenic strategies. The same principle applies to lung metastases of other primary tumors. The exact mechanisms of vessel co-option need to be further elucidated, but it is known that the co-opted vessels regress by the action of Angiopoietin-2 (Ang-2), a vessel destabilizing cytokine expressed by the endothelial cells of the pre-existing mature vessels. In the absence of VEGF, vessel regression leads to tumor cell loss and hypoxia, with a subsequent switch to a neoangiogenic phenotype by the remaining tumor cells. Unravelling the vessel co-option mechanisms and involved players may be fruitful for numerous reasons, and the particularities of this form of vascularization should be carefully considered when planning anti-angiogenic interventions or designing clinical trials for this purpose. In view of the current knowledge, rationale for therapeutic approaches of dual inhibition of Ang-2 and VEGF are swiftly gaining strength and may serve as a launchpad to more successful NSCLC anti-vascular treatments.
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Affiliation(s)
- Ana Luísa Coelho
- Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.,Faculdade de Medicina, University of Porto, Porto, Portugal
| | - Mónica Patrícia Gomes
- Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Raquel Jorge Catarino
- Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.,Faculdade de Medicina, University of Porto, Porto, Portugal
| | - Christian Rolfo
- Phase I, Early Clinical Trials Unit, Antwerp University Hospital, Edegem, Belgium.,Centre of Oncological Research (CORE), Antwerp University, Edegem, Belgium
| | - Agostinho Marques Lopes
- Faculdade de Medicina, University of Porto, Porto, Portugal.,Centro Hospitalar de S. João, Pulmonology Department, Porto, Portugal
| | - Rui Manuel Medeiros
- Instituto Português de Oncologia, Molecular Oncology Group, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.,Liga Portuguesa Contra o Cancro (NRNorte), Research Department, Porto, Portugal
| | - António Manuel Araújo
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal.,Centro Hospitalar do Porto, Medical Oncology Department, Porto, Portugal
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18
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Wo H, He J, Zhao Y, Yu H, Chen F, Yi H. The Efficacy and Toxicity of Gefitinib in Treating Non-small Cell Lung Cancer: A Meta-analysis of 19 Randomized Clinical Trials. J Cancer 2018; 9:1455-1465. [PMID: 29721056 PMCID: PMC5929091 DOI: 10.7150/jca.23356] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 02/05/2018] [Indexed: 01/22/2023] Open
Abstract
Background: This meta-analysis evaluated the efficacy and toxicity of gefitinib with other commonly used drugs in different treatment settings and epidermal growth factor receptor (EGFR) mutation status. Methods: Nineteen randomize clinical trials (RCTs) of 6,554 patients with NSCLC were pooled in this meta-analysis by random-effects or fixed-effects model, whichever is proper. Results: In first-line therapy, gefitinib showed higher odds than chemotherapy (OR = 2.19, 95% CI: 1.20-4.01), but less than other targeted therapies (OR = 0.58, 95% CI: 0.38-0.88). As non-first-line therapy, the overall survival (OS) and progression-free survival (PFS) were similar between gefitinib and controls (HR = 1.00, 95% CI: 0.93-1.08; HR = 0.91, 95% CI: 0.72-1.15), respectively. With the regard to toxicity, the incidences of dry skin, rash and pruritus were higher in gefitinib compared with controls, while gefitinib significantly reduced the incidence of hematologic toxicity. Conclusion: Gefitinib might be more efficient than chemotherapy, but less efficient than other targeted therapies in ORR, especially in EGFR mutation-positive patients. Gefitinib can decrease the odds of hematologic toxicity compared to controls. Future studies, especially those with EGFR mutation-positive patients, will be needed to confirm our findings.
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Affiliation(s)
- Hongmei Wo
- Department of Health Economics, School of Health Policy and Management, Nanjing Medical University, Nanjing, 211166, China
| | - Jing He
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Yang Zhao
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Hao Yu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Feng Chen
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
| | - Honggang Yi
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 211166, China
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19
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Nintedanib in advanced NSCLC of adenocarcinoma histology: a profile of its use. DRUGS & THERAPY PERSPECTIVES 2018. [DOI: 10.1007/s40267-018-0481-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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20
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Liu G, Wang C, E M. [Mechanism and Prospect of Radiotherapy Combined with Apotatinib
in the Treatment of Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017; 20:847-851. [PMID: 29277185 PMCID: PMC5973393 DOI: 10.3779/j.issn.1009-3419.2017.12.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
非小细胞肺癌是危害人类生命健康的最常见的恶性肿瘤之一。大多数患者确诊时为晚期，不符合手术适应症，主要的治疗方法是放化疗联合。近年来，随着抗血管生成治疗恶性肿瘤理论的提出，阿帕替尼作为一种新型的抗肿瘤药物，与放疗联合具有协同作用。可能的机制包括使血管正常化，改善肿瘤内乏氧情况，调节促血管生成因子水平等。将阿帕替尼与放疗联合有望成为一种新的治疗策略应用于非小细胞肺癌的治疗中，提高肺癌的治疗效果。
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Affiliation(s)
- Guohui Liu
- Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Chunbo Wang
- Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Mingyan E
- Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
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21
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Maj E, Filip-Psurska B, Milczarek M, Psurski M, Kutner A, Wietrzyk J. Vitamin D derivatives potentiate the anticancer and anti-angiogenic activity of tyrosine kinase inhibitors in combination with cytostatic drugs in an A549 non-small cell lung cancer model. Int J Oncol 2017; 52:337-366. [PMID: 29345296 PMCID: PMC5741374 DOI: 10.3892/ijo.2017.4228] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 11/17/2017] [Indexed: 12/16/2022] Open
Abstract
Numerous in vitro and in vivo studies have demonstrated that calcitriol [1,25(OH)2D3] and different vitamin D analogs possess antineoplastic activity, regulating proliferation, differentiation and apoptosis, as well as angiogenesis. Vitamin D compounds have been shown to exert synergistic effects when used in combination with different agents used in anticancer therapies in different cancer models. The aim of this study was to evaluate the mechanisms of the cooperation of the vitamin D compounds [1,24(OH)2D3 (PRI-2191) and 1,25(OH)2D3] with tyrosine kinase inhibitors (imatinib and sunitinib) together with cytostatics (cisplatin and docetaxel) in an A549 non-small cell lung cancer model. The cytotoxic effects of the test compounds used in different combinations were evaluated on A549 lung cancer cells, as well as on human lung microvascular endothelial cells (HLMECs). The effects of such combinations on the cell cycle and cell death were also determined. In addition, changes in the expression of proteins involved in cell cycle regulation, angiogenesis and the action of vitamin D were analyzed. Moreover, the effects of 1,24(OH)2D3 on the anticancer activity of sunitinib and sunitinib in combination with docetaxel were examined in an A549 lung cancer model in vivo. Experiments aiming at evaluating the cytotoxicity of the combinations of the test agents revealed that imatinib and sunitinib together with cisplatin or docetaxel exerted potent anti-proliferative effects in vitro on A549 lung cancer cells and in HLMECs; however, 1,24(OH)2D3 and 1,25(OH)2D3 enhanced the cytotoxic effects only in the endothelial cells. Among the test agents, sunitinib and cisplatin decreased the secretion of vascular endothelial growth factor (VEGF)-A from the A549 lung cancer cells. The decrease in the VEGF-A level following incubation with cisplatin correlated with a higher p53 protein expression, while no such correlation was observed following treatment of the A549 cells with sunitinib. Sunitinib together with docetaxel and 1,24(OH)2D3 exhibited a more potent anticancer activity in the A549 lung cancer model compared to double combinations and to treatment with the compounds alone. The observed anticancer activity may be the result of the influence of the test agents on the process of tumor angiogenesis, for example, through the downregulation of VEGF-A expression in tumor and also on the induction of cell death inside the tumor.
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Affiliation(s)
- Ewa Maj
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Beata Filip-Psurska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Magdalena Milczarek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Mateusz Psurski
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
| | - Andrzej Kutner
- Pharmaceutical Research Institute, 01-793 Warsaw, Poland
| | - Joanna Wietrzyk
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland
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22
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Wozniak-Knopp G, Stadlmayr G, Perthold JW, Stadlbauer K, Woisetschläger M, Sun H, Rüker F. Designing Fcabs: well-expressed and stable high affinity antigen-binding Fc fragments. Protein Eng Des Sel 2017; 30:657-671. [DOI: 10.1093/protein/gzx042] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 07/16/2017] [Indexed: 01/15/2023] Open
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23
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Ackermann M, Kim YO, Wagner WL, Schuppan D, Valenzuela CD, Mentzer SJ, Kreuz S, Stiller D, Wollin L, Konerding MA. Effects of nintedanib on the microvascular architecture in a lung fibrosis model. Angiogenesis 2017; 20:359-372. [PMID: 28283856 DOI: 10.1007/s10456-017-9543-z] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 03/06/2017] [Indexed: 01/17/2023]
Abstract
Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5 mg/kg). Nintedanib was started after the onset of lung pathology (50 mg/kg twice daily, orally). Micro-computed tomography was performed via volumetric assessment. Static lung compliance and forced vital capacity were determined by invasive measurements. Mice were subjected to bronchoalveolar lavage and histologic analyses, or perfused with a casting resin. Microvascular corrosion casts were imaged by scanning electron microscopy and synchrotron radiation tomographic microscopy, and quantified morphometrically. Bleomycin administration resulted in a significant increase in higher-density areas in the lungs detected by micro-computed tomography, which was significantly attenuated by nintedanib. Nintedanib significantly reduced lung fibrosis and vascular proliferation, normalized the distorted microvascular architecture, and was associated with a trend toward improvement in lung function and inflammation. Nintedanib resulted in a prominent improvement in pulmonary microvascular architecture, which outperformed the effect of nintedanib on lung function and inflammation. These findings uncover a potential new mode of action of nintedanib that may contribute to its efficacy in idiopathic pulmonary fibrosis.
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Affiliation(s)
- Maximilian Ackermann
- Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128, Mainz, Germany.
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immune Therapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Willi L Wagner
- Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128, Mainz, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.,Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Cristian D Valenzuela
- Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Steven J Mentzer
- Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sebastian Kreuz
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Detlef Stiller
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Lutz Wollin
- Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Moritz A Konerding
- Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128, Mainz, Germany
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24
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Gann CN, Morsli N, Kaiser R. Industry corner: perspectives and controversies - The challenges of patient access to new medicines. Ann Oncol 2017; 28:658-663. [PMID: 27831504 DOI: 10.1093/annonc/mdw569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- C-N Gann
- Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany
| | - N Morsli
- Boehringer Ingelheim Corporation, Reims, France
| | - R Kaiser
- Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany
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25
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Manegold C, Adjei A, Bussolino F, Cappuzzo F, Crino L, Dziadziuszko R, Ettinger D, Fennell D, Kerr K, Le Chevalier T, Leighl N, Papotti M, Paz-Ares L, Pérol M, Peters S, Pirker R, Quoix E, Reck M, Smit E, Vokes E, van Zandwijk N, Zhou C. Novel active agents in patients with advanced NSCLC without driver mutations who have progressed after first-line chemotherapy. ESMO Open 2017; 1:e000118. [PMID: 29435365 PMCID: PMC5729303 DOI: 10.1136/esmoopen-2016-000118] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 10/30/2016] [Indexed: 12/26/2022] Open
Abstract
Despite the efficacy of a number of first-line treatments, most patients with advanced-stage non-small cell lung cancer (NSCLC) experience disease progression that warrants further treatment. In this review, we examine the role of novel active agents for patients who progress after first-line therapy and who are not candidates for targeted therapies. More therapeutic options are needed for the management of patients with NSCLC after failure of first-line chemotherapy. A PubMed search was performed for articles from January 2012 to May 2015 using the keywords NSCLC, antiangiogenic, immunotherapy, second-line, novel therapies and English language articles only. Relevant papers were reviewed; papers outside that period were considered on a case-by-case basis. A search of oncology congresses was performed to identify relevant abstracts over this period. In recent years, antiangiogenic agents and immune checkpoint inhibitors have been added to our armamentarium to treat patients with advanced NSCLC who have progressed on first-line chemotherapy. These include nintedanib, a triple angiokinase inhibitor; ramucirumab, a vascular endothelial growth factor receptor-2 antibody; and nivolumab, pembrolizumab and atezolizumab, just three of a growing list of antibodies targeting the programmed death receptor-1 (PD-1)/PD ligand-1 pathway. Predictive and prognostic factors in NSCLC treatment will help to optimise treatment with these novel agents. The approval of new treatments for patients with NSCLC after the failure of first-line chemotherapy has increased options after a decade of few advances, and holds promise for future evolution of the management of NSCLC.
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Affiliation(s)
- Christian Manegold
- Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
| | - Alex Adjei
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
| | - Federico Bussolino
- Department of Oncology, University of Turin, Turin and Candiolo Cancer Institute, Candiolo, Italy
| | - Federico Cappuzzo
- Medical Oncology Department, Istituto Toscano Tumori, Livorno, Italy
| | - Lucio Crino
- Medical Oncology Department, Perugia University Medical School, Perugia, Italy
| | - Rafal Dziadziuszko
- Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland
| | - David Ettinger
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland, USA
| | - Dean Fennell
- Department of Oncology, University of Leicester & Leicester University Hospitals, Leicester, UK
| | - Keith Kerr
- Department of Pathology, Aberdeen University Medical School, Aberdeen, UK
| | | | - Natasha Leighl
- Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Mauro Papotti
- Department of Oncology, University of Turin, Turin, Italy
| | - Luis Paz-Ares
- Servicio de Oncología Médica, Doce de Octubre University Hospital, Madrid, Spain
| | - Maurice Pérol
- Département de Cancérologie Médicale, Centre Léon Bérard, Lyon, France
| | - Solange Peters
- Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - Robert Pirker
- Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Quoix
- Pulmonology Department, University Hospital, Strasbourg, France
| | - Martin Reck
- Department of Thoracic Oncology, Airway Research Center North (ARCN), member of the German Center for Lung Research (DZL), Lung Clinic Grosshansdorf, Grosshansdorf, Germany
| | - Egbert Smit
- Department of Pulmonary Diseases, VU University Medical Centre, Amsterdam, The Netherlands; Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Everett Vokes
- Department of Medicine, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA
| | - Nico van Zandwijk
- Asbestos Diseases Research Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Caicun Zhou
- Department of Oncology, Shanghai Pulmonary Hospital, Shanghai, China
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26
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27
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Manzo A, Carillio G, Montanino A, Costanzo R, Sandomenico C, Rocco G, Morabito A. Focus on Nintedanib in NSCLC and Other Tumors. Front Med (Lausanne) 2016; 3:68. [PMID: 28066768 PMCID: PMC5165233 DOI: 10.3389/fmed.2016.00068] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/05/2016] [Indexed: 11/13/2022] Open
Abstract
Nintedanib is a new triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. Evidence about its efficacy in addition to second-line chemotherapy in non-small cell lung cancer (NSCLC) has been produced by two large randomized phase III clinical trials (LUME-Lung 1 and LUME-Lung 2), conducted in patients with pretreated NSCLC, without major risk factors for bleeding. In the LUME-Lung 1, the addition of nintedanib to docetaxel significantly improved progression-free survival, which was the primary end point of the trial (3.4 vs. 2.7 months, hazard ratio: 0.79; p = 0.0019). Furthermore, a significant improvement in median overall survival (from 10.3 to 12.6 months) was observed in patients with adenocarcinoma histology, with a greater advantage in patients who progressed within 9 months after start of first-line treatment (from 7.9 to 10.9 months) and in patients who were most refractory to first-line chemotherapy (from 6.3 to 9.8 months). Adverse events were more common in the docetaxel plus nintedanib group, and they included diarrhea and increased liver enzymes, while no statistically significant increase in the incidence of bleeding and hypertension events by the addition of nintedanib was observed. On these bases, the combination of docetaxel and nintedanib can be considered a new option for the second-line treatment for patients with advanced NSCLC with adenocarcinoma histology. Future challenges are the identification of predictive factors to help the decision of using nintedanib in eligible patients.
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Affiliation(s)
- Anna Manzo
- Thoracic Medical Oncology, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS , Napoli , Italy
| | - Guido Carillio
- Department of Oncology and Hematology, Azienda Ospedaliera Pugliese-Ciaccio , Catanzaro , Italy
| | - Agnese Montanino
- Thoracic Medical Oncology, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS , Napoli , Italy
| | - Raffaele Costanzo
- Thoracic Medical Oncology, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS , Napoli , Italy
| | - Claudia Sandomenico
- Thoracic Medical Oncology, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS , Napoli , Italy
| | - Gaetano Rocco
- Thoracic Surgery, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS , Napoli , Italy
| | - Alessandro Morabito
- Thoracic Medical Oncology, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS , Napoli , Italy
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28
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Huang Q, Duan L, Qian X, Fan J, Lv Z, Zhang X, Han J, Wu F, Guo M, Hu G, Du J, Chen C, Jin Y. IL-17 Promotes Angiogenic Factors IL-6, IL-8, and Vegf Production via Stat1 in Lung Adenocarcinoma. Sci Rep 2016; 6:36551. [PMID: 27819281 PMCID: PMC5098156 DOI: 10.1038/srep36551] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 10/18/2016] [Indexed: 01/07/2023] Open
Abstract
Inflammation and angiogenesis are two hallmarks of carcinoma. The proinflammatory cytokine interleukin-17 (IL-17) facilitates angiogenesis in lung cancer; however, the underlying mechanism is not fully understood. In this study, tumour microvessel density (MVD) was positively associated with IL-17, interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial cell growth factor (VEGF) expression in human lung adenocarcinoma tissues, and it was increased in tumour tissues of A549-IL-17 cell-bearing nude mice. Importantly, positive correlations were also detected between IL-17 expression and IL-6, IL-8 and VEGF expression in human lung adenocarcinoma tissues. Furthermore, IL-6, IL-8 and VEGF production, as well as STAT1 phosphorylation, were increased in tumour tissues of A549-IL-17 cell-bearing nude mice in vivo and in A549 and H292 cells following IL-17 stimulation in vitro. In addition, STAT1 knockdown using an inhibitor and siRNA attenuated the IL-17-mediated increases in IL-6, IL-8 and VEGF expression in A549 and H292 cells. In conclusion, IL-17 may promote the production of the angiogenic inducers IL-6, IL-8 and VEGF via STAT1 signalling in lung adenocarcinoma.
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Affiliation(s)
- Qi Huang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Limin Duan
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Xin Qian
- Department of Respiratory Medicine, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, Hubei, 442000, P.R. China
| | - Jinshuo Fan
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Zhilei Lv
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Xiuxiu Zhang
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jieli Han
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Feng Wu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Mengfei Guo
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Guorong Hu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
| | - Jiao Du
- Zhongshan Hospital, Xiamen University, 201-209 Hubin Road, Xiamen, Fujian, 361004, P.R. China
| | - Caiyun Chen
- Department of Respiratory Medicine,the First Hospital of Xi'an City, Xi'an, Shanxi, 710002, P.R. China
| | - Yang Jin
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
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29
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Benzophenone-3 increases metastasis potential in lung cancer cells via epithelial to mesenchymal transition. Cell Biol Toxicol 2016; 33:251-261. [DOI: 10.1007/s10565-016-9368-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 10/19/2016] [Indexed: 01/06/2023]
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30
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Park K, Kim JH, Cho EK, Kang JH, Shih JY, Zimmermann AH, Lee P, Alexandris E, Puri T, Orlando M. East Asian Subgroup Analysis of a Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-small Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL). Cancer Res Treat 2016; 48:1177-1186. [PMID: 26910471 PMCID: PMC5080808 DOI: 10.4143/crt.2015.401] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 01/26/2016] [Indexed: 12/31/2022] Open
Abstract
PURPOSE REVEL demonstrated improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) with docetaxel+ramucirumab versus docetaxel+placebo in 1,253 intent-to-treat (ITT) stage IV non-small cell lung cancer patients with disease progression following platinum-based chemotherapy. Results from the East Asian subgroup analysis are reported. MATERIALS AND METHODS Subgroup analyses were performed in the East Asian ITT population (n=89). Kaplan-Meier analysis and Cox proportional hazards regression were performed for OS and PFS, and the Cochran-Mantel-Haenszel test was performed for response rate. RESULTS In docetaxel+ramucirumab (n=43) versus docetaxel+placebo (n=46), median OS was 15.44 months versus 10.17 months (hazard ratio [HR], 0.762; 95% confidence interval [CI], 0.444 to 1.307), median PFS was 4.88 months versus 2.79 months (HR, 0.658; 95% CI, 0.408 to 1.060), and ORR was 25.6% (95% CI, 13.5 to 41.2) versus 8.7% (95% CI, 2.4 to 20.8). Due to increased incidence of neutropenia and febrile neutropenia in East Asian patients, starting dose of docetaxel was reduced for newly enrolled East Asian patients (75 to 60 mg/m2, n=24). In docetaxel+ramucirumab versus docetaxel+placebo, incidence of neutropenia was 84.4% versus 72.7% (75 mg/m2) and 54.5% versus 38.5% (60 mg/m2). Incidence of febrile neutropenia was 43.8% versus 12.1% (75 mg/m2) and 0% versus 7.7% (60 mg/m2). CONCLUSION Results of this subgroup analysis showed a trend favoring ramucirumab+docetaxel for median OS, PFS, and improved ORR in East Asian patients, consistent with ITT population results. Reduction of starting dose of docetaxel in East Asian patients was associated with improved safety.
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Affiliation(s)
- Keunchil Park
- Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joo-Hang Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Eun Kyung Cho
- Division of Hematology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea
| | - Jin-Hyoung Kang
- Department of Medical Oncology, College of Medicine, The Catholic University of Korea, St. Mary’s Hospital, Seoul, Korea
| | - Jin-Yuan Shih
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Pablo Lee
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Tarun Puri
- Eli Lilly and Company, Gurgaon, Haryana, India
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Chen J, Chen J, Wu X, Shi T, Kang M. Efficacy of targeted agents in the treatment of elderly patients with advanced non-small-cell lung cancer: a systematic review and meta-analysis. Onco Targets Ther 2016; 9:4797-803. [PMID: 27536143 PMCID: PMC4976916 DOI: 10.2147/ott.s100618] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Purpose The efficacy of targeted agents (TAs) in the treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. We aimed to assess the efficacy of TAs in the treatment of advanced NSCLC in this setting. Materials and methods Relevant trials were identified by searching electronic databases and conference meetings. Prospective randomized controlled trials assessing chemotherapies with or without TAs in elderly patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS) and progression-free survival (PFS) in elderly patients with advanced NSCLC. Results A total of 4,093 elderly patients from 17 randomized controlled trials were included for analysis. The addition of TAs to chemotherapy significantly improved PFS (hazard ratio [HR] 0.85, 95% confidence interval [CI]: 0.75–0.96, P=0.01) when compared to chemotherapy alone. There was also a tendency to improve OS in the combination groups (HR 0.92, 95% CI: 0.85–1.01, P=0.064). Subgroup analysis based on treatment line indicated that TAs plus chemotherapy as first-line chemotherapy in elderly patients with advanced NSCLC significantly improved PFS (HR 0.80, 95% CI: 0.68–0.95, P=0.01) and OS (HR 0.91, 95% CI: 0.83–0.99, P=0.037), while the use of TA-containing regimens as second-line therapy in these patients did not significantly improve PFS (HR 0.91, 95% CI: 0.75–1.10, P=0.33) and OS (HR 1.04, 95% CI: 0.81–1.33, P=0.77) in comparison with chemotherapy alone. No publication bias was detected by Begg’s and Egger’s tests for OS. Conclusion The findings of this study suggest that the addition of TAs to first-line chemotherapy in elderly patients with advanced NSCLC offers an improved PFS and OS. Further trials are recommended to clearly investigate the efficacy of adding specific TAs to first-line chemotherapy for advanced NSCLC in this setting.
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Affiliation(s)
- Jianqing Chen
- Department of Medical Oncology, The Affiliated Chenggong Hospital, Xiamen University, Xiamen, Fujian Province, People's Republic of China
| | - Jianbo Chen
- Department of Medical Oncology, The Affiliated Chenggong Hospital, Xiamen University, Xiamen, Fujian Province, People's Republic of China
| | - Xiaoan Wu
- Department of Medical Oncology, The Affiliated Chenggong Hospital, Xiamen University, Xiamen, Fujian Province, People's Republic of China
| | - Tao Shi
- Department of Medical Oncology, The Affiliated Chenggong Hospital, Xiamen University, Xiamen, Fujian Province, People's Republic of China
| | - Meiling Kang
- Department of Medical Oncology, The Affiliated Chenggong Hospital, Xiamen University, Xiamen, Fujian Province, People's Republic of China
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Koufos N, Syrios J, Michailidou D, Xynos ID, Lazaris A, Kavantzas N, Tomos P, Kakaris S, Kosmas C, Tsavaris N. Distinct patterns of angiogenic factor expression as a predictive factor of response to chemotherapy in stage IIIA non-small-cell lung cancer patients. Mol Clin Oncol 2016; 5:440-446. [PMID: 27699040 DOI: 10.3892/mco.2016.966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 02/03/2016] [Indexed: 11/06/2022] Open
Abstract
The expression of various angiogenic factors was assessed in tumour samples of patients with stage III non-small-cell lung cancer (NSCLC) and further evaluated in terms of response to induction paclitaxel-ifosfamide-cisplatin chemotherapy. Freshly isolated lung tumour specimens obtained by bronchoscopy from 70 stage IIIA NSCLC chemotherapy-naïve patients were sampled and analysed for vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2 and VEGFR-3. Microvessel density was assessed through evaluating the angiogenic markers CD34 and CD105. Immunostaining scores were calculated by multiplying the percentage of labeled cells by the intensity of staining for each examined parameter. The overall mean immunostaining score value from all NSCLC samples was 7.83, 5.56 and 15.86 for VEGFR-1, VEGFR-2 and VEGFR-3, respectively. The overall mean value of the endothelial antigen CD34 was 16.29, whereas the expression of the CD105 antigen in endothelial cells yielded a multivariate distribution. Patients who responded to chemotherapy expressed significantly higher VEGFR-1 and VEGFR-3 mean values compared with non-responders (P<0.001). No significant difference was noted in VEGFR-2 mean values between these two groups (P=0.06). The CD34 mean value was significantly higher in responders (P<0.001), whereas there was no significant difference in CD105 expression between the two groups (P=0.07). Angiogenic marker expression proved to be a potential predictive factor of response to chemotherapy in stage III NSCLC. which merits further investigation.
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Affiliation(s)
- Nikolaos Koufos
- Oncology Unit, Department of Pathophysiology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - John Syrios
- 2nd Department of Medical Oncology, 'St. Savvas' Cancer Hospital, 11522 Athens, Greece
| | - Despina Michailidou
- Oncology Unit, Department of Pathophysiology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioannis D Xynos
- Imperial Clinical Trials Unit-Cancer, Department of Surgery and Cancer, Charing Cross Hospital, Imperial College, London W6 8RF, UK
| | - Andreas Lazaris
- 1st Department of Pathology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nicolaos Kavantzas
- 1st Department of Pathology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Periclis Tomos
- 2nd Department of Propedeutic Surgery, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Stamatis Kakaris
- 1st Department of Thoracic Surgery, 'Sotiria' General Hospital of Chest Diseases, 11527 Athens, Greece
| | - Christos Kosmas
- 2nd Division of Medical Oncology, Department of Medicine, Metaxa Cancer Hospital, 18537 Piraeus, Greece
| | - Nikolas Tsavaris
- Oncology Unit, Department of Pathophysiology, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece
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de Marinis F, Bria E, Ciardiello F, Crinò L, Douillard JY, Griesinger F, Lambrechts D, Perol M, Ramalingam SS, Smit EF, Gridelli C. International Experts Panel Meeting of the Italian Association of Thoracic Oncology on Antiangiogenetic Drugs for Non-Small Cell Lung Cancer: Realities and Hopes. J Thorac Oncol 2016; 11:1153-69. [PMID: 27063293 DOI: 10.1016/j.jtho.2016.03.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/07/2016] [Accepted: 03/26/2016] [Indexed: 12/21/2022]
Abstract
Angiogenesis, one of the hallmarks of cancer, occurs when new blood vessels feed malignant cells, providing oxygen and nutrients, promoting tumor growth, and allowing tumor cells to escape into the circulation, thus leading to metastases. To date, a series of antiangiogenic drugs (either monoclonal antibodies or small molecules) have been approved by regulatory agencies for the treatment of advanced non-small cell lung cancer, and they are currently available for both first- and second-line therapy. The overall benefit of these drugs seems modest (although clearly significant), especially when administered as a single agent, and there is no clear consensus with regard to which patients should be candidates to receive these drugs across the different disease settings. From the biological perspective, angiogenesis represents a difficult and complex process to explore, given the interference with other key pathways and the dynamic evolution during the disease's history. Indeed, this process is complicated by the presence of multiple targets to hit, polymorphisms, hypoxia-dependent modifications, and epigenetics. These difficulties do not allow capture of which specific key pathways can be identified as biomarkers of efficacy so as to maximize to overall benefit of such drugs. An International Experts Panel Meeting was inspired by the absence of clear recommendations to address which patients should receive antiangiogenic drugs in the context of advanced non-small cell lung cancer so as to support decisions for clinical practice on a daily basis and determine priorities for future research. After a literature review and panelists consensus, a series of recommendations were defined to support decisions for the daily clinical practice and to indicate a potential road map for translational research.
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Affiliation(s)
- Filippo de Marinis
- Thoracic Oncology Division, European Institute of Oncology, Milan, Italy
| | - Emilio Bria
- Medical Oncology, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Fortunato Ciardiello
- Medical Oncology, Department of Clinical and Experimental Medicine 'F. Magrassi e A. Lanzara, Second University of Naples, Naples, Italy
| | - Lucio Crinò
- Medical Oncology Division, S. Maria della Misericordia Hospital, Perugia, Italy
| | | | - Frank Griesinger
- Department of Hematology and Oncology, University Division, Internal Medicine-Oncology, Pius-Hospital Oldenburg, University of Oldenburg, Germany
| | - Diether Lambrechts
- VIB Vesalius Research Center, Department of Oncology, University of Leuven, Belgium
| | - Maurice Perol
- Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France
| | | | - Egbert F Smit
- Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Cesare Gridelli
- Medical Oncology, A.O. 'S.G. Moscati' Hospital, Avellino, Italy.
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Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:13. [PMID: 26791086 PMCID: PMC4721009 DOI: 10.1186/s13046-016-0293-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 01/13/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Interleukin-37 (IL-37), a newly identified member of the IL-1 family, has been known to play an immunosuppressive role in a variety of inflammatory disorders, but whether it participates in the regulation of pathogenesis of non-small cell lung cancer (NSCLC) has not been investigated. METHODS Real-time polymerase chain reaction (PCR), western blotting, and immunohistochemical staining were employed to detect IL-37 expression in NSCLC tissues and corresponding adjacent tissues. The correlations between IL-37 expression and clinicopathological characteristics, prognosis were analyzed. Stable clone with overexpression of IL-37 was generated in H1299 cell lines. Cell growth, cell cycle and cell apoptosis assays were carried out for detecting proliferation and apoptosis of H1299 cells. The effects of IL-37 on NSCLC progression in vivo was performed in a xenografted lung tumor model in nude mice. The concentrations of IL-37 and VEGF in the s growth medium supernatants were quantified by ELISA. The antiangiogenic effect of IL-37 on HUVEC was measured by tube formation assay. RESULTS IL-37 mRNA and protein expressions were significantly decreased in NSCLC tissues, and decreased intratumoral IL-37 expression was significantly associated with tumor state, TNM stage and poor prognosis in NSCLC patients. In addition, intratumoral IL-37 expression was an independent prognostic factors for Overall survival (hazard ratio = 2.047; P = 0.011). Overexpression of IL-37 exerted no direct effect on cell proliferation and apoptosis of H1299 lung cancer cells in vitro, but significantly inhibited tumor growth in a H1299 xenograft model in vivo. Furthermore, there was no significant change in immune cell infiltration in IL-37 over-expressing tumors; instead, we found decreased microvessel density (MVD) and VEGF levels in IL-37-expressing tumors. Additional studies showed IL-37 could directly inhibit HUVEC cells growth and capillary structure formation. Finally, we found that decreased IL-37 expression was associated with high MVD in NSCLC patients. CONCLUSIONS Our findings demonstrate a protective role for IL-37 in lung cancer development, possibly through inhibiting tumor angiogenesis. IL-37 could serve as a promising therapeutic target for NSCLC.
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Hohenforst-Schmidt W, Zarogoulidis P, Pitsiou G, Linsmeier B, Tsavlis D, Kioumis I, Papadaki E, Freitag L, Tsiouda T, Turner JF, Browning R, Simoff M, Sachpekidis N, Tsakiridis K, Zaric B, Yarmus L, Baka S, Stratakos G, Rittger H. Drug Eluting Stents for Malignant Airway Obstruction: A Critical Review of the Literature. J Cancer 2016; 7:377-90. [PMID: 26918052 PMCID: PMC4749359 DOI: 10.7150/jca.13611] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 11/01/2015] [Indexed: 02/07/2023] Open
Abstract
Lung cancer being the most prevalent malignancy in men and the 3(rd) most frequent in women is still associated with dismal prognosis due to advanced disease at the time of diagnosis. Novel targeted therapies are already on the market and several others are under investigation. However non-specific cytotoxic agents still remain the cornerstone of treatment for many patients. Central airways stenosis or obstruction may often complicate and decrease quality of life and survival of these patients. Interventional pulmonology modalities (mainly debulking and stent placement) can alleviate symptoms related to airways stenosis and improve the quality of life of patients. Mitomycin C and sirolimus have been observed to assist a successful stent placement by reducing granuloma tissue formation. Additionally, these drugs enhance the normal tissue ability against cancer cell infiltration. In this mini review we will concentrate on mitomycin C and sirolimus and their use in stent placement.
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Affiliation(s)
| | - Paul Zarogoulidis
- 2. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgia Pitsiou
- 2. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Bernd Linsmeier
- 3. Department of General Surgery, Coburg Clinic, Coburg, Germany
| | - Drosos Tsavlis
- 2. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Kioumis
- 2. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Papadaki
- 2. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Lutz Freitag
- 4. Department of Interventional Pneumology, Ruhrlandklinik, University Hospital Essen, University of Essen-Duisburg, Tueschener Weg 40, 45239 Essen, Germany
| | - Theodora Tsiouda
- 2. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - J Francis Turner
- 5. Division of Interventional Pulmonology & Medical Oncology, Cancer Treatment Centers of America, Western Regional Medical Center, Goodyear, AZ
| | - Robert Browning
- 6. Pulmonary & Critical Care Medicine, Interventional Pulmonology, National Naval Medical Center, Walter Reed Army Medical Center, Bethesda, U.S.A
| | - Michael Simoff
- 7. Bronchoscopy and Interventional Pulmonology, Pulmonary and Critical Care Medicine, Henry Ford Hospital, Wayne State University, School of Medicine, MI, USA
| | - Nikolaos Sachpekidis
- 8. Cardiothoracic Surgery Department, ``Saint Luke`` Private Hospital, Thessaloniki, Panorama, Greece
| | - Kosmas Tsakiridis
- 8. Cardiothoracic Surgery Department, ``Saint Luke`` Private Hospital, Thessaloniki, Panorama, Greece
| | - Bojan Zaric
- 9. Institute for Pulmonary Diseases of Vojvodina, Clinic for Thoracic Oncology, Faculty of Medicine, University of Novi Sad, Serbia
| | - Lonny Yarmus
- 10. Division of Pulmonary and Critical Care Medicine, Sheikh Zayed Cardiovascular & Critical Care Tower, Baltimore, U.S.A
| | - Sofia Baka
- 11. Oncology Department, ``Interbalkan`` European Medical Center, Thessaloniki, Greece
| | - Grigoris Stratakos
- 12. 1st Respiratory Medicine Department of National University of Athens, "Sotiria" General Hospital Athens, Greece
| | - Harald Rittger
- 1. Medical Clinic I, ''Fuerth'' Hospital, University of Erlangen, Fuerth, Germany
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Zhang J, Jiang X, Jiang Y, Guo M, Zhang S, Li J, He J, Liu J, Wang J, Ouyang L. Recent advances in the development of dual VEGFR and c-Met small molecule inhibitors as anticancer drugs. Eur J Med Chem 2015; 108:495-504. [PMID: 26717201 DOI: 10.1016/j.ejmech.2015.12.016] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 12/05/2015] [Accepted: 12/10/2015] [Indexed: 02/05/2023]
Abstract
Vascular endothelial growth factor receptor (VEGFR) is a very important receptor tyrosine kinase (RTK) that can induce angiogenesis, increase cell growth and metastasis, reduce apoptosis, alter cytoskeletal function, and affect other biologic changes. Moreover, it is identified to be deregulated in varieties of human cancers. Therefore, VEGFR turn out to be a remarkable target of significant types of anticancer drugs in clinical trials. On the other side, c-Met is the receptor of hepatocyte growth factor (HGF) and a receptor tyrosine kinase. Previous studies have shown that c-Met elicits many different signaling pathways mediating cell proliferation, migration, differentiation, and survival. Furthermore, the correlation between aberrant signaling of the HGF/c-Met pathway and aggressive tumor growth, poor prognosis in cancer patients has been established. Recent reports had shown that c-Met/HGF and VEGFR/VEGF (vascular endothelial growth factor) can act synergistically in the progression of many diseases. They were also found to be over expressed in many human cancers. Thus, in a variety of malignancies, VEGFR and c-Met receptor tyrosine kinases have acted as therapeutic targets. With the development of molecular biology techniques, further understanding of the human tumor disease pathogenesis and interrelated signaling pathways known to tumor cells, using a single target inhibitors have been difficult to achieve the desired therapeutic effect. At this point, with respect to the combination of two inhibitors, a single compound which is able to inhibit both VEGFR and c-Met may put forward the advantage of raising anticancer activity. With the strong interest in these compounds, this review represents a renewal of previous works on the development of dual VEGFR and c-Met small molecule inhibitors as novel anti-cancer agents. Newly collection derivatives have been mainly describing in their biological profiles and chemical structures.
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Affiliation(s)
- Jin Zhang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiangdong Jiang
- Department of Information Engineering, Chongqing Vocational Institute of Safety Technology, Chongqing, 404020, China
| | - Yingnan Jiang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingrui Guo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Shouyue Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jingjing Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jun He
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Jinhui Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
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Frezzetti D, Gallo M, Roma C, D'Alessio A, Maiello MR, Bevilacqua S, Normanno N, De Luca A. Vascular Endothelial Growth Factor A Regulates the Secretion of Different Angiogenic Factors in Lung Cancer Cells. J Cell Physiol 2015; 231:1514-21. [DOI: 10.1002/jcp.25243] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Daniela Frezzetti
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Marianna Gallo
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Cristin Roma
- Laboratory of Pharmacogenomics; Centro di Ricerche Oncologiche di Mercogliano (CROM)-Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Amelia D'Alessio
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Monica R. Maiello
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Simona Bevilacqua
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Nicola Normanno
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
| | - Antonella De Luca
- Cell Biology and Biotherapy Unit; Istituto Nazionale Tumori “Fondazione G. Pascale”-IRCCS; Naples Italy
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Coelho AL, Araújo AM, Gomes MP, Catarino RJ, Andrade EB, Lopes AM, Medeiros RM. Combined Ang-2 and VEGF serum levels: holding hands as a new integral biomarker in non-small-cell lung cancers. Future Oncol 2015; 11:3233-42. [PMID: 26562248 DOI: 10.2217/fon.15.207] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
AIM Evaluate if serum levels of VEGF and Ang-2 are correlated in non-small-cell lung cancers (NSCLCs) and its implications in the diagnostic and prognostic of the disease. PATIENTS & METHODS Unselected cohort of 145 NSCLC patients and 30 control individuals. The serum levels of Ang-2 and VEGF of each patient were measured by ELISA prior to treatment. RESULTS & CONCLUSIONS Serum levels of Ang-2 and VEGF are correlated (p < 0.0001). High serum levels of Ang-2 and VEGF isolated and both combined (high(Ang-2/VEGF)) correlate with likelihood of presenting NSCLC (p = 0.016; p = 0.003; p < 0.0001, respectively). Serum levels of Ang-2 and high(Ang-2/VEGF) but not VEGF alone are independent prognostic factors (p = 0.001; p = 0.619; p = 0.005). High(Ang-2/VEGF) serum levels could be exploited as a new valuable integral biomarker in NSCLC.
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Affiliation(s)
- Ana Luísa Coelho
- Instituto Português de Oncologia - Porto, Molecular Oncology Group, Portugal.,Faculdade de Medicina - University of Porto, Porto, Portugal
| | - António Manuel Araújo
- Centro Hospitalar do Porto - Medical Oncology Department, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar - University of Porto, Porto, Portugal
| | - Mónica Patrícia Gomes
- Instituto Português de Oncologia - Porto, Molecular Oncology Group, Portugal.,Instituto de Ciências Biomédicas Abel Salazar - University of Porto, Porto, Portugal
| | - Raquel Jorge Catarino
- Instituto Português de Oncologia - Porto, Molecular Oncology Group, Portugal.,Instituto de Ciências Biomédicas Abel Salazar - University of Porto, Porto, Portugal
| | - Elva Bonifácio Andrade
- Instituto de Biologia Molecular e Celular - Immunobiology Research Group, Porto, Portugal
| | - Agostinho Marques Lopes
- Faculdade de Medicina - University of Porto, Porto, Portugal.,Centro Hospitalar de S. João - Pulmonology Department, Porto, Portugal
| | - Rui Manuel Medeiros
- Instituto Português de Oncologia - Porto, Molecular Oncology Group, Portugal.,Instituto de Ciências Biomédicas Abel Salazar - University of Porto, Porto, Portugal.,Liga Portuguesa Contra o Cancro (NRNorte) - Research Department, Porto, Portugal
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Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial. Lung Cancer 2015; 90:288-95. [DOI: 10.1016/j.lungcan.2015.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 09/02/2015] [Accepted: 09/05/2015] [Indexed: 01/10/2023]
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Sheng J, Yang YP, Yang BJ, Zhao YY, Ma YX, Hong SD, Zhang YX, Zhao HY, Huang Y, Zhang L. Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer: A Meta-Analysis and Systemic Review. Medicine (Baltimore) 2015; 94:e1282. [PMID: 26252298 PMCID: PMC4616571 DOI: 10.1097/md.0000000000001282] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 06/29/2015] [Accepted: 07/01/2015] [Indexed: 12/21/2022] Open
Abstract
Preclinical researches indicated a potential synergistic effect of taxanes-containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta-analyses.Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2.A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87-0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71-0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47-1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08-1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82-0.96, P = 0.02) as well as application in second-line (HR 0.91, 95% CI 0.85-0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable.In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future.
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Affiliation(s)
- Jin Sheng
- From the Department of Medical Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; and Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Trichostatin A suppresses lung adenocarcinoma development in Grg1 overexpressing transgenic mice. Biochem Biophys Res Commun 2015; 463:1230-6. [PMID: 26086099 DOI: 10.1016/j.bbrc.2015.06.090] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 06/12/2015] [Indexed: 12/22/2022]
Abstract
Trichostatin A (TSA) is a histone deacetylase inhibitor and a potential therapeutic for various malignancies. The in vivo effect of TSA, however, has not been investigated in a transgenic lung cancer model. Previously, we generated transgenic mice with overexpression of Groucho-related-gene 1 (Grg1) and these mice all developed mucinous lung adenocarcinoma. Grg1 is a transcriptional co-repressor protein, the function of which is thought to depend on HDAC activity. However, functions outside the nucleus have also been proposed. We tested the supposition that Grg1-induced tumorigenesis is HDAC-dependent by assaying the therapeutic effect of TSA in the Grg1 transgenic mouse model. We found that TSA significantly inhibited lung tumorigenesis in Grg1 transgenic mice (p < 0.01). TSA did not affect overall Grg1 protein levels, but instead reduced ErbB1 and ErbB2 expression, which are upregulated by Grg1 in the absence of TSA. We confirmed this effect in A549 cells. Furthermore, lapatinib, an inhibitor of both ErbB1 and ErbB2, effectively masked the effect of TSA on the inhibition of A549 cell proliferation and migration, suggesting TSA does work, at least in part, by downregulating ErbB receptors. We additionally found that TSA reduced the expression of VEGF and VEGFR2, but not basic FGF and FGFR1. Our findings indicate that TSA effectively inhibits Grg1-induced lung tumorigenesis through the down-regulation of ErbB1 and ErbB2, as well as reduced VEGF signaling. This suggests TSA and other HDAC inhibitors could have therapeutic value in the treatment of lung cancers with Grg1 overexpression.
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Sadiq MA, Hanout M, Sarwar S, Hassan M, Do DV, Nguyen QD, Sepah YJ. Platelet derived growth factor inhibitors: A potential therapeutic approach for ocular neovascularization. Saudi J Ophthalmol 2015; 29:287-91. [PMID: 26586980 PMCID: PMC4625223 DOI: 10.1016/j.sjopt.2015.05.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 04/15/2015] [Accepted: 05/09/2015] [Indexed: 11/28/2022] Open
Abstract
Retinochoroidal vascular diseases are the leading causes of blindness in the developed world. They include diabetic retinopathy (DR), retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration (AMD), and pathological myopia, among many others. Several different therapies are currently under consideration for the aforementioned disorders. In the following section, agents targeting platelet-derived growth factor (PDGF) are discussed as a potential therapeutic option for retinochoroidal vascular diseases. PDGF plays an important role in the angiogenesis cascade that is activated in retinochoroidal vascular diseases. The mechanism of action, side effects, efficacy, and the potential synergistic role of these agents in combination with other treatment options is discussed. The future of treatment of retinochoroidal vascular diseases, particularly AMD, has become more exciting due to agents such as PDGF antagonists.
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Affiliation(s)
- Mohammad Ali Sadiq
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mostafa Hanout
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Salman Sarwar
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Muhammad Hassan
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Diana V Do
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Quan Dong Nguyen
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yasir Jamal Sepah
- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA
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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: 425] [Impact Index Per Article: 42.5] [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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Nintedanib: A Review of Its Use as Second-Line Treatment in Adults with Advanced Non-Small Cell Lung Cancer of Adenocarcinoma Histology. Target Oncol 2015; 10:303-10. [DOI: 10.1007/s11523-015-0367-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Scagliotti GV, Bironzo P, Vansteenkiste JF. Addressing the unmet need in lung cancer: The potential of immuno-oncology. Cancer Treat Rev 2015; 41:465-75. [PMID: 25936526 DOI: 10.1016/j.ctrv.2015.04.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 03/19/2015] [Accepted: 04/02/2015] [Indexed: 12/15/2022]
Abstract
Chemotherapy is currently the standard of care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Furthermore, only a small percentage of patients derive benefit from later-line therapy, with most experiencing deteriorating quality of life and significant toxicities. More recently, molecular targeted therapies have provided improvements in outcomes. However, these treatments only offer a clear benefit in subsets of tumours harbouring the appropriate genomic alteration (mutation, amplification, translocation). Most of the genomic abnormalities susceptible to therapeutic intervention are detected in adenocarcinoma, mainly in never smokers, while alterations in the genome of other histological subtypes are known but specific agents targeting these alterations have yet to be developed. Thus, the therapeutic management of these subtypes represents an ongoing challenge. Recent advances in immunotherapy have highlighted the potential of immuno-oncology based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. This review discusses the current unmet medical needs in NSCLC, the limits of current first-line and later-line chemotherapy and targeted agents, and the emergence of new therapeutic strategies.
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Affiliation(s)
- G V Scagliotti
- University of Torino, Department of Oncology, Orbassano, Torino, Italy.
| | - P Bironzo
- University of Torino, Department of Oncology, Orbassano, Torino, Italy
| | - J F Vansteenkiste
- Respiratory Oncology Unit and Trial Unit, Department of Pulmonology, University Hospitals KU Leuven, Leuven, Belgium
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Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J 2015; 45:1434-45. [PMID: 25745043 PMCID: PMC4416110 DOI: 10.1183/09031936.00174914] [Citation(s) in RCA: 663] [Impact Index Per Article: 66.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 01/05/2015] [Indexed: 12/21/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease characterised by fibrosis of the lung parenchyma and loss of lung function. Although the pathogenic pathways involved in IPF have not been fully elucidated, IPF is believed to be caused by repetitive alveolar epithelial cell injury and dysregulated repair, in which there is uncontrolled proliferation of lung fibroblasts and differentiation of fibroblasts into myofibroblasts, which excessively deposit extracellular matrix (ECM) proteins in the interstitial space. A number of profibrotic mediators including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and transforming growth factor-β are believed to play important roles in the pathogenesis of IPF. Nintedanib is a potent small molecule inhibitor of the receptor tyrosine kinases PDGF receptor, FGF receptor and vascular endothelial growth factor receptor. Data from in vitro studies have shown that nintedanib interferes with processes active in fibrosis such as fibroblast proliferation, migration and differentiation, and the secretion of ECM. In addition, nintedanib has shown consistent anti-fibrotic and anti-inflammatory activity in animal models of lung fibrosis. These data provide a strong rationale for the clinical efficacy of nintedanib in patients with IPF, which has recently been demonstrated in phase III clinical trials. Nintedanib interferes with processes active in fibrosis, e.g. fibroblast proliferation, migration anddifferentiationhttp://ow.ly/Iae9z
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Affiliation(s)
- Lutz Wollin
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | - Eva Wex
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Gisela Schnapp
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - Susanne Stowasser
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany
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Huang Y, Carbone DP. Mechanisms of and strategies for overcoming resistance to anti-vascular endothelial growth factor therapy in non-small cell lung cancer. Biochim Biophys Acta Rev Cancer 2015; 1855:193-201. [PMID: 25598052 DOI: 10.1016/j.bbcan.2015.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 01/05/2015] [Accepted: 01/08/2015] [Indexed: 11/15/2022]
Abstract
Sustained angiogenesis is a hallmark of cancer. Because of the primary role of vascular endothelial growth factors (VEGFs) and their receptors in angiogenesis, VEGF-targeted agents have been developed to inhibit these signaling processes in non-small cell lung cancer (NSCLC). However, the clinical benefits are transient and resistance often rapidly develops. Insights into the molecular mechanisms of resistance would help to develop novel strategies to improve the efficacy of antiangiogenic therapies. This review discusses the mechanisms of resistance to anti-VEGF therapy and the postulated strategies to optimize antiangiogenic therapy. A number of multitargeted tyrosine kinase inhibitors currently in phase III clinical development for NSCLC are summarized. The emerging combination of antiangiogenic therapy with tumor immunotherapy is also discussed.
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Affiliation(s)
- Yuhui Huang
- Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Department of Cancer Biology, Mayo Clinic Florida, Griffin Building Room 321B, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
| | - David P Carbone
- The Ohio State University Medical Center, Columbus, OH, USA.
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Rijavec E, Genova C, Barletta G, Biello F, Dal Bello MG, Coco S, Truini A, Vanni I, Alama A, Boccardo F, Grossi F. Efficacy of motesanib diphosphate in non-small-cell lung cancer. Expert Opin Pharmacother 2014; 15:1771-80. [PMID: 25032887 DOI: 10.1517/14656566.2014.938639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Angiogenesis plays a crucial role in the proliferation and in the metastatic spread of tumour cells. Several agents with anti-angiogenic activity have been tested in advanced non-small-cell lung cancer (NSCLC) patients. Motesanib (AMG 706) is a promising anti-angiogenic multi-targeted tyrosine kinase inhibitor (TKI), which has been investigated as a monotherapy or in combination with chemotherapy, in several types of cancer. AREAS COVERED We have reviewed the literature, and we have presented the results of clinical trials that have investigated the administration of motesanib in advanced NSCLC patients. EXPERT OPINION Encouraging results have been described with the administration of motesanib as first-line treatment in combination with carboplatin and paclitaxel in Asian patients with non-squamous advanced NSCLC. Further studies are needed in order to identify the predictive biomarkers of response and to select patients who may benefit from this anti-angiogenic treatment.
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Affiliation(s)
- Erika Rijavec
- IRCCS AOU San Martino IST - Istituto Nazionale per la Ricerca sul Cancro, UOS Tumori Polmonari , Largo Rosanna Benzi No 10, 16132 Genova , Italy +39 0105600665 ; +39 0105600795 ;
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Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384:665-73. [PMID: 24933332 DOI: 10.1016/s0140-6736(14)60845-x] [Citation(s) in RCA: 913] [Impact Index Per Article: 83.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Ramucirumab is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. We aimed to assess efficacy and safety of treatment with docetaxel plus ramucirumab or placebo as second-line treatment for patients with stage IV non-small-cell-lung cancer (NSCLC) after platinum-based therapy. METHODS In this multicentre, double-blind, randomised phase 3 trial (REVEL), we enrolled patients with squamous or non-squamous NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen. Patients were randomly allocated (1:1) with a centralised, interactive voice-response system (stratified by sex, region, performance status, and previous maintenance therapy [yes vs no]) to receive docetaxel 75 mg/m(2) and either ramucirumab (10 mg/kg) or placebo on day 1 of a 21 day cycle until disease progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was overall survival in all patients allocated to treatment. We assessed adverse events according to treatment received. This study is registered with ClinicalTrials.gov, number NCT01168973. FINDINGS Between Dec 3, 2010, and Jan 24, 2013, we screened 1825 patients, of whom 1253 patients were randomly allocated to treatment. Median overall survival was 10·5 months (IQR 5·1-21·2) for 628 patients allocated ramucirumab plus docetaxel and 9·1 months (4·2-18·0) for 625 patients who received placebo plus docetaxel (hazard ratio 0·86, 95% CI 0·75-0·98; p=0·023). Median progression-free survival was 4·5 months (IQR 2·3-8·3) for the ramucirumab group compared with 3·0 months (1·4-6·9) for the control group (0·76, 0·68-0·86; p<0·0001). We noted treatment-emergent adverse events in 613 (98%) of 627 patients in the ramucirumab safety population and 594 (95%) of 618 patients in the control safety population. The most common grade 3 or worse adverse events were neutropenia (306 patients [49%] in the ramucirumab group vs 246 [40%] in the control group), febrile neutropenia (100 [16%] vs 62 [10%]), fatigue (88 [14%] vs 65 [10%]), leucopenia (86 [14%] vs 77 [12%]), and hypertension (35 [6%] vs 13 [2%]). The numbers of deaths from adverse events (31 [5%] vs 35 [6%]) and grade 3 or worse pulmonary haemorrhage (eight [1%] vs eight [1%]) did not differ between groups. Toxicities were manageable with appropriate dose reductions and supportive care. INTERPRETATION Ramucirumab plus docetaxel improves survival as second-line treatment of patients with stage IV NSCLC. FUNDING Eli Lilly.
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Affiliation(s)
- Edward B Garon
- David Geffen School of Medicine at UCLA/Translational Research in Oncology-US Network, Los Angeles, CA, USA.
| | - Tudor-Eliade Ciuleanu
- Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Oscar Arrieta
- Instituto Nacional de Cancerologia (INCAN), Mexico City, Mexico
| | | | | | | | - Keunchil Park
- Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Vera Gorbunova
- Department of Chemotherapy, N N Blokhin Cancer Research Center, Moscow, Russia
| | | | | | | | | | | | - Michael Thomas
- Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Paolo Bidoli
- Medical Oncology, San Gerardo Hospital, Monza, Italy
| | | | - Steven Gans
- St Jansdal Hospital, Herderwijk, Netherlands
| | - Joo-Hang Kim
- Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea
| | | | - Nina Karaseva
- City Clinical Oncology Dispensary, St Petersburg, Russia
| | - Martin Reck
- LungenClinic Grosshansdorf, German Center for Lung Research (DZL), Grosshansdorf, Germany
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Kotsinas A, Papanagnou P, Evangelou K, Trigas GC, Kostourou V, Townsend P, Gorgoulis VG. ARF: a versatile DNA damage response ally at the crossroads of development and tumorigenesis. Front Genet 2014; 5:236. [PMID: 25101116 PMCID: PMC4106421 DOI: 10.3389/fgene.2014.00236] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 07/03/2014] [Indexed: 11/13/2022] Open
Abstract
Alternative reading frame (ARF) is a tumor suppressor protein that senses oncogenic and other stressogenic signals. It can trigger p53-dependent and -independent responses with cell cycle arrest and apoptosis induction being the most prominent ones. Other ARF activities, particularly p53-independent ones, that could help in understanding cancer development and provide potential therapeutic exploitation are underrated. Although ARF is generally not expressed in normal tissues, it is essential for ocular and male germ cells development. The underlying mechanism(s) in these processes, while not clearly defined, point toward a functional link between ARF, DNA damage and angiogenesis. Based on a recent study from our group demonstrating a functional interplay between ataxia-telangiectasia mutated (ATM) and ARF during carcinogenesis, we discuss the role of ARF at the crossroads of cancer and developmental processes.
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Affiliation(s)
- Athanassios Kotsinas
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens Athens, Greece
| | - Panagiota Papanagnou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens Athens, Greece
| | - Konstantinos Evangelou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens Athens, Greece
| | - George C Trigas
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens Athens, Greece
| | - Vassiliki Kostourou
- Vascular Adhesion Lab, Biomedical Sciences Research Center Alexander Fleming Athens, Greece
| | - Paul Townsend
- Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre Manchester, UK ; Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre Manchester, UK
| | - Vassilis G Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens Athens, Greece ; Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre Manchester, UK ; Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre Manchester, UK ; Biomedical Research Foundation, Academy of Athens Athens, Greece
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