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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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Neal J, Pavlakis N, Kim SW, Goto Y, Lim SM, Mountzios G, Fountzilas E, Mochalova A, Christoph DC, Bearz A, Quantin X, Palmero R, Antic V, Chun E, Edubilli TR, Lin YC, Huseni M, Ballinger M, Graupner V, Curran D, Vervaet P, Newsom-Davis T. CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy. J Clin Oncol 2024; 42:2393-2403. [PMID: 38552197 PMCID: PMC11227305 DOI: 10.1200/jco.23.02166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/04/2023] [Accepted: 02/01/2024] [Indexed: 04/28/2024] Open
Abstract
PURPOSE Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy. METHODS This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS). RESULTS One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively). CONCLUSION Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/mortality
- Docetaxel/therapeutic use
- Docetaxel/administration & dosage
- Docetaxel/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Lung Neoplasms/drug therapy
- Lung Neoplasms/pathology
- Lung Neoplasms/mortality
- Pyridines/therapeutic use
- Pyridines/administration & dosage
- Pyridines/adverse effects
- Male
- Female
- Anilides/therapeutic use
- Anilides/administration & dosage
- Anilides/adverse effects
- Middle Aged
- Aged
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/adverse effects
- Adult
- Aged, 80 and over
- Progression-Free Survival
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Affiliation(s)
- Joel Neal
- Stanford Cancer Institute, Stanford University, Palo Alto, CA
| | - Nick Pavlakis
- Royal North Shore Hospital, University of Sydney, St Leonards, Australia
| | - Sang-We Kim
- Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Sun Min Lim
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | | | | | | | - Xavier Quantin
- Montpellier Cancer Institute, Inserm U1194, University of Montpellier, Montpellier, France
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Alhadeethi A, Adel Awwad S, Abed M, Amin AM, Aboelkhier MM, Yassin MNA, Morsi MH, Kashbour MO. Nintedanib in Combination With Chemotherapy in the Treatment of Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Cureus 2024; 16:e53812. [PMID: 38465177 PMCID: PMC10924634 DOI: 10.7759/cureus.53812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 02/07/2024] [Indexed: 03/12/2024] Open
Abstract
Lung cancer remains a major global health challenge, contributing to substantial morbidity and mortality rates. Nintedanib, a tyrosine kinase inhibitor, has demonstrated potential as a treatment for lung cancer. We aim to evaluate nintedanib's efficacy in treating patients with non-small cell lung cancer (NSCLC), depending on the available evidence. Our search for relevant articles was conducted on PubMed, Cochrane Library, Scopus, and Web of Science for randomized controlled trials (RCTs) that involved adult patients with NSCLC up to August 15, 2023. These trials compared the combination of nintedanib and chemotherapy to either placebo plus chemotherapy or chemotherapy alone. Our main outcomes include progression-free survival (PFS) and overall survival (OS). We utilized the Review Manager Software V.5.4 (The Cochrane Collaboration) to analyze all relevant data. Three identified trials, which included 2270 patients, fulfilled the inclusion criteria. Our analysis showed significantly improved PFS (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.71-0.88, P < 0.0001) in patients receiving nintedanib compared to placebo. However, OS was not statistically significant (HR = 0.96; 95% CI 0.88-1.05, P = 0.35). In conclusion, a combination of nintedanib and chemotherapy in treating patients with NSCLC was associated with improved PFS than chemotherapy alone but not with improved OS. Further clinical trials assessing nintedanib in the setting of NSCLC are necessary before any further recommendations can be made.
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Affiliation(s)
- Abdulhameed Alhadeethi
- Department of General Medicine, Medical Research Group of Egypt, Negida Academy LCC, Arlington, USA
- Department of General Medicine, Al-Salam Teaching Hospital, Mosul, IRQ
| | - Sara Adel Awwad
- College of Medicine, Jordan University of Science and Technology, Irbid, JOR
| | - Mohamed Abed
- Department of Internal Medicine, Faculty of Medicine, University of Tripoli, Tripoli, LBY
| | - Ahmed Mostafa Amin
- Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, EGY
| | - Menna M Aboelkhier
- Department of Internal Medicine, Faculty of Science, Cairo University, Cairo, EGY
| | | | - Maha H Morsi
- Department of Oncology, Medical Research Group of Egypt, Negida Academy LLC, Arlington, USA
- Department of Chemical Pathology, Misr University for Science and Technology, Giza, EGY
| | - Muataz Omar Kashbour
- Department of Diagnostic Radiology, National Cancer Institute, Misrata, LBY
- Department of Radiology, Medical Research Group of Libya, Negida Research Academy, Arlington, USA
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Yan S, Xue S, Wang T, Gao R, Zeng H, Wang Q, Jia X. Efficacy and safety of nintedanib in patients with non-small cell lung cancer, and novel insights in radiation-induced lung toxicity. Front Oncol 2023; 13:1086214. [PMID: 37637045 PMCID: PMC10449572 DOI: 10.3389/fonc.2023.1086214] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Nintedanib is a tyrosine kinase inhibitor of fibroblast growth factor-, vascular endothelial growth factor-, and platelet-derived growth factor receptors. These three receptors promote new blood vessel formation and maintenance, which is essential for tumor growth and spread. Several trials have shown that nintedanib plays a substantial role in treating patients with non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis. Recently, several clinical trials of nintedanib to treat NSCLC have been reported. In this review, we focus on our current understanding of nintedanib treatment for advanced NSCLC patients and summarize the literature on using nintedanib in radiation-induced lung toxicity and the efficacy and tolerability of nintedanib.
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Affiliation(s)
| | | | | | | | | | | | - Xiaojing Jia
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
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Borcherding N, Jethava Y, Vikas P. Repurposing Anti-Cancer Drugs for COVID-19 Treatment. Drug Des Devel Ther 2020; 14:5045-5058. [PMID: 33239864 PMCID: PMC7680713 DOI: 10.2147/dddt.s282252] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 10/29/2020] [Indexed: 12/24/2022] Open
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic has caused catastrophic damage to human life across the globe along with social and financial hardships. According to the Johns Hopkins University Coronavirus Resource Center, more than 41.3 million people worldwide have been infected, and more than 1,133,000 people have died as of October 22, 2020. At present, there is no available vaccine and a scarcity of efficacious therapies. However, there is tremendous ongoing effort towards identifying effective drugs and developing novel vaccines. Early data from Adaptive COVID-19 Treatment Trials (ACTT) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and compassionate use study have shown promise for remdesivir, leading to emergency authorization by the Food and Drug Administration (FDA) for treatment of hospitalized COVID-19 patients. However, several randomized studies have now shown no benefit or increased adverse events associated with remdesivir treatment. Drug development is a time-intensive process and requires extensive safety and efficacy evaluations. In contrast, drug repurposing is a time-saving and cost-effective drug discovery strategy geared towards using existing drugs instead of de novo drug discovery. Treatments for cancer and COVID-19 often have similar goals of controlling inflammation, inhibiting cell division, and modulating the host microenvironment to control the disease. In this review, we focus on anti-cancer drugs that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials.
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Affiliation(s)
- Nicholas Borcherding
- Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, IA, USA
- Department of Pathology, University of Iowa, College of Medicine, Iowa City, IA, USA
- Cancer Biology Graduate Program, University of Iowa, College of Medicine, Iowa City, IA, USA
- Medical Scientist Training Program, University of Iowa, College of Medicine, Iowa City, IA, USA
| | - Yogesh Jethava
- Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, IA, USA
- Department of Internal Medicine, University of Iowa, College of Medicine, Iowa City, IA, USA
| | - Praveen Vikas
- Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, IA, USA
- Department of Internal Medicine, University of Iowa, College of Medicine, Iowa City, IA, USA
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Truffi M, Sorrentino L, Corsi F. Fibroblasts in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1234:15-29. [PMID: 32040852 DOI: 10.1007/978-3-030-37184-5_2] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The implications of a tumor microenvironment in cancer initiation and progression have drawn interest in recent years. Within the tumor stroma, fibroblasts represent a predominant cell type and are responsible for the majority of extracellular components within the tumor microenvironment, such as matrix and soluble factors. A switch from quiescent fibroblasts to cancer-associated fibroblasts triggers a large variety of pro-tumorigenic signals that support tumor progression and shape the surrounding pathological stroma, with the remodeling of tissue architecture and repression of the local immune response. The heterogeneous nature of cancer-associated fibroblasts and their multiple functions are subject of active research as they could represent promising targets for cutting-edge therapeutic approaches to cancer and the tumor microenvironment.
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Affiliation(s)
- Marta Truffi
- Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy.,Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli studi di Milano, Milano, Italy
| | - Luca Sorrentino
- Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli studi di Milano, Milano, Italy
| | - Fabio Corsi
- Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy. .,Department of Biomedical and Clinical Sciences "Luigi Sacco", Università degli studi di Milano, Milano, Italy.
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Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts. Br J Cancer 2020; 122:986-994. [PMID: 32015511 PMCID: PMC7109053 DOI: 10.1038/s41416-020-0744-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/15/2020] [Indexed: 12/11/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis. Methods We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo. Results CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups. Conclusions Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.
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Vickers AD, Winfree KB, Cuyun Carter G, Kiiskinen U, Jen MH, Stull D, Kaye JA, Carbone DP. Relative efficacy of interventions in the treatment of second-line non-small cell lung cancer: a systematic review and network meta-analysis. BMC Cancer 2019; 19:353. [PMID: 30987609 PMCID: PMC6466705 DOI: 10.1186/s12885-019-5569-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 04/02/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Locally advanced or metastatic non-small cell lung cancer (NSCLC) that has progressed after first-line treatment has a poor prognosis. Recent randomized clinical trials (RCTs) have demonstrated survival benefits of alternative treatments to docetaxel. However, information is lacking on which patients benefit the most and what drug or regimen is optimal. We report a systematic review and network meta-analysis (NMA) of second-line treatments in all subgroup combinations determined by histology, programmed death ligand 1 (PD-L1) expression, and epidermal growth factor receptor (EGFR) mutation. METHODS MEDLINE, PubMed, EMBASE, Biosciences Information Service (using the Dialog Platform), Cochrane Library, and abstracts from scientific meetings were searched for RCTs published up to September 2015. Key outcomes were overall survival (OS) and progression-free survival (PFS). Bayesian hierarchical exchangeable NMAs were conducted to calculate mean survival times and relative differences for eight subgroups, using docetaxel as the reference comparator. For OS, the NMA was based on hazard ratios applied to a first-order fractional polynomial model fitted to the reference treatment. For PFS, a second-order fractional polynomial model was fitted to reconstructed patient-level data for the entire network of evidence. RESULTS The search identified 30 studies containing 17 different treatment regimens. Docetaxel plus ramucirumab was associated with a significant improvement in OS and PFS, relative to docetaxel, regardless of patient type. Docetaxel plus nintedanib showed similar efficacy to docetaxel plus ramucirumab in the nonsquamous populations. EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib showed superior levels of efficacy in EGFR mutation-positive populations and the one PD-1 immunotherapy (nivolumab) studied showed superior efficacy in the populations exhibiting high PD-L1 expression. CONCLUSIONS In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to synthesize evidence of the efficacy of each treatment. Benefits are optimized by targeting specific treatments to individual patients guided by histology, PD-L1 expression, and EGFR mutation status. SYSTEMATIC REVIEW REGISTRATION This review is registered in PROSPERO (registration number: CRD42014013780 available at www.crd.york.ac.uk/PROSPERO ).
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Affiliation(s)
- Adrian D Vickers
- RTI Health Solutions, The Pavilion, Towers Business Park, Wilmslow Road, Didsbury, Manchester, M20 2LS, UK.
| | | | | | | | - Min-Hua Jen
- Eli Lilly and Company Limited, Windlesham, Surrey, UK
| | - Donald Stull
- RTI Health Solutions, Research Triangle Park, NC, USA
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Corrà F, Agnoletto C, Minotti L, Baldassari F, Volinia S. The Network of Non-coding RNAs in Cancer Drug Resistance. Front Oncol 2018; 8:327. [PMID: 30211115 PMCID: PMC6123370 DOI: 10.3389/fonc.2018.00327] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/31/2018] [Indexed: 12/12/2022] Open
Abstract
Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.
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Affiliation(s)
- Fabio Corrà
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Linda Minotti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Federica Baldassari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Stefano Volinia
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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Sapalidis K, Zarogoulidis P, Pavlidis E, Laskou S, Katsaounis A, Koulouris C, Giannakidis D, Mantalovas S, Huang H, Bai C, Wen Y, Wang L, Sardeli C, Amaniti A, Karapantzos I, Karapantzou C, Hohenforst-Schmidt W, Konstantinou F, Kesisoglou I, Benhassen N. Aerosol Immunotherapy with or without Cisplatin for metastatic lung cancer non-small cell lung cancer disease: In vivo Study. A more efficient combination. J Cancer 2018; 9:1973-1977. [PMID: 29896282 PMCID: PMC5995940 DOI: 10.7150/jca.24782] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 03/07/2018] [Indexed: 12/30/2022] Open
Abstract
Lung cancer is the leading cause of cancer death after prostate cancer for males and breast cancer for females. There are novel therapies in the past five years such as; tyrosine kinase inhibitors and most recently in the last two years immunotherapy. Immunotherapy is currently being investigated if it can be administered alone or in combination. Previously we have investigated whether immunotherapy compounds can be produced as aerosols, and in the current study we investigated the safety and efficiency independently of the programmed death-ligand 1. The aerosol administration of both cisplatin and nivolumab is possible. The combination of the two drugs has a synergistic effect and therefore should be considered an option. Time of administration for immunotherapy is also very important.
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Affiliation(s)
- Konstantinos Sapalidis
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Paul Zarogoulidis
- Pulmonary Department-Oncology Unit, “Theageneio” Cancer Hospital, Thessaloniki, Greece
| | - Efstathios Pavlidis
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Stella Laskou
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Athanasios Katsaounis
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Charilaos Koulouris
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Dimitrios Giannakidis
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Stylianos Mantalovas
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Haidong Huang
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Chong Bai
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Yuting Wen
- Department of Respiratory Diseases, The Affiliated Jiangning hospital of Nanjing Medical University, Nanjing, China
| | - Li Wang
- Department of Respiratory Diseases, The Affiliated Jiangning hospital of Nanjing Medical University, Nanjing, China
| | - Chrysanthi Sardeli
- Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aikaterini Amaniti
- Anesthesiology Department, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Ilias Karapantzos
- Ear, Nose and Throat Department, "Saint Luke" Private Hospital, Panorama, Thessaloniki, Greece
| | - Chrysanthi Karapantzou
- Ear, Nose and Throat Department, "Saint Luke" Private Hospital, Panorama, Thessaloniki, Greece
| | | | - Fotis Konstantinou
- Thoracic Surgery Department, University General Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Isaak Kesisoglou
- 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece
| | - Naim Benhassen
- Medical Clinic I, "Fuerth" Hospital, University of Erlangen, Fuerth, Germany
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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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Belli C, Trapani D, Viale G, D'Amico P, Duso BA, Della Vigna P, Orsi F, Curigliano G. Targeting the microenvironment in solid tumors. Cancer Treat Rev 2018; 65:22-32. [PMID: 29502037 DOI: 10.1016/j.ctrv.2018.02.004] [Citation(s) in RCA: 349] [Impact Index Per Article: 49.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 02/06/2018] [Accepted: 02/09/2018] [Indexed: 01/06/2023]
Abstract
Tumorigenesis is a complex and dynamic process involving different cellular and non-cellular elements composed of tumor microenvironment (TME). The interaction of TME with cancer cells is responsible for tumor development, progression and drug resistance. TME consists of non malignant cells of the tumor such as cancer associated fibroblasts (CAFs), endothelial cells and pericytes composing tumor vasculature, immune and inflammatory cells, bone marrow derived cells, and the extracellular matrix (ECM) establishing a complex cross-talk with tumor. These interactions contribute towards proliferation and invasion of the tumor by producing growth factors, chemokines and matrix-degrading enzymes. ECM is a complex system containing macromolecules with distinctive physical, biochemical and biomechanical properties. During tumorigenesis this system is deregulated favoring the generation of tumorigenic microenvironment enhancing tumor-associated angiogenesis and inflammation. An important step of anticancer treatment is the identification of the biological alterations present in TME in order to target these key molecular players. Multitargeted approaches, providing a simultaneous inhibition of TME components, may offer a more efficient way to treat cancer. In this manuscript we overview the function of each components of TME and the treatments targeting the key players.
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Affiliation(s)
- Carmen Belli
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy.
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Giulia Viale
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Paolo D'Amico
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Bruno Achutti Duso
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Paolo Della Vigna
- Interventional Radiology Division, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Franco Orsi
- Interventional Radiology Division, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
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13
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Hanley CJ, Mellone M, Ford K, Thirdborough SM, Mellows T, Frampton SJ, Smith DM, Harden E, Szyndralewiez C, Bullock M, Noble F, Moutasim KA, King EV, Vijayanand P, Mirnezami AH, Underwood TJ, Ottensmeier CH, Thomas GJ. Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4. J Natl Cancer Inst 2018; 110:4060751. [PMID: 28922779 PMCID: PMC5903651 DOI: 10.1093/jnci/djx121] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 03/08/2017] [Accepted: 05/18/2017] [Indexed: 12/15/2022] Open
Abstract
Background Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed. Methods CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided. Results Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04). Conclusions These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types.
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Affiliation(s)
- Christopher J Hanley
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Massimiliano Mellone
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Kirsty Ford
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Steve M Thirdborough
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Toby Mellows
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Steven J Frampton
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - David M Smith
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Elena Harden
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | | | - Marc Bullock
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Fergus Noble
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Karwan A Moutasim
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Emma V King
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | | | - Alex H Mirnezami
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | - Timothy J Underwood
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
| | | | - Gareth J Thomas
- Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton, UK
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14
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Créquit P, Chaimani A, Yavchitz A, Attiche N, Cadranel J, Trinquart L, Ravaud P. Comparative efficacy and safety of second-line treatments for advanced non-small cell lung cancer with wild-type or unknown status for epidermal growth factor receptor: a systematic review and network meta-analysis. BMC Med 2017; 15:193. [PMID: 29082855 PMCID: PMC5662096 DOI: 10.1186/s12916-017-0954-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 10/09/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Docetaxel, pemetrexed, erlotinib, and gefitinib are recommended as second-line treatment for advanced non-small cell lung cancer (NSCLC) with wild-type or unknown status for epidermal growth factor receptor (EGFR). However, the number of published randomized clinical trials (RCTs) on this topic is increasing. Our objective was to assess the comparative effectiveness and tolerability of all second-line treatments for advanced NSCLC with wild-type or unknown status for EGFR by a systematic review and network meta-analysis. METHODS MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov, and the US Food and Drug Administration website, as well as other sources, were searched for available reports up to June 6, 2017. Two reviewers independently selected published and unpublished reports of RCTs comparing any second-line treatments, extracted data and assessed the risk of bias of all included trials. We performed a Bayesian network meta-analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included objective response (ObR), the number of serious adverse events, and quality of life. RESULTS We included 102 RCTs involving 36,058 patients (62% male, median age 61 years, 81% with stage IV cancer, 80% smokers, and 92% with performance status 0-1). We revealed a differential reporting of outcomes between efficacy and safety outcomes. Half of the trials reported safety outcomes and less than 20% quality of life. For OS, nivolumab was more effective than docetaxel (hazard ratio (HR) 0.69, 95% credible interval (CrI) 0.56-0.83), pemetrexed (0.67, 0.52-0.83), erlotinib (0.68, 0.53-0.86), and gefitinib (0.66, 0.53-0.83). Pembrolizumab, atezolizumab, and pemetrexed plus erlotinib were also significantly more effective than docetaxel, pemetrexed, erlotinib, and gefitinib. For PFS, erlotinib plus cabozantinib was more effective than docetaxel (HR 0.39, 95% CrI 0.18-0.84), pemetrexed (0.38, 0.18-0.82), erlotinib (0.37, 0.18-0.78), and gefitinib (0.38, 0.18-0.82). Cabozantinib and pemetrexed plus erlotinib were also significantly more effective than the four recommended treatments. For ObR, no treatment was significantly more effective. The effectiveness of the four recommended treatments was similar and they were ranked among the 25 less-effective treatments. For safety, evidence is insufficient to draw certain conclusions. CONCLUSIONS Nivolumab, pembrolizumab, atezolizumab, and pemetrexed plus erlotinib may be the most effective second-line treatments for NSCLC in terms of OS. The four recommended treatments seem to have relatively poor performance. However, the impact on life expectancy of immunotherapy versus other treatments should be further explored by future analyses, and more trials comparing the novel treatments are needed to reduce uncertainty in these results. TRIAL REGISTRATION Registration number: PROSPERO ( CRD42015017592 ).
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Affiliation(s)
- Perrine Créquit
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France. .,Université Paris Descartes - Sorbonne Paris cité, Paris, France. .,Centre d'Epidémiologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Paris, France. .,Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France. .,Cochrane France, Paris, France. .,Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, 1 place du Parvis Notre Dame, 75004, Paris, France.
| | - Anna Chaimani
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France.,Université Paris Descartes - Sorbonne Paris cité, Paris, France.,Cochrane France, Paris, France
| | - Amélie Yavchitz
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France.,Université Paris Descartes - Sorbonne Paris cité, Paris, France.,Cochrane France, Paris, France.,Service d'Anesthésie-Réanimation, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nassima Attiche
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France
| | - Jacques Cadranel
- Service de Pneumologie, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France.,Sorbonne Universités, UPMC Univ., Paris 06, GRC-04, Théranoscan, Paris, France
| | - Ludovic Trinquart
- Cochrane France, Paris, France.,Boston University School of Public Health, Department of Biostatistics, Boston, MA, USA
| | - Philippe Ravaud
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France.,Université Paris Descartes - Sorbonne Paris cité, Paris, France.,Centre d'Epidémiologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Paris, France.,Cochrane France, Paris, France.,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
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15
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Mashreghi M, Azarpara H, Bazaz MR, Jafari A, Masoudifar A, Mirzaei H, Jaafari MR. Angiogenesis biomarkers and their targeting ligands as potential targets for tumor angiogenesis. J Cell Physiol 2017; 233:2949-2965. [DOI: 10.1002/jcp.26049] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 06/12/2017] [Indexed: 12/20/2022]
Affiliation(s)
- Mohammad Mashreghi
- NanotechnologyResearch Center; Mashhad University of Medical Sciences; Mashhad Iran
- School of Pharmacy; Mashhad University of Medical Sciences; Mashhad Iran
| | - Hassan Azarpara
- School of Medicine; Iran University of Medical Sciences; Tehran Iran
| | - Mahere R. Bazaz
- Division of Biotechnology, Faculty of Veterinary Medicine; Ferdowsi University of Mashhad; Mashhad Iran
| | - Arash Jafari
- School of Medicine; Birjand University of Medical Sciences; Birjand Iran
| | - Aria Masoudifar
- Department of Molecular Biotechnology, Cell Science Research Center; Royan Institute for Biotechnology; ACECR Isfahan Iran
| | - Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine; Mashhad University of Medical Sciences; Mashhad Iran
| | - Mahmoud R. Jaafari
- NanotechnologyResearch Center; Mashhad University of Medical Sciences; Mashhad Iran
- School of Pharmacy; Mashhad University of Medical Sciences; Mashhad Iran
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16
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Popat S, Mellemgaard A, Reck M, Hastedt C, Griebsch I. Nintedanib plus docetaxel as second-line therapy in patients with non-small-cell lung cancer of adenocarcinoma histology: a network meta-analysis vs new therapeutic options. Future Oncol 2017; 13:1159-1171. [PMID: 28326832 DOI: 10.2217/fon-2016-0493] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
PATIENTS & METHODS We provide an update to a network meta-analysis evaluating the relative efficacy of nintedanib + docetaxel versus other second-line agents in adenocarcinoma histology non-small-cell lung cancer. RESULTS Overall similarity of nintedanib + docetaxel versus ramucirumab + docetaxel, and versus nivolumab. Comparing nintedanib + docetaxel with nivolumab, hazards ratio (HR) of overall survival and progression-free survival (PFS) pointed in opposite directions (overall survival: HR: 1.20 [95% credible interval: 0.92-1.58]; PFS: HR: 0.91 [0.68-1.21]). Exploratory subgroup analysis indicated superiority of nivolumab in high PD-L1 expression level subgroups; results were more favorable for nintedanib in all subgroups with low (<1%, <5%, <10%) PD-L1 expression levels - in particular, with regard to PFS. CONCLUSION Results demonstrated similar efficacy of nintedanib + docetaxel compared with the new therapeutic options ramucirumab + docetaxel and nivolumab, with potential differences in subgroups according to PD-L1 expression level.
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Affiliation(s)
- Sanjay Popat
- Department of Medicine (Lung), Royal Marsden Hospital, London, UK
| | | | - Martin Reck
- Department of Thoracic Oncology, LungenClinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany
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17
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Corrales L, Nogueira A, Passiglia F, Listi A, Caglevic C, Giallombardo M, Raez L, Santos E, Rolfo C. Second-Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological, and Molecular Aspects of Nintedanib. Front Med (Lausanne) 2017; 4:13. [PMID: 28293555 PMCID: PMC5329017 DOI: 10.3389/fmed.2017.00013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 02/06/2017] [Indexed: 12/11/2022] Open
Abstract
Lung carcinoma is the leading cause of death by cancer in the world. Nowadays, most patients will experience disease progression during or after first-line chemotherapy demonstrating the need for new, effective second-line treatments. The only approved second-line therapies for patients without targetable oncogenic drivers are docetaxel, gemcitabine, pemetrexed, and erlotinib and for patients with target-specific oncogenes afatinib, osimertinib, crizotinib, alectinib, and ceritinib. In recent years, evidence on the role of antiangiogenic agents have been established as important and effective therapeutic targets in non-small cell lung cancer (NSCLC). Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors (vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor). Several preclinical and clinical studies have proven the usefulness of nintedanib as an anticancer agent for NSCLC. The most important study was the phase III LUME-Lung 1 trial, which investigated the combination of nintedanib with docetaxel for second-line treatment in advanced NSCLC patients. The significant improvement in overall survival and the manageable safety profile led to the approval of this new treatment in Europe. This review focuses on the preclinical and clinical studies with nintedanib in NSCLC.
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Affiliation(s)
- Luis Corrales
- Clinical Oncology Department, Hospital San Juan de Dios, San José, Costa Rica
| | - Amanda Nogueira
- Phase I – Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium
| | - Francesco Passiglia
- Phase I – Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Angela Listi
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Christian Caglevic
- Medical Oncology Department, Instituto Oncológico Fundación Arturo López Pérez, Santiago, Chile
| | - Marco Giallombardo
- Phase I – Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium
| | - Luis Raez
- Thoracic Oncology Program, Memorial Cancer Institute, Memorial Health Care System, Pembroke Pines, FL, USA
| | - Edgardo Santos
- Oncology Department, Lynn Cancer Institute, Boca Raton, FL, USA
| | - Christian Rolfo
- Phase I – Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium
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18
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Abdelhameed AS, Nusrat S, Paliwal S, Zaman M, Zaidi N, Khan RH. A multitechnique approach to probe the interaction of a therapeutic tyrosine kinase inhibitor nintedanib and bovine serum albumin. Prep Biochem Biotechnol 2017; 47:655-663. [DOI: 10.1080/10826068.2016.1275014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Ali Saber Abdelhameed
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Saima Nusrat
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Sanjhi Paliwal
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Masihuz Zaman
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Nida Zaidi
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Rizwan Hasan Khan
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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Targeting Neovasculature with Multitargeted Antiangiogenesis Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer. BioDrugs 2017; 30:421-439. [PMID: 27670779 DOI: 10.1007/s40259-016-0194-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Chemotherapy has reached a plateau in the efforts for survival improvement in non-small cell lung cancer (NSCLC). The growing knowledge of NSCLC molecular pathobiology has led to the development of new treatments that target specific tumor functions. Angiogenesis is a tumor function leading to the formation of new tumor vessels that are crucial for its survival. Although vascular endothelial growth factor (VEGF) plays a primary role in angiogenesis, the inhibition of the VEGF pathway with VEGF-receptor (VEGFR) tyrosine kinase inhibitors (TKIs) is associated with a modest survival benefit due to the development of resistance by the tumor that has been mainly attributed to the up-regulation of other stimulators of angiogenesis. Thus, the use of multitargeted antiangiogenesis TKIs (MATKIs) for simultaneous inhibition of multiple angiogenic pathways has been proposed. This review summarizes data about novel treatment strategies incorporating the inhibition of angiogenesis with MATKIs in NSCLC. The data from all relevant studies shows that MATKIs do not offer additional survival benefit to currently available chemotherapeutic options in unselected NSCLC patients. However, the diversity in disease response to MATKI-containing regimens implies that specific patient subgroups may benefit from or be harmed by these agents. In this context, most studies agree that the VEGFR-targeting MATKIs are harmful in squamous NSCLC while specific MATKIs (i.e., motesanib, vandetanib and nintedanib) are associated with improved progression free survival in non-squamous NSCLC. However, overall survival benefit was found only in adenocarcinoma and Asian non-squamous NSCLC patients with the use of nintedanib and motesanib, respectively.
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20
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Pavana RK, Choudhary S, Bastian A, Ihnat MA, Bai R, Hamel E, Gangjee A. Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents. Bioorg Med Chem 2017; 25:545-556. [PMID: 27894589 PMCID: PMC5191990 DOI: 10.1016/j.bmc.2016.11.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 11/08/2016] [Accepted: 11/11/2016] [Indexed: 02/07/2023]
Abstract
The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described. These compounds also inhibited blood vessel formation in the chicken chorioallantoic membrane (CAM) assay, and some potently inhibited tubulin assembly (with activity comparable to that of combretastatin A-4 (CA)). In addition, some of the analogs circumvent the most clinically relevant tumor resistance mechanisms (P-glycoprotein and β-III tubulin expression) to microtubule targeting agents (MTA). These MTAs bind at the colchicine site on tubulin. Two analogs displayed two to three digit nanomolar GI50 values across the entire NCI 60 tumor cell panel and one of these, compound 7, freely water soluble as its HCl salt, afforded excellent in vivo antitumor activity against an orthotopic triple negative 4T1 breast cancer model and was superior to doxorubicin.
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Affiliation(s)
- Roheeth Kumar Pavana
- Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States
| | - Shruti Choudhary
- Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States
| | - Anja Bastian
- Department of Physiology, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, United States
| | - Michael A Ihnat
- Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK 73117, United States
| | - Ruoli Bai
- Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States
| | - Ernest Hamel
- Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, United States
| | - Aleem Gangjee
- Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, United States.
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21
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Zauderer MG. Standard Chemotherapy Options and Clinical Trials of Novel Agents for Mesothelioma. ASBESTOS AND MESOTHELIOMA 2017. [DOI: 10.1007/978-3-319-53560-9_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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22
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Lin Z, Zhang Q, Luo W. Angiogenesis inhibitors as therapeutic agents in cancer: Challenges and future directions. Eur J Pharmacol 2016; 793:76-81. [PMID: 27840192 DOI: 10.1016/j.ejphar.2016.10.039] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 10/08/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023]
Abstract
Angiogenesis has become an attractive target for cancer therapy since the US Food and Drug Administration (FDA) approved the first angiogenesis inhibitor (bevacizumab) for the treatment of metastatic colorectal cancer in 2004. In following years, a large number of angiogenesis inhibitors have been discovered and developed, ranging from monoclonal antibodies, endogenous peptides, to small organic molecules and microRNAs. Many of them are now entering the clinical trial, or achieving approval for clinical use. However, major limitations have been observed about angiogenesis inhibitors by continued clinical investigations, such as resistance, enhancing tumor hypoxia and reducing delivery of chemotherapeutic agents, which might be the main reason for poor improvement in overall survival after angiogenesis inhibitor administration in clinic. Therefore, optimal anti-angiogenic therapy strategies become critical. The present review summarizes recent researches in angiogenesis inhibitors, and proposes a perspective on future directions in this field.
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Affiliation(s)
- Zhexuan Lin
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Quanwei Zhang
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Wenhong Luo
- The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, Guangdong, China.
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Créquit P, Trinquart L, Ravaud P. Live cumulative network meta-analysis: protocol for second-line treatments in advanced non-small-cell lung cancer with wild-type or unknown status for epidermal growth factor receptor. BMJ Open 2016; 6:e011841. [PMID: 27489157 PMCID: PMC4985872 DOI: 10.1136/bmjopen-2016-011841] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 06/16/2016] [Accepted: 07/14/2016] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Many second-line treatments for advanced non-small-cell lung cancer (NSCLC) have been assessed in randomised controlled trials, but which treatments work the best remains unclear. Novel treatments are being rapidly developed. We need a comprehensive up-to-date evidence synthesis of all these treatments. We present the protocol for a live cumulative network meta-analysis (NMA) to address this need. METHODS AND ANALYSIS We will consider trials of second-line treatments in patients with advanced NSCLC with wild-type or unknown epidermal growth factor receptor status. We will consider any single agent of cytotoxic chemotherapy, targeted therapy, combination of cytotoxic chemotherapy and targeted therapy and any combination of targeted therapies. The primary outcomes will be overall survival and progression-free survival. The live cumulative NMA will be initiated with a NMA and then iterations will be repeated at regular intervals to keep the NMA up-to-date over time. We have defined the update frequency as 4 months, based on an assessment of the pace of evidence production on this topic. Each iteration will consist of six methodological steps: adaptive search for treatments and trials, screening of reports and selection of trials, data extraction, assessment of risk of bias, update of the network of trials and synthesis, and dissemination. We will set up a research community in lung cancer, with different groups of contributors of different skills. We will distribute tasks through online crowdsourcing. This proof-of-concept study in second-line treatments of advanced NSCLC will allow one for assessing the feasibility of live cumulative NMA and opening the path for this new form of synthesis. ETHICS AND DISSEMINATION Ethical approval is not required because our study will not include confidential participant data and interventions. The description of all the steps and the results of this live cumulative NMA will be available online. TRIAL REGISTRATION NUMBER CRD42015017592.
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Affiliation(s)
- Perrine Créquit
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France
- Université Paris Descartes—Sorbonne Paris cité, Paris, France
| | - Ludovic Trinquart
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France
- Université Paris Descartes—Sorbonne Paris cité, Paris, France
- Centre d'Epidémiologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Paris, France
- Cochrane France, Paris, France
| | - Philippe Ravaud
- Centre de Recherche Epidémiologie et Statistique Paris Sorbonne Cité, INSERM U1153, Paris, France
- Université Paris Descartes—Sorbonne Paris cité, Paris, France
- Centre d'Epidémiologie Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Paris, France
- Cochrane France, Paris, France
- Department of Epidemiology, Mailman School of Public Health, Columbia University New York, New York, USA
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Akl MR, Nagpal P, Ayoub NM, Tai B, Prabhu SA, Capac CM, Gliksman M, Goy A, Suh KS. Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies. Oncotarget 2016; 7:44735-44762. [PMID: 27007053 PMCID: PMC5190132 DOI: 10.18632/oncotarget.8203] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 03/10/2016] [Indexed: 12/30/2022] Open
Abstract
Fibroblast growth factor (FGF) signaling is essential for normal and cancer biology. Mammalian FGF family members participate in multiple signaling pathways by binding to heparan sulfate and FGF receptors (FGFR) with varying affinities. FGF2 is the prototype member of the FGF family and interacts with its receptor to mediate receptor dimerization, phosphorylation, and activation of signaling pathways, such as Ras-MAPK and PI3K pathways. Excessive mitogenic signaling through the FGF/FGFR axis may induce carcinogenic effects by promoting cancer progression and increasing the angiogenic potential, which can lead to metastatic tumor phenotypes. Dysregulated FGF/FGFR signaling is associated with aggressive cancer phenotypes, enhanced chemotherapy resistance and poor clinical outcomes. In vitro experimental settings have indicated that extracellular FGF2 affects proliferation, drug sensitivity, and apoptosis of cancer cells. Therapeutically targeting FGF2 and FGFR has been extensively assessed in multiple preclinical studies and numerous drugs and treatment options have been tested in clinical trials. Diagnostic assays are used to quantify FGF2, FGFRs, and downstream signaling molecules to better select a target patient population for higher efficacy of cancer therapies. This review focuses on the prognostic significance of FGF2 in cancer with emphasis on therapeutic intervention strategies for solid and hematological malignancies.
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Affiliation(s)
- Mohamed R. Akl
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Poonam Nagpal
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Nehad M. Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Betty Tai
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Sathyen A. Prabhu
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Catherine M. Capac
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Matthew Gliksman
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Andre Goy
- Lymphoma Division, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - K. Stephen Suh
- Genomics and Biomarkers Program, The John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
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Mukaida N, Sasaki S. Fibroblasts, an inconspicuous but essential player in colon cancer development and progression. World J Gastroenterol 2016; 22:5301-5316. [PMID: 27340347 PMCID: PMC4910652 DOI: 10.3748/wjg.v22.i23.5301] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 04/22/2016] [Accepted: 05/21/2016] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironments have a crucial role in cancer initiation and progression, and share many molecular and pathological features with wound healing process. Unless treated, tumors, however, do not heal in contrast to wounds that heal within a limited time framework. Wounds heal in coordination of a myriad of types of cells, particularly endothelial cells, leukocytes, and fibroblasts. Similar sets of cells also contribute to cancer initiation and progression, and as a consequence, anti-cancer treatment strategies have been proposed and tested by targeting endothelial cells and/or leukocytes. Compared with endothelial cells and leukocytes, less attention has been paid to the roles of cancer-associated fibroblasts (CAFs), fibroblasts present in tumor tissues, because their heterogeneity hinders the elucidation on them at cellular and molecular levels. Here, we will discuss the origin of CAFs and their crucial roles in cancer initiation and progression, and the possibility to develop a novel type of anti-cancer treatment by manipulating the migration and functions of CAFs.
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Guthrie S, Bienkowska-Gibbs T, Manville C, Pollitt A, Kirtley A, Wooding S. The impact of the National Institute for Health Research Health Technology Assessment programme, 2003-13: a multimethod evaluation. Health Technol Assess 2016; 19:1-291. [PMID: 26307643 DOI: 10.3310/hta19670] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme supports research tailored to the needs of NHS decision-makers, patients and clinicians. This study reviewed the impact of the programme, from 2003 to 2013, on health, clinical practice, health policy, the economy and academia. It also considered how HTA could maintain and increase its impact. METHODS Interviews (n = 20): senior stakeholders from academia, policy-making organisations and the HTA programme. Bibliometric analysis: citation analysis of publications arising from HTA programme-funded research. Researchfish survey: electronic survey of all HTA grant holders. Payback case studies (n = 12): in-depth case studies of HTA programme-funded research. RESULTS We make the following observations about the impact, and routes to impact, of the HTA programme: it has had an impact on patients, primarily through changes in guidelines, but also directly (e.g. changing clinical practice); it has had an impact on UK health policy, through providing high-quality scientific evidence - its close relationships with the National Institute for Health and Care Excellence (NICE) and the National Screening Committee (NSC) contributed to the observed impact on health policy, although in some instances other organisations may better facilitate impact; HTA research is used outside the UK by other HTA organisations and systematic reviewers - the programme has an impact on HTA practice internationally as a leader in HTA research methods and the funding of HTA research; the work of the programme is of high academic quality - the Health Technology Assessment journal ensures that the vast majority of HTA programme-funded research is published in full, while the HTA programme still encourages publication in other peer-reviewed journals; academics agree that the programme has played an important role in building and retaining HTA research capacity in the UK; the HTA programme has played a role in increasing the focus on effectiveness and cost-effectiveness in medicine - it has also contributed to increasingly positive attitudes towards HTA research both within the research community and the NHS; and the HTA focuses resources on research that is of value to patients and the UK NHS, which would not otherwise be funded (e.g. where there is no commercial incentive to undertake research). The programme should consider the following to maintain and increase its impact: providing targeted support for dissemination, focusing resources when important results are unlikely to be implemented by other stakeholders, particularly when findings challenge vested interests; maintaining close relationships with NICE and the NSC, but also considering other potential users of HTA research; maintaining flexibility and good relationships with researchers, giving particular consideration to the Technology Assessment Report (TAR) programme and the potential for learning between TAR centres; maintaining the academic quality of the work and the focus on NHS need; considering funding research on the short-term costs of the implementation of new health technologies; improving the monitoring and evaluation of whether or not patient and public involvement influences research; improve the transparency of the priority-setting process; and continuing to monitor the impact and value of the programme to inform its future scientific and administrative development.
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Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer? Oncotarget 2016; 6:18206-23. [PMID: 26156021 PMCID: PMC4627246 DOI: 10.18632/oncotarget.4524] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 06/05/2015] [Indexed: 12/25/2022] Open
Abstract
Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) might be new therapeutic strategies for advanced non-small cell lung cancer (NSCLC). Here a total of 12,520 patients from 23 randomized controlled trials (RCTs) were enrolled to evaluate the efficacy and safety of VEGFR-TKIs quantitatively in advanced NSCLC. Compared with non-VEGFR-TKIs, VEGFR-TKIs regimen significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.805-0.874, P < 0.001], objective response rates (ORR) [relative risk (RR): 1.374, 95% CI: 1.193-1.583, P < 0.001] and disease control rates (DCR) (RR: 1.113, 95% CI: 1.027-1.206, P = 0.009), but not overall survival (OS) (HR: 0.960, 95% CI: 0.921-1.002, P = 0.060) for NSCLC patients. The RR of all-grade neutropenia, thrombocytopenia, hypertension, hemorrhage, fatigue, anorexia, stomatitis, diarrhea, rash, hand-foot skin reaction (HFSR) were increased in patients received VEGFR-TKIs. As for high-grade (≥ 3) adverse events (AEs), VEGFR-TKIs were associated with higher RR of neutropenia, thrombocytopenia, hypertension, fatigue, stomatitis, diarrhea, rash and HFSR. This study demonstrates VEGFR-TKIs improve PFS, ORR and DCR, but not OS in advanced NSCLC patients. VEGFR-TKIs induce more frequent and serious AEs compared with control therapies.
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Créquit P, Trinquart L, Yavchitz A, Ravaud P. Wasted research when systematic reviews fail to provide a complete and up-to-date evidence synthesis: the example of lung cancer. BMC Med 2016; 14:8. [PMID: 26792360 PMCID: PMC4719540 DOI: 10.1186/s12916-016-0555-0] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 01/07/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Multiple treatments are frequently available for a given condition, and clinicians and patients need a comprehensive, up-to-date synthesis of evidence for all competing treatments. We aimed to quantify the waste of research related to the failure of systematic reviews to provide a complete and up-to-date evidence synthesis over time. METHODS We performed a series of systematic overviews and networks of randomized trials assessing the gap between evidence covered by systematic reviews and available trials of second-line treatments for advanced non-small cell lung cancer. We searched the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, MEDLINE, EMBASE, and other resources sequentially by year from 2009 to March 2, 2015. We sequentially compared the amount of evidence missing from systematic reviews to the randomized evidence available for inclusion each year. We constructed cumulative networks of randomized evidence over time and evaluated the proportion of trials, patients, treatments, and treatment comparisons not covered by systematic reviews on December 31 each year from 2009 to 2015. RESULTS We identified 77 trials (28,636 patients) assessing 47 treatments with 54 comparisons and 29 systematic reviews (13 published after 2013). From 2009 to 2015, the evidence covered by existing systematic reviews was consistently incomplete: 45 % to 70 % of trials; 30 % to 58 % of patients; 40 % to 66 % of treatments; and 38 % to 71 % of comparisons were missing. In the cumulative networks of randomized evidence, 10 % to 17 % of treatment comparisons were partially covered by systematic reviews and 55 % to 85 % were partially or not covered. CONCLUSIONS We illustrate how systematic reviews of a given condition provide a fragmented, out-of-date panorama of the evidence for all treatments. This waste of research might be reduced by the development of live cumulative network meta-analyses.
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Affiliation(s)
- Perrine Créquit
- Centre de Recherche Epidémiologie et Statistique Sorbonne Paris Cité, INSERM U1153, Paris, France.
- Université Paris Descartes - Sorbonne Paris Cité, Paris, France.
| | - Ludovic Trinquart
- Centre de Recherche Epidémiologie et Statistique Sorbonne Paris Cité, INSERM U1153, Paris, France.
- Université Paris Descartes - Sorbonne Paris Cité, Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Centre d'Epidémiologie Clinique, Paris, France.
- Cochrane France, Paris, France.
| | - Amélie Yavchitz
- Centre de Recherche Epidémiologie et Statistique Sorbonne Paris Cité, INSERM U1153, Paris, France.
- Université Paris Descartes - Sorbonne Paris Cité, Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Centre d'Epidémiologie Clinique, Paris, France.
| | - Philippe Ravaud
- Centre de Recherche Epidémiologie et Statistique Sorbonne Paris Cité, INSERM U1153, Paris, France.
- Université Paris Descartes - Sorbonne Paris Cité, Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Hôtel-Dieu, Centre d'Epidémiologie Clinique, Paris, France.
- Cochrane France, Paris, France.
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA.
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De Vlieghere E, Verset L, Demetter P, Bracke M, De Wever O. Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics. Virchows Arch 2015; 467:367-82. [PMID: 26259962 DOI: 10.1007/s00428-015-1818-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 07/21/2015] [Accepted: 07/27/2015] [Indexed: 12/11/2022]
Abstract
Cancer-associated fibroblasts (CAFs) are drivers of tumour progression and are considered as a target and a tool in cancer diagnostic and therapeutic applications. An increased abundance of CAFs or CAF signatures are recognized as a bad prognostic marker in several cancer types. Tumour-environment biomimetics strongly improve our understanding of the communication between CAFs, cancer cells and other host cells. Several experimental drugs targeting CAFs are in clinical trials for multiple tumour entities; alternatively, CAFs can be exploited as a tool to characterize the functionality of circulating tumour cells or to capture them as a tool to prevent metastasis. The continuous interaction between tissue engineers, biomaterial experts and cancer researchers creates the possibility to biomimic the tumour-environment and provides new opportunities in cancer diagnostics and management.
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Affiliation(s)
- Elly De Vlieghere
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | - Laurine Verset
- Departments of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Pieter Demetter
- Departments of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Marc Bracke
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium.
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Reck M, Mellemgaard A. Emerging treatments and combinations in the management of NSCLC: clinical potential of nintedanib. Biologics 2015; 9:47-56. [PMID: 26170616 PMCID: PMC4494183 DOI: 10.2147/btt.s57356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
There remains an unmet need for effective, well-tolerated treatment options in advanced non-small cell lung cancer (NSCLC) to alleviate the disease burden for a broad selection of patients. Nintedanib is a potent, oral, triple angiokinase inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, and was recently approved in Europe for use in combination with docetaxel for the treatment of adults with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma tumor histology, following first-line chemotherapy. Nintedanib has been investigated extensively in preclinical research and in a number of clinical studies, the most important of which was the Phase III LUME-Lung 1 study, which investigated nintedanib in combination with docetaxel in patients with advanced NSCLC after failure of first-line chemotherapy. In this study, which led to the approval of nintedanib, addition of nintedanib to docetaxel significantly improved overall survival in patients with adenocarcinoma histology. Nintedanib demonstrated a manageable safety profile in combination with docetaxel. This review focuses on the clinical experience with nintedanib in NSCLC and discusses the clinical potential of this agent for use in combination with chemotherapy.
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Affiliation(s)
- Martin Reck
- Department of Thoracic Oncology, Lung Clinic Grosshansdorf, and member of the Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
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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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