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Huynh TH, Jang SC, Ban YH, Lee EY, Kim T, Kang I, An JS, Kang S, Han J, Kwon Y, Oh D, Park HG, Cho JC, Jang J, Oh KB, Nam SJ, Lee SK, Oh DC. Discovery of Spirosnuolides A-D, Type I/III Hybrid Polyketide Spiro-Macrolides for a Chemotherapeutic Lead against Lung Cancer. JACS AU 2024; 4:4821-4832. [PMID: 39735922 PMCID: PMC11672126 DOI: 10.1021/jacsau.4c00803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 12/31/2024]
Abstract
Four new macrolides, spirosnuolides A-D (1-4, respectively), were discovered from the termite nest-derived Kitasatospora sp. INHA29. Spirosnuolides A-D are 18-membered macrolides sharing an embedded [6,6]-spiroketal functionality inside the macrocycle and are conjugated with structurally uncommon side chains featuring cyclopentenone, 1,4-benzoquinone, hydroxyfuroic acid, or butenolide moieties. Structure elucidation was achieved using a combination of spectroscopic analyses, multiple chemical derivatizations (methylation, methanolysis, Luche reduction, and Mosher's reaction), X-ray diffraction analysis, and computational ECD calculations. Interestingly, genome sequencing analysis suggests that spirosnuolides were biosynthesized through a rare type I/III hybrid polyketide synthase. Importantly, spirosnuolide B displayed potent antiproliferative effects against various cancer cell lines at nanomolar concentrations, particularly against HCC827 cells, an EGFR mutant non-small-cell lung cancer (NSCLC) cell line, with a high safety index value. Based on in vitro studies, the antiproliferative mechanism of spirosnuolide B involved the activation of AMPK signaling, leading to cell cycle arrest and apoptosis in HCC827 cells. Its potent efficacy was also proven in vivo by the effective inhibition of tumor growth in mouse xenograft studies. Moreover, cotreatment with spirosnuolide B and gefitinib, synergistically enhanced the antiproliferative activity and apoptosis, suggesting a potential strategy to overcome gefitinib resistance in EGFR mutant NSCLC.
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Affiliation(s)
- Thanh-Hau Huynh
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Sung Chul Jang
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yeon Hee Ban
- Department
of Molecular Bioscience, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Eun-Young Lee
- Department
of Chemistry and Nanoscience, Ewha Womans
University, Seoul 03760, Republic
of Korea
| | - Taeho Kim
- Division
of Life Science, Department of Bio & Medical Big Data (BK21 Four
Program), Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Ilnam Kang
- Department
of Biological Sciences, Inha University, Incheon 22212, Republic of Korea
| | - Joon Soo An
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Sangwook Kang
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jaeho Han
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yun Kwon
- Research
Institute of Pharmaceutical Science, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Daehyun Oh
- Research
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Hyeung-geun Park
- Research
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Jang-Cheon Cho
- Department
of Biological Sciences, Inha University, Incheon 22212, Republic of Korea
| | - Jichan Jang
- Division
of Life Science, Department of Bio & Medical Big Data (BK21 Four
Program), Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Ki-Bong Oh
- Department
of Agricultural Biotechnology, College of Agriculture and Life Sciences
and Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Sang-Jip Nam
- Department
of Chemistry and Nanoscience, Ewha Womans
University, Seoul 03760, Republic
of Korea
| | - Sang Kook Lee
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Dong-Chan Oh
- Natural
Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
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Li T, Ma W, Al-Obeidi E. Evolving Precision First-Line Systemic Treatment for Patients with Unresectable Non-Small Cell Lung Cancer. Cancers (Basel) 2024; 16:2350. [PMID: 39001412 PMCID: PMC11240640 DOI: 10.3390/cancers16132350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
First-line systemic therapy for patients with advanced or metastatic non-small cell lung cancer (NSCLC) has rapidly evolved over the past two decades. First, molecularly targeted therapy for a growing number of gain-of-function molecular targets has been shown to improve progression-free survival (PFS) and overall survival (OS) with favorable toxicity profiles compared to platinum-containing chemotherapy and can be given as first-line systemic therapy in ~25% of patients with NSCLC. Actionable genetic alterations include EGFR, BRAF V600E, and MET exon 14 splicing site-sensitizing mutations, as well as ALK-, ROS1-, RET-, and NTRK-gene fusions. Secondly, inhibitors of programmed cell death protein 1 or its ligand 1 (PD-1/L1) such as pembrolizumab, atezolizumab, or cemiplimab monotherapy have become a standard of care for ~25% of patients with NSCLC whose tumors have high PD-L1 expression (total proportion score (TPS) ≥50%) and no sensitizing EGFR/ALK alterations. Lastly, for the remaining ~50% of patients who are fit and whose tumors have no or low PD-L1 expression (TPS of 0-49%) and no sensitizing EGFR/ALK aberrations, platinum-containing chemotherapy with the addition of a PD-1/L1 inhibitor alone or in combination of a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor improves PFS and OS compared to chemotherapy alone. The objectives of this review are to summarize the current data and perspectives on first-line systemic treatment in patients with unresectable NSCLC and propose a practical algorithm for implementing precision biomarker testing at diagnosis.
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Affiliation(s)
- Tianhong Li
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (W.M.)
- Medical Service, Hematology/Oncology, Veterans Affairs Northern California Health Care System, 10535 Hospital Way, Mather, CA 95655, USA
| | - Weijie Ma
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (W.M.)
- Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Ebaa Al-Obeidi
- Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA; (W.M.)
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3
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Khokhar B, Chiang B, Iglay K, Reynolds K, Rodriguez-Ormaza N, Spalding W, Freedland E. QT-Interval Prolongation, Torsades de Pointes, and Heart Failure With EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: Systematic Review. Clin Lung Cancer 2024; 25:285-318. [PMID: 38553324 DOI: 10.1016/j.cllc.2024.02.005] [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: 10/25/2023] [Revised: 02/07/2024] [Accepted: 02/11/2024] [Indexed: 06/01/2024]
Abstract
A systematic literature review was conducted to determine the incidence and mortality of QT-interval prolongation (QTp), torsades de pointes (TdP), and heart failure (HF) in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR) TKIs. Of 296 identified publications, 95 met eligibility criteria and were abstracted for QTp/TdP and HF outcomes (QTp/TdP: 83 publications, including 5 case study publications; HF: 79 publications, including 6 case study publications [involving 8 patients]). QTp incidence ranged from 0% to 27.8% in observational studies and from 0% to 11% in clinical trials, with no deaths due to QTp. There were no TdP events or deaths due to TdP. The incidence of HF ranged from 0% to 8%, and HF mortality rates ranged from 0% to 4%. Patients receiving treatment with EGFR TKIs should be monitored for signs of QTp, TdP, and HF per prescribing information. Standardized definitions and methods to improve monitoring of QTp, TdP, and HF-related events are needed in patients with NSCLC.
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Affiliation(s)
- Bilal Khokhar
- Global Evidence and Outcomes, Takeda Development Center Americas, Inc., Lexington, MA.
| | - Beatrice Chiang
- Global Patient Safety Evaluation, Takeda Development Center Americas, Inc., Lexington, MA
| | - Kristy Iglay
- Real-world Evidence and Patient Outcomes, CERobs Consulting, LLC, Wrightsville Beach, NC
| | - Kamika Reynolds
- Real-world Evidence and Patient Outcomes, CERobs Consulting, LLC, Wrightsville Beach, NC; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Nidia Rodriguez-Ormaza
- Real-world Evidence and Patient Outcomes, CERobs Consulting, LLC, Wrightsville Beach, NC; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - William Spalding
- Global Evidence and Outcomes, Takeda Development Center Americas, Inc., Lexington, MA
| | - Eric Freedland
- Global Patient Safety Evaluation, Takeda Development Center Americas, Inc., Lexington, MA
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Liquid Biopsy for Oral Cancer Diagnosis: Recent Advances and Challenges. J Pers Med 2023; 13:jpm13020303. [PMID: 36836537 PMCID: PMC9960348 DOI: 10.3390/jpm13020303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/04/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
"Liquid biopsy" is an efficient diagnostic tool used to analyse biomaterials in human body fluids, such as blood, saliva, breast milk, and urine. Various biomaterials derived from a tumour and its microenvironment are released into such body fluids and contain important information for cancer diagnosis. Biomaterial detection can provide "real-time" information about individual tumours, is non-invasive, and is more repeatable than conventional histological analysis. Therefore, over the past two decades, liquid biopsy has been considered an attractive diagnostic tool for malignant tumours. Although biomarkers for oral cancer have not yet been adopted in clinical practice, many molecular candidates have been investigated for liquid biopsies in oral cancer diagnosis, such as the proteome, metabolome, microRNAome, extracellular vesicles, cell-free DNAs, and circulating tumour cells. This review will present recent advances and challenges in liquid biopsy for oral cancer diagnosis.
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Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open 2023; 6:e2255050. [PMID: 36753281 PMCID: PMC9909498 DOI: 10.1001/jamanetworkopen.2022.55050] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
IMPORTANCE Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear. OBJECTIVE To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases. DESIGN, SETTING, AND PARTICIPANTS This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled. INTERVENTIONS The eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone. MAIN OUTCOMES AND MEASURES The primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. RESULTS A total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. CONCLUSIONS AND RELEVANCE In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01951469.
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Affiliation(s)
- Xue Hou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Meichen Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Guowu Wu
- Cancer Center, Department of Medical Oncology, Meizhou People’s Hospital, Meizhou, China
| | - Weineng Feng
- Department of Head and Neck/Thoracic Medical Oncology, the First People's Hospital of Foshan, Foshan, China
| | - Jin Su
- Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Honghua Jiang
- Department of Oncology, Southern Theater Air Force Hospital, Guangzhou, China
| | - Guanming Jiang
- Dongguan Institute of Clinical Cancer Research, Department of Medical Oncology, Southern Medical University-affiliated Dongguan People's Hospital, Dongguan, China
| | - Jing Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Baishen Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhixuan You
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qing Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Statistics, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Likun Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Diwan D, Cheng L, Usmani Z, Sharma M, Holden N, Willoughby N, Sangwan N, Baadhe RR, Liu C, Gupta VK. Microbial cancer therapeutics: A promising approach. Semin Cancer Biol 2022; 86:931-950. [PMID: 33979677 DOI: 10.1016/j.semcancer.2021.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 04/24/2021] [Accepted: 05/04/2021] [Indexed: 01/27/2023]
Abstract
The success of conventional cancer therapeutics is hindered by associated dreadful side-effects of antibiotic resistance and the dearth of antitumor drugs' selectivity and specificity. Hence, the conceptual evolution of anti-cancerous therapeutic agents that selectively target cancer cells without impacting the healthy cells or tissues, has led to a new wave of scientific interest in microbial-derived bioactive molecules. Such strategic solutions may pave the way to surmount the shortcomings of conventional therapies and raise the potential and hope for the cure of wide range of cancer in a selective manner. This review aims to provide a comprehensive summary of anti-carcinogenic properties and underlying mechanisms of bioactive molecules of microbial origin, and discuss the current challenges and effective therapeutic application of combinatorial strategies to attain minimal systemic side-effects.
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Affiliation(s)
- Deepti Diwan
- Washington University, School of Medicine, Saint Louis, MO, USA
| | - Lei Cheng
- Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 230032, China
| | - Zeba Usmani
- Department of Chemistry and Biotechnology, Tallinn University of Technology, 12618, Tallinn, Estonia
| | - Minaxi Sharma
- Department of Food Technology, Akal College of Agriculture, Eternal University, Baru Sahib, Himachal Pradesh, 173101, India
| | - Nicola Holden
- Centre for Safe and Improved Food, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK
| | - Nicholas Willoughby
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Neelam Sangwan
- Department of Biochemistry, Central University of Haryana, Mahendergarh, Haryana, 123031, India
| | - Rama Raju Baadhe
- Department of Biotechnology, National Institute of Technology, Warangal, Telangana, 506004, India
| | - Chenchen Liu
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Vijai Kumar Gupta
- Centre for Safe and Improved Food, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK; Biorefining and Advanced Materials Research Center, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh, EH9 3JG, UK.
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Gijtenbeek RG, van der Noort V, Aerts JG, Staal-van den Brekel JA, Smit EF, Krouwels FH, Wilschut FA, Hiltermann TJN, Timens W, Schuuring E, Janssen JD, Goosens M, van den Berg PM, de Langen AJ, Stigt JA, van den Borne BE, Groen HJ, van Geffen WH, van der Wekken AJ. Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer. ERJ Open Res 2022; 8:00239-2022. [PMID: 36267895 PMCID: PMC9574558 DOI: 10.1183/23120541.00239-2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/05/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.
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Affiliation(s)
- Rolof G.P. Gijtenbeek
- Dept of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
| | - Vincent van der Noort
- Dept of Biometrics, Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Joachim G.J.V. Aerts
- Dept of Pulmonary Diseases, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | | | - Egbert F. Smit
- Dept of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Frans H. Krouwels
- Dept of Respiratory Medicine, Spaarne Hospital, Hoofddorp, The Netherlands
| | - Frank A. Wilschut
- Dept of Respiratory Medicine, Gelderse Vallei Hospital, Ede, The Netherlands
| | - T. Jeroen N. Hiltermann
- Dept of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Wim Timens
- Dept of Pathology and Medical Biology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Ed Schuuring
- Dept of Pathology and Medical Biology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Joost D.J. Janssen
- Dept of Respiratory Medicine, Máxima Medical Centre, Eindhoven/Veldhoven, The Netherlands
| | - Martijn Goosens
- Dept of Pulmonary Medicine, Gelre Hospitals, Zutphen, The Netherlands
| | | | - A. Joop de Langen
- Dept of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos A. Stigt
- Dept of Respiratory Medicine, Isala Hospital, Zwolle, The Netherlands
| | | | - Harry J.M. Groen
- Dept of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Wouter H. van Geffen
- Dept of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
| | - Anthonie J. van der Wekken
- Dept of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
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8
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Abbott K, Salamat JM, Flannery PC, Chaudhury CS, Chandran A, Vishveshwara S, Mani S, Huang J, Tiwari AK, Pondugula SR. Gefitinib Inhibits Rifampicin-Induced CYP3A4 Gene Expression in Human Hepatocytes. ACS OMEGA 2022; 7:34034-34044. [PMID: 36188260 PMCID: PMC9520547 DOI: 10.1021/acsomega.2c03270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/02/2022] [Indexed: 06/16/2023]
Abstract
During multidrug combination chemotherapy, activation of the nuclear receptor and the transcription factor human pregnane xenobiotic receptor (hPXR) has been shown to play a role in the development of chemoresistance. Mechanistically, this could occur due to the cancer drug activation of hPXR and the subsequent upregulation of hPXR target genes such as the drug metabolism enzyme, cytochrome P450 3A4 (CYP3A4). In the context of hPXR-mediated drug resistance, hPXR antagonists would be useful adjuncts to PXR-activating chemotherapy. However, there are currently no clinically approved hPXR antagonists in the market. Gefitinib (GEF), a tyrosine kinase inhibitor used for the treatment of advanced non-small-cell lung cancer and effectively used in combinational chemotherapy treatments, is a promising candidate owing to its hPXR ligand-like features. We, therefore, investigated whether GEF would act as an hPXR antagonist when combined with a known hPXR agonist, rifampicin (RIF). At therapeutically relevant concentrations, GEF successfully inhibited the RIF-induced upregulation of endogenous CYP3A4 gene expression in human primary hepatocytes and human hepatocells. Additionally, GEF inhibited the RIF induction of hPXR-mediated CYP3A4 promoter activity in HepG2 human liver carcinoma cells. The computational modeling of molecular docking predicted that GEF could bind to multiple sites on hPXR including the ligand-binding pocket, allowing for potential as a direct antagonist as well as an allosteric inhibitor. Indeed, GEF bound to the ligand-binding domain of the hPXR in cell-free assays, suggesting that GEF directly interacts with the hPXR. Taken together, our results suggest that GEF, at its clinically relevant therapeutic concentration, can antagonize the hPXR agonist-induced CYP3A4 gene expression in human hepatocytes. Thus, GEF could be a potential candidate for use in combinational chemotherapies to combat hPXR agonist-induced chemoresistance. Further studies are warranted to determine whether GEF has sufficient hPXR inhibitor abilities to overcome the hPXR agonist-induced chemoresistance.
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Affiliation(s)
- Kodye
L. Abbott
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
- Auburn
University Research Initiative in Cancer, Auburn University, Auburn, Alabama 36849, United States
- Salk
Institute for Biological Studies, La Jolla, California 92037, United States
| | - Julia M. Salamat
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
- Auburn
University Research Initiative in Cancer, Auburn University, Auburn, Alabama 36849, United States
| | - Patrick C. Flannery
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
- Auburn
University Research Initiative in Cancer, Auburn University, Auburn, Alabama 36849, United States
- Salk
Institute for Biological Studies, La Jolla, California 92037, United States
| | - Chloe S. Chaudhury
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
- Auburn
University Research Initiative in Cancer, Auburn University, Auburn, Alabama 36849, United States
| | - Aneesh Chandran
- Department
of Biotechnology and Microbiology, Kannur
University, Kannur, Kerala 670661, India
| | | | - Sridhar Mani
- Albert Einstein
Cancer Center, Albert Einstein College of
Medicine, New York 10461, United States
| | - Jianfeng Huang
- Salk
Institute for Biological Studies, La Jolla, California 92037, United States
| | - Amit K. Tiwari
- Center
of Medical Bio-Allied Health Sciences Research, Ajman University, Ajman 306, United Arab Emirates
- Department
of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, Ohio 43606, United States
- Department
of Cell and Cancer Biology, University of
Toledo, Toledo, Ohio 43614, United
States
| | - Satyanarayana R. Pondugula
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
- Auburn
University Research Initiative in Cancer, Auburn University, Auburn, Alabama 36849, United States
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9
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ZHANG G, CHENG R, NIU Y, WANG H, YAN X, ZHANG M, ZHANG X, YANG J, WEI C, MA Z. Efficacy Differences of First-line EGFR-TKIs Alone vs in Combination with Chemotherapy in Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutation and Concomitant Non-EGFR Genetic Alterations. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:651-657. [PMID: 36172729 PMCID: PMC9549422 DOI: 10.3779/j.issn.1009-3419.2022.102.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) mutations are often associated with non-EGFR genetic alterations, which may be a reason for the poor efficacy of EGFR tyrosine kinase inhibitors (TKIs). Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations. METHODS Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant non-EGFR genetic alterations were retrospectively collected. And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy. Demographic, clinical and pathological data were collected, and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression. Survival data were obtained through face-to-face or telephone follow-up. The differences between the two groups in objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were investigated. RESULTS 107 patients were included, including 63 cases in the combination group and 44 cases in the monotherapy group. The ORR were 78% and 50% (P=0.003), and DCR were 97% and 77% (P=0.002), respectively. At a median follow-up of 13.7 mon, a PFS event occurred in 38.1% and 81.8% of patients in the two groups, with median PFS of 18.8 mon and 5.3 mon, respectively (P<0.000,1). Median OS was unreached in the combination group, and 27.8 mon in the monotherapy group (P=0.31). According to the Cox multivariate regression analysis, combination therapy was an independent prognostic factor of PFS CONCLUSIONS: In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations, combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy, which should be the preferred treatment option.
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Affiliation(s)
- Guowei ZHANG
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China,Guowei ZHANG, E-mail:
| | - Ruirui CHENG
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Yuanyuan NIU
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Huijuan WANG
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Xiangtao YAN
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Mina ZHANG
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Xiaojuan ZHANG
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Jinpo YANG
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Chunhua WEI
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Zhiyong MA
- Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
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10
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Zhang G, Yan B, Guo Y, Yang H, Li J. "Sandwich" Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients. Front Oncol 2022; 12:952939. [PMID: 35903676 PMCID: PMC9321780 DOI: 10.3389/fonc.2022.952939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/16/2022] [Indexed: 02/03/2023] Open
Abstract
EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.
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Affiliation(s)
- Guoqing Zhang
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Beibei Yan
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Guo
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hang Yang
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jindong Li
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Behl A, Sarwalia P, Kumar S, Behera C, Mintoo MJ, Datta TK, Gupta PN, Chhillar AK. Codelivery of Gemcitabine and MUC1 Inhibitor Using PEG-PCL Nanoparticles for Breast Cancer Therapy. Mol Pharm 2022; 19:2429-2440. [PMID: 35639628 DOI: 10.1021/acs.molpharmaceut.2c00175] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In breast cancer therapy, Gemcitabine (Gem) is an antineoplastic antimetabolite with greater anticancer efficacy and tolerability. However, effectiveness of Gem is limited by its off-target effects. The synergistic potential of MUC1 (mucin 1) inhibitors and Gem-loaded polymeric nanoparticles (NPs) was discussed in this work in order to reduce dose-related toxicities and enhance the therapeutic efficacy. The double emulsion solvent evaporation method was used to prepare poly(ethylene glycol) methyl ether-block-poly-caprolactone (PEG-PCL)-loaded Gem and MUC 1 inhibitor NPs. The average size of Gem and MUC 1 inhibitor-loaded NPs was 128 nm, with a spherical shape. Twin-loaded NPs containing Gem and the MUC1 inhibitor decreased IC50 and behaved synergistically. Furthermore, in vitro mechanistic studies, that is, loss of MMP, clonogenic assay, Annexin V FITC assay, and Western blotting to confirm apoptosis with simultaneous induction of autophagy using acridine orange (AO) staining were performed in this study. Furthermore, the investigated NPs upon combination exhibited greater loss of MMP and decreased clonogenic potential with simultaneous induction of autophagy in MCF-7 cells. Annexin V FITC clearly showed the percentage of apoptosis while Western blotting protein expression analysis revealed an increase in caspase-3 activity with simultaneous decrease in Bcl-2 protein expression, a hallmark of apoptosis. The effectiveness of the Ehrlich ascites solid (EAT) mice treated with Gem-MUC1 inhibitor NPs was higher than that of the animals treated alone. Overall, the combined administration of Gem and MUC1 inhibitor-loaded NPs was found to be more efficacious than Gem and MUC1 inhibitor delivered separately.
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Affiliation(s)
- Akanksha Behl
- Centre for Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124 001, India
| | - Parul Sarwalia
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Sushil Kumar
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Chittaranjan Behera
- PK-PD Tox and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Mubashir Javed Mintoo
- Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Tirtha Kumar Datta
- Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Prem N Gupta
- PK-PD Tox and Formulation Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India
| | - Anil K Chhillar
- Centre for Biotechnology, Maharshi Dayanand University, Rohtak, Haryana 124 001, India
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12
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Asami K, Ando M, Nishimura T, Yokoi T, Tamura A, Minato K, Mori M, Ogushi F, Yamamoto A, Yoshioka H, Kawahara M, Atagi S. A randomized phase II study of docetaxel or pemetrexed with or without the continuation of gefitinib after disease progression in elderly patients with non-small cell lung cancer harboring EGFR mutations (JMTO LC12-01). Thorac Cancer 2022; 13:1827-1836. [PMID: 35562327 PMCID: PMC9200881 DOI: 10.1111/1759-7714.14465] [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: 01/30/2022] [Revised: 04/24/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Gefitinib (G) is a recommended molecular-targeted agent for elderly patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Docetaxel (Doc) and pemetrexed (Pem) have similar efficacies, and either is often used as the sole agent during treatment. The efficacy of continuing G after progressive disease (PD) develops has been reported. It remains unclear whether the continuation of G in combination with a single cytotoxic agent beyond PD is beneficial for elderly patients. Here, we conducted a randomized phase II study to assess the efficacy and safety of cytotoxic chemotherapy with G for elderly patients with progressive EGFR-mutant NSCLC. METHODS Elderly patients with EGFR-mutant NSCLC with PD previously treated with G were enrolled. Patients received Pem 500 mg/m or Doc 60 mg/m every 21 days and were randomly assigned to receive chemotherapy with 250 mg G (G+ Doc/Pem arm) or without G (Doc/Pem arm) until further disease progression or unacceptable toxicity. RESULTS This trial was terminated early owing to slow accrual. A group of 22 patients underwent analysis. The primary endpoint, progression-free survival (PFS), was significantly longer in the G + Doc/Pem arm (median: 1.6 months vs. 5.6 months, hazard ratio = 0.40, 95% CI: 0.16-0.99, p = 0.0391). Adverse events ≥ grade 3 were more frequent in the G + Doc/Pem arm (45.5% vs. 90.9%, p = 0.032). CONCLUSIONS Patients on G and Pem or Doc beyond PD showed a longer PFS than those on single-agent chemotherapy; however, it was associated with increased toxicity.
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Affiliation(s)
| | - Masahiko Ando
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Takashi Nishimura
- Department of Respiratory Medicine, Kyoto Katsura Hospital, Kyoto, Japan
| | - Takashi Yokoi
- Department of Thoracic Oncology, Hyogo College of Medicine, Hyogo, Japan
| | - Atsuhisa Tamura
- Department of Center for Pulmonary Diseases, Tokyo National Hospital, Tokyo, Japan
| | - Koichi Minato
- Department of Respiratory Medicine, Gunma Prefectural Cancer Center, Gunma, Japan
| | - Masahide Mori
- Department of Thoracic Oncology, National Hospital Organization Osaka Toneyama Medical Center, Osaka, Japan
| | - Fumitaka Ogushi
- Department of Respiratory Medicine, Kochi National Hospital, Kochi, Japan
| | - Akiyoshi Yamamoto
- Department of Respiratory Medicine, Takamatsu Red Cross Hospital, Kagawa, Japan
| | - Hiroshige Yoshioka
- Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan
| | - Masaaki Kawahara
- Department of Respiratory Medicine, KKR Otemae Hospital, Osaka, Japan
| | - Shinji Atagi
- Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan
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13
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Ao L, Fang S, Zhang K, Gao Y, Cui J, Jia W, Shan Y, Zhang J, Wang G, Liu J, Zhou F. Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:163. [PMID: 35501907 PMCID: PMC9063085 DOI: 10.1186/s13046-022-02369-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/19/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Inevitably developed resistance of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) limited its clinical benefit on non-small cell lung cancer (NSCLC). Upfront combination therapy is promising to prevent this resistance. Compelling clinical evidence indicated the failure of third-generation EGFR TKIs combined with either immunotherapy or antiangiogenic agents. In comparison, combined treatment of third-generation EGFR TKIs and chemotherapy might be a favorable choice. Herein, we systematically analyzed and compared the effects of pemetrexed and a novel third-generation EGFR TKI aumolertinib combined in different sequences, subsequently revealed the potential mechanisms and proved the optimal combination schedule with clinical retrospective study. METHODS Three combination schedules involving pemetrexed and aumolertinib in different sequences were developed. Their inhibition effects on cell proliferation and metastasis were firstly compared upon three human NSCLC cell lines in vitro, by cell counting kit-8, colony formation, wound healing and transwell assays respectively. Further evaluation in vivo was proceeded upon H1975 and HCC827 xenograft model. Gene and protein expression were detected by Q-PCR and western blot. Drug concentration was determined by LC-MS/MS. VEGF secretion was determined by ELISA. Tumor vessel was visualized by immunofluorescence. Lastly, a clinical retrospective study was raised with 65 patients' data. RESULTS The combination of pemetrexed and aumolertinib exhibited a sequence-dependent and EGFR mutant-dependent synergistic effect in vitro and in vivo. Only treatment with aumolertinib following pemetrexed (P-A) exhibited synergistic effect with stronger anti-tumor growth and anti-metastasis ability than monotherapy and also other combination sequences. This synergism could exclusively be observed in H1975 and HCC827 but not A549. Pathway analysis showed that P-A significantly enhanced the suppression of EGFR pathway. In addition, our results intriguingly found an obvious reduction of VEGF secretion and the accompanying normalization of the intratumor vessel, consequently increasing intratumoral accumulation of pemetrexed in P-A group. Finally, the clinical retrospective study verified the synergistic effect of P-A combination by significantly superior tumor response than aumolertinib monotherapy. CONCLUSION Aumolertinib-pemetrexed combined therapy is promising for EGFR mutant NSCLC but only in right administration sequence. P-A could become an advantageous combination strategy in clinical with synergistic inhibition of tumor growth and metastasis.
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Affiliation(s)
- Luyao Ao
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Shencun Fang
- Department of Respiratory Medicine, Nanjing Chest Hospital, The Affiliated Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Kexin Zhang
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Yang Gao
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Jiawen Cui
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Wenjing Jia
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Yunlong Shan
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Jingwei Zhang
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China
| | - Guangji Wang
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China.
| | - Jiali Liu
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China.
| | - Fang Zhou
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, 210009, Jiangsu, China.
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Imran M, Akhileshwar Jha L, Hasan N, Shrestha J, Pangeni R, Parvez N, Mohammed Y, Kumar Jha S, Raj Paudel K. “Nanodecoys”- Future of drug delivery by encapsulating nanoparticles in natural cell membranes. Int J Pharm 2022; 621:121790. [DOI: 10.1016/j.ijpharm.2022.121790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 04/12/2022] [Accepted: 04/28/2022] [Indexed: 12/22/2022]
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Alam M, Alam S, Shamsi A, Adnan M, Elasbali AM, Al-Soud WA, Alreshidi M, Hawsawi YM, Tippana A, Pasupuleti VR, Hassan MI. Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer. Front Oncol 2022; 12:869672. [PMID: 35402265 PMCID: PMC8990771 DOI: 10.3389/fonc.2022.869672] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Non-small cell lung carcinoma (NSCLC) comprises 80%-85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoing in vitro and in vivo and clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC.
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Affiliation(s)
- Manzar Alam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, India
| | - Shoaib Alam
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, India
| | - Anas Shamsi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, India
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Abdelbaset Mohamed Elasbali
- Department of Clinical Laboratory Science, College of Applied Sciences-Qurayyat, Jouf University, Sakaka, Saudi Arabia
| | - Waleed Abu Al-Soud
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia
- Health Sciences Research Unit, Jouf University, Sakaka, Saudi Arabia
| | - Mousa Alreshidi
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
- Molecular Diagnostics and Personalized Therapeutics Unit, University of Hail, Hail, Saudi Arabia
| | | | - Anitha Tippana
- Regional Agricultural Research Station, Acharya N. G. Ranga Agricultural University (ANGRAU), Tirupati, India
| | - Visweswara Rao Pasupuleti
- Department of Biomedical Sciences and Therapeutics, Faculty of Medicine & Health Sciences, University Malaysia Sabah, Kota Kinabalu, Malaysia
- Department of Biochemistry, Faculty of Medicine and Health Sciences, Abdurrab University, Pekanbaru, Indonesia
- Centre for International Collaboration and Research, Reva University, Rukmini Knowledge Park, Bangalore, India
| | - Md. Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, India
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Glycosphingolipids in human embryonic stem cells and breast cancer stem cells, and potential cancer therapy strategies based on their structures and functions. Glycoconj J 2022; 39:177-195. [PMID: 35267131 DOI: 10.1007/s10719-021-10032-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/27/2021] [Accepted: 12/08/2021] [Indexed: 12/26/2022]
Abstract
Expression profiles of glycosphingolipids (GSLs) in human embryonic stem cell (hESC) lines and their differentiated embryoid body (EB) outgrowth cells, consisting of three germ layers, were surveyed systematically. Several globo- and lacto-series GSLs were identified in undifferentiated hESCs and during differentiation of hESCs to EB outgrowth cells, and core structure switching of these GSLs to gangliosides was observed. Such switching was attributable to altered expression of key glycosyltransferases (GTs) in GSL biosynthetic pathways, reflecting the unique stage-specific transitions and mechanisms characteristic of the differentiation process. Lineage-specific differentiation of hESCs was associated with further GSL alterations. During differentiation of undifferentiated hESCs to neural progenitor cells, core structure switching from globo- and lacto-series to primarily gangliosides (particularly GD3) was again observed. During differentiation to endodermal cells, alterations of GSL profiles were distinct from those in differentiation to EB outgrowth or neural progenitor cells, with high expression of Gb4Cer and low expression of stage-specific embryonic antigen (SSEA)-3, -4, or GD3 in endodermal cells. Again, such profile changes resulted from alterations of key GTs in GSL biosynthetic pathways. Novel glycan structures identified on hESCs and their differentiated counterparts presumably play functional roles in hESCs and related cancer or cancer stem cells, and will be useful as surface biomarkers. We also examined GSL expression profiles in breast cancer stem cells (CSCs), using a model of epithelial-mesenchymal transition (EMT)-induced human breast CSCs. We found that GD2 and GD3, together with their common upstream GTs, GD3 synthase (GD3S) and GD2/GM2 synthase, maintained stem cell phenotype in breast CSCs. Subsequent studies showed that GD3 was associated with epidermal growth factor receptor (EGFR), and activated EGFR signaling in breast CSCs and breast cancer cell lines. GD3S knockdown enhanced cytotoxicity of gefitinib (an EGFR kinase inhibitor) in resistant MDA-MB468 cells, both in vitro and in vivo. Our findings indicate that GD3S contributes to gefitinib resistance in EGFR-positive breast cancer cells, and is a potentially useful therapeutic target in drug-resistant breast cancers.
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Epstein Barr virus-positive B-cell lymphoma is highly vulnerable to MDM2 inhibitors in vivo. Blood Adv 2021; 6:891-901. [PMID: 34861697 PMCID: PMC8945299 DOI: 10.1182/bloodadvances.2021006156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/25/2021] [Indexed: 11/20/2022] Open
Abstract
MDM2 inhibitors have potent in vivo activity against and could be a novel therapy for EBV-positive B-cell lymphoma. EBV positivity or loss of BCL6 expression can be a potential predictive biomarker for response to MDM2 inhibitors in patients with lymphoma Epstein-Barr virus–positive (EBV-positive) B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2is) navtemadlin and idasanutlin have potent in vivo activity in EBV-positive B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV-positive xenograft–associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2is resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that were either EBV-positive or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV-positive lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including 1 whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV-positive lymphoma with MDM2is and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2is.
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Kwan TY, Chowdhury EH. Clinical Outcomes of Chemotherapeutic Molecules as Single and Multiple Agents in Advanced Non-Small-Cell Lung Carcinoma (NSCLC) Patients. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1252. [PMID: 34833470 PMCID: PMC8618045 DOI: 10.3390/medicina57111252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/05/2021] [Accepted: 11/09/2021] [Indexed: 01/11/2023]
Abstract
Background and Objectives: Lung cancer is the second most common cancer in the world. Non-small-cell lung carcinoma (NSCLC) makes up 85% of all lung cancer cases and the majority of patients are diagnosed when the cancer is advanced. Over the years, many anticancer drugs have been designed and introduced into the market to treat patients with advanced NSCLC. This review aims to discuss the comparative therapeutic benefits of conventional chemotherapeutics and other drugs available for treating advanced NSCLC. Materials and Methods: A literature search for first-line treatment of advanced NSCLC was carried out on PubMed and Google Scholar. Objective response rate (ORR) and overall survival were chosen as target endpoints. Results: Monotherapy showed lower treatment endpoints compared to combination therapy. Different combinations of platinum-based doublets demonstrated similar efficacies in treating NSCLC. However, pemetrexed-platinum doublets showed significantly better treatment endpoint in patients with non-squamous NSCLC. Most studies showing the best complete response rate (CRR) utilized epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), while most studies producing the best overall survival included programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in their treatment regimens. Conclusions: The findings of this review indicate that targeted therapy using specific inhibitors is now the most promising first-line anticancer treatment available in the market. However, chemotherapy is still effective in treating advanced NSCLC and is viable as a first-line treatment.
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Affiliation(s)
| | - Ezharul Hoque Chowdhury
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia;
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Shu Y, Zhang Q, He X, Chen L. Cost-Effectiveness Analysis of Gefitinib Plus Chemotherapy versus Gefitinib Alone for Advanced Non-Small-Cell Lung Cancer with EGFR Mutations in China. Cancer Manag Res 2021; 13:8297-8306. [PMID: 34764692 PMCID: PMC8572736 DOI: 10.2147/cmar.s334643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/23/2021] [Indexed: 12/21/2022] Open
Abstract
Objective The aim of this study was to evaluate the cost-effectiveness of gefitinib plus chemotherapy (GCP) versus gefitinib alone for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations in China. Methods A decision-analytic Markov model was conducted to simulate the disease process of advanced NSCLC patients with EGFR mutations. Three distinct health states: progression-free survival (PFS), progressive disease (PD) and death were included. Clinical data were derived from the NEJ009 study. The cost was evaluated from the perspective of the Chinese society. Quality-adjusted life-years (QALYs) and incremental cost–effectiveness ratios (ICER) were calculated over a 10-year lifetime horizon. One-way sensitivity analysis and probabilistic sensitivity analysis were also performed to explore the uncertainty of parameters in the study. Results The base case analysis demonstrated that gefitinib plus chemotherapy gained 2.44 QALYs at an average cost of $59,571.34, while the effectiveness and cost of gefitinib group were 1.82 QALYs and $52,492.75, respectively. The ICER for gefitinib plus chemotherapy was $11,499.98 per QALY gained. The ICER was lower than the accepted willingness-to-pay (WTP) threshold, which was three times gross domestic product (GDP) per capita of China ($31,498.70 per QALY). Variation of parameters did not reverse the cost-effectiveness of gefitinib plus chemotherapy through univariable and probabilistic sensitivity analyses. Conclusion Our results showed that gefitinib plus chemotherapy is a cost-effective treatment option compared with gefitinib for advanced NSCLC patients with EGFR mutations in China.
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Affiliation(s)
- Yamin Shu
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China.,Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People's Republic of China.,Department of Pharmacy, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Qilin Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xucheng He
- Pengzhou Second People's Hospital, Pengzhou, People's Republic of China
| | - Li Chen
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China.,Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, People's Republic of China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People's Republic of China
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20
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Ke Y, Yang X, Luo D. miR-193a-3p Overexpression Inhibits Proliferation and Enhances Paclitaxel Chemosensitivity in Human Non-Small-Cell Lung Cancer Cells. INT J PHARMACOL 2021. [DOI: 10.3923/ijp.2021.541.548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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21
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Stock-Martineau S, Shepherd FA. EGFR Tyrosine Kinase Inhibitor Monotherapy Should Remain the Standard First-Line Treatment in Advanced EGFR-Mutant NSCLC. J Thorac Oncol 2021; 16:1793-1797. [PMID: 34716003 DOI: 10.1016/j.jtho.2021.08.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/14/2021] [Accepted: 08/20/2021] [Indexed: 12/25/2022]
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22
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Honkala A, Malhotra SV, Kummar S, Junttila MR. Harnessing the predictive power of preclinical models for oncology drug development. Nat Rev Drug Discov 2021; 21:99-114. [PMID: 34702990 DOI: 10.1038/s41573-021-00301-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2021] [Indexed: 12/21/2022]
Abstract
Recent progress in understanding the molecular basis of cellular processes, identification of promising therapeutic targets and evolution of the regulatory landscape makes this an exciting and unprecedented time to be in the field of oncology drug development. However, high costs, long development timelines and steep rates of attrition continue to afflict the drug development process. Lack of predictive preclinical models is considered one of the key reasons for the high rate of attrition in oncology. Generating meaningful and predictive results preclinically requires a firm grasp of the relevant biological questions and alignment of the model systems that mirror the patient context. In doing so, the ability to conduct both forward translation, the process of implementing basic research discoveries into practice, as well as reverse translation, the process of elucidating the mechanistic basis of clinical observations, greatly enhances our ability to develop effective anticancer treatments. In this Review, we outline issues in preclinical-to-clinical translatability of molecularly targeted cancer therapies, present concepts and examples of successful reverse translation, and highlight the need to better align tumour biology in patients with preclinical model systems including tracking of strengths and weaknesses of preclinical models throughout programme development.
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Affiliation(s)
- Alexander Honkala
- Department of Cell Development & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Sanjay V Malhotra
- Department of Cell Development & Cancer Biology, Oregon Health & Science University, Portland, OR, USA.,Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Shivaani Kummar
- Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. .,Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA.
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Arunmanee W, Duangkaew M, Taweecheep P, Aphicho K, Lerdvorasap P, Pitchayakorn J, Intasuk C, Jiraratmetacon R, Syamsidi A, Chanvorachote P, Chaotham C, Pornputtapong N. Resurfacing receptor binding domain of Colicin N to enhance its cytotoxic effect on human lung cancer cells. Comput Struct Biotechnol J 2021; 19:5225-5234. [PMID: 34630940 PMCID: PMC8479544 DOI: 10.1016/j.csbj.2021.09.008] [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: 05/07/2021] [Revised: 09/05/2021] [Accepted: 09/08/2021] [Indexed: 11/24/2022] Open
Abstract
Colicin N (ColN) is a bacteriocin secreted by Escherichia coli (E. coli) to kill other Gram-negative bacteria by forcefully generating ion channels in the inner membrane. In addition to its bactericidal activity, ColN have been reported to selectively induce apoptosis in human lung cancer cells via the suppression of integrin modulated survival pathway. However, ColN showed mild toxicity against human lung cancer cells which could be improved for further applications. The protein resurfacing strategy was chosen to engineer ColN by extensive mutagenesis at solvent-exposed residues on ColN. The highly accessible Asp and Glu on wildtype ColN (ColNWT) were replaced by Lys to create polycationic ColN (ColN+12). Previous studies have shown that increase of positive charges on proteins leads to the enhancement of mammalian cell penetration as well as increased interaction with negatively charged surface of cancer cells. Those solvent-exposed residues of ColN were identified by Rosetta and AvNAPSA (Average number of Neighboring Atoms Per Sidechain Atom) approaches. The findings revealed that the structural features and stability of ColN+12 determined by circular dichroism were similar to ColNWT. Furthermore, the toxicity of ColN+12 was cancer selective. Human lung cancer cells, H460 and H23, were sensitive to ColN but human dermal papilla cells were not. ColN+12 also showed more potent toxicity than ColNWT in cancer cells. This confirmed that polycationic resurfacing method has enabled us to improve the anticancer activity of ColN towards human lung cancer cells.
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Affiliation(s)
- Wanatchaporn Arunmanee
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Methawee Duangkaew
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pornchanok Taweecheep
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kanokpol Aphicho
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Panuwat Lerdvorasap
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Jesada Pitchayakorn
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chayada Intasuk
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Runglada Jiraratmetacon
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Armini Syamsidi
- Department of Pharmacy, Faculty of Science, Tadulako University, Central Sulawesi 94118, Indonesia
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chatchai Chaotham
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Natapol Pornputtapong
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Corresponding author.
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Papini F, Sundaresan J, Leonetti A, Tiseo M, Rolfo C, Peters GJ, Giovannetti E. Hype or hope - Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Crit Rev Oncol Hematol 2021; 166:103454. [PMID: 34455092 DOI: 10.1016/j.critrevonc.2021.103454] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 02/08/2023] Open
Abstract
Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.
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Affiliation(s)
- Filippo Papini
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy
| | - Janani Sundaresan
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Alessandro Leonetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Christian Rolfo
- The Center of Thoracic Oncology at the Tisch Cancer Institute, Mount Sinai, NYC, United States
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Biochemistry, Medical University of Gdansk, Poland
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy.
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Xu Z, Hao X, Lin L, Li J, Xing P. Concurrent chemotherapy and first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) with or without an antiangiogenic agent as first-line treatment in advanced lung adenocarcinoma harboring an EGFR mutation. Thorac Cancer 2021; 12:2233-2240. [PMID: 34180588 PMCID: PMC8365005 DOI: 10.1111/1759-7714.14057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Previous studies have demonstrated the combination of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and other antitumor agents may delay drug resistance. In this study, we retrospectively reviewed the efficacy and safety of first-line concurrent EGFR-TKIs and platinum-based doublet chemotherapy with or without an antiangiogenic agent for advanced lung adenocarcinoma patients in the real world. METHODS A total of 30 patients with advanced lung adenocarcinoma and activating EGFR mutations concurrently received an EGFR-TKI and platinum-based doublet chemotherapy with or without bevacizumab. The safety profile and efficacy were retrospectively reviewed. RESULTS At the median follow-up time of 22.1 months, 18 patients had experienced disease progression, and six patients had died because of disease. The median progression-free survival (mPFS) was 21.2 months (95% CI: 12.631-29.798). Of the 28 patients who had measurable lesions, the objective response rate and disease control rate were 71.4% and 96.4%, respectively (one patient achieved complete remission, 19 patients had a partial response and seven patients had stable disease). Male patients had significantly longer mPFS than female patients (32.6 vs. 14.6 months, HR = 3.593, 95% CI: 1.158-11.148, p = 0.027). The most frequently seen grade 3/4 adverse events were hematological toxicities, seen in three cases (10%). Three patients ceased bevacizumab due to vascular events, including hypertension (grade 2, 6.7%) and venous thrombosis (grade 2, 3.3%), and continued EGFR-TKI and platinum-based doublet chemotherapy. CONCLUSIONS The combination of first-generation EGFR-TKIs with platinum-based chemotherapy may be a first-line treatment for advanced lung adenocarcinoma patients harboring activated EGFR mutations and is well tolerated.
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Affiliation(s)
- Ziyi Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xuezhi Hao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Lin Lin
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Puyuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Zemanova M, Cernovska M, Havel L, Bartek T, Lukesova S, Jakesova J, Vanasek J, Reiterer P, Kultan J, Andrasina I, Siskova L, Koubkova L, Skrickova J, Salajka F, Pesek M, Klepetko P, Beniak J, Fricke H, Kadlecova P, Korolkiewicz RP, Hraska M, Bartunkova J, Spisek R. Autologous dendritic cell-based immunotherapy (DCVAC/LuCa) and carboplatin/paclitaxel in advanced non-small cell lung cancer: A randomized, open-label, phase I/II trial. Cancer Treat Res Commun 2021; 28:100427. [PMID: 34284344 DOI: 10.1016/j.ctarc.2021.100427] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 01/04/2023]
Abstract
PURPOSE To investigate the efficacy and safety of an active cellular immunotherapy (DCVAC/LuCa) and chemotherapy in patients with stage IV non-small cell lung cancer (NSCLC). PATIENTS AND METHODS SLU01 was a multicenter, open-label, parallel-group, randomized, phase I/II trial. NSCLC patients were randomized in a ratio of 1:1:1 to receive: DCVAC/LuCa and chemotherapy (carboplatin and paclitaxel; Group A); DCVAC/LuCa, chemotherapy, pegylated interferon-α2b, and hydroxychloroquine (Group B); or chemotherapy alone (Group C). DCVAC/LuCa was administered subcutaneously every 3-6 weeks (up to 15 doses). The primary endpoint was overall survival (OS). During the study, enrollment into Group B was discontinued for strategic reasons. RESULTS Forty-five patients were randomized to Group A, 29 patients to Group B, and 38 patients to Group C. The median OS in the modified intention-to-treat (mITT) population was 3.7 months longer in Group A than in Group C (15.5 vs. 11.8 months; p = 0.0179; hazard ratio = 0.54; 95% confidence interval: 0.32-0.91). This OS effect was consistent across subgroups of the mITT population (females, males, current smokers, former smokers, and patients with non-squamous and squamous cell histology). The most common treatment-emergent adverse events of any grade reported in Groups A, B, and C, respectively, were neutropenia (50.0%, 29.6%, and 20.6%), fatigue (40.0%, 18.5%, and 20.6%), anemia (35.0%, 44.4%, and 32.4%), paresthesia (27.5%, 25.9%, and 17.6%), and alopecia (25.0%, 29.6%, and 41.2%). CONCLUSION DCVAC/LuCa in combination with carboplatin and paclitaxel extended OS and was well tolerated.
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Affiliation(s)
- Milada Zemanova
- Department of Oncology, General Teaching Hospital, Prague, Czech Republic; First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marketa Cernovska
- First Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Respiratory Medicine, Thomayer Hospital, Prague, Czech Republic
| | - Libor Havel
- First Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Respiratory Medicine, Thomayer Hospital, Prague, Czech Republic
| | - Tomas Bartek
- Department of Respiratory Medicine and Tuberculosis, University Hospital Ostrava, Ostrava, Czech Republic
| | - Sarka Lukesova
- Department of Oncology, Hospital Nachod, Nachod, Czech Republic
| | - Jitka Jakesova
- Department of Oncology, Hospital Pribram, Pribram, Czech Republic
| | | | - Pavel Reiterer
- Department of Pneumology, Masaryk Hospital Usti and Labem, Usti and Labem, Czech Republic
| | - Juraj Kultan
- Department of Respiratory Medicine, University Hospital Olomouc, Olomouc, Czech Republic
| | - Igor Andrasina
- Department of Oncology, Vychodoslovensky onkologicky ustav, a.s., Kosice, Slovak Republic
| | - Lenka Siskova
- Department of Oncology, Hospital of Tomas Bata in Zlin, Zlin, Czech Republic
| | - Leona Koubkova
- Department of Pneumology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Prague, Czech Republic
| | - Jana Skrickova
- Department of Respiratory Medicine and Tuberculosis, University Hospital Brno, Brno, Czech Republic
| | - Frantisek Salajka
- Department of Pneumology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Milos Pesek
- Department of Pneumology, University Hospital Pilsen, Charles University in Prague, Prague, Czech Republic
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Chen Y, Wen S, Wu Y, Shi L, Xu X, Shen B. Efficacy and safety of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy or antiangiogenic therapy as first-line treatment in patients with EGFR-mutant non-small cell lung cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 163:103393. [PMID: 34119658 DOI: 10.1016/j.critrevonc.2021.103393] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 03/16/2021] [Accepted: 06/08/2021] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE We conducted a meta-analysis to synthesize the results of published randomized controlled trials conducted to evaluate the efficacy and safety of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) combined with chemotherapy or antiangiogenic therapy. METHODS PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov databases were searched and literatures from international conferences were read to identify eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS) and treatment-emergent adverse events (TEAEs). RESULTS 10 studies, all on first-generation EGFR-TKI combination therapy, involving 2367 patients were included. Combination therapy resulted in significant improvements in ORR (RR: 1.11, 95% CI: 1.06-1.17, P < 0.001), DCR (RR: 1.03, 95% CI: 1.01-1.05, P = 0.007), PFS (HR: 0.56, 95% CI: 0.51-0.62, P < 0.001), OS (HR: 0.74, 95% CI: 0.64-0.84, P = 0.002) over monotherapy. This improvement was more apparent in the EGFR-TKIs combination chemotherapy group, and indirect comparisons revealed that EGFR-TKIs combined with chemotherapy appeared to be superior to combined with antiangiogenic therapy in ORR (RR: 1.19, 95% CI: 1.07-1.32), DCR (RR: 1.04, 95% CI: 1.02-1.08), and OS (HR: 0.79, 95% CI: 0.66-0.96). Of additional concern is the increased incidence of TEAEs in combination therapy. CONCLUSION As a first-line treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), first-generation EGFR-TKIs combined with chemotherapy or antiangiogenic therapy was associated with significant improvement in ORR, DCR, PFS and OS compared with monotherapy.
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Affiliation(s)
- Yuzhong Chen
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China
| | - Shaodi Wen
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China
| | - Yuan Wu
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China
| | - Lin Shi
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China
| | - Xiaoyue Xu
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China
| | - Bo Shen
- The Affilated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital & Jiangsu Institute Of Cancer Research, 42 Baiziting, Nanjing, Jiangsu, 210009, China.
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Tao G, Chityala PK. Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management. Toxicol Res (Camb) 2021; 10:476-486. [PMID: 34141161 PMCID: PMC8201561 DOI: 10.1093/toxres/tfab026] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 12/18/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) family is a class of receptor tyrosine kinase playing a central role in carcinogenesis and cancer progression. The members of this family, particularly EGFR and human epidermal growth factor receptor 2 (HER2), are the most extensively studied drug targets for malignancy. Today, numerous tyrosine kinase inhibitors targeting EGFR family have been developed to combat non-small-cell lung cancer and breast cancer. However, severe gastrointestinal (GI) toxicity leading to dose reduction and treatment discontinuation hampers the therapeutic outcome of EGFR inhibitors. Diarrhea is one of the most frequent GI side effects, especially when it comes to second-generation EGFR inhibitors. Enterocytes apoptosis and increased inflammation accompany with many oral EGFR inhibitors. Loperamide and budesonide are the first-line treatment to manage such adverse effects. However, current prophylaxis and management are all empirical interventions to relieve the symptom. They do not specifically target the toxicological mechanism of EGFR inhibitors. Hereby, those anti-diarrhea agents do not work well when used in cancer patients experiencing EGFR inhibitor-induced diarrhea. On the other hand, the toxicological mechanism of EGFR inhibitor-induced diarrhea is poorly understood. Thus, determining the mechanism behind such diarrhea is urgently in need for developing genuinely effective anti-diarrhea agents. This review aims to call attention to EGFR inhibitor-induced diarrhea, a highly occurring and devastating cancer drug toxicity.
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Affiliation(s)
- Gabriel Tao
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Pavan Kumar Chityala
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Li Q, Ma L, Qiu B, Wen Y, Liang W, Hu W, Chen N, Zhang T, Xu S, Chen L, Guo M, Zhao Y, Liu S, Guo J, Wang J, Wang S, Wang X, Pang Q, Long H, Liu H. Benefit from Adjuvant TKIs Versus TKIs Plus Chemotherapy in EGFR-Mutant Stage III-pN2 Lung Adenocarcinoma. Curr Oncol 2021; 28:1424-1436. [PMID: 33916930 PMCID: PMC8167779 DOI: 10.3390/curroncol28020135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 11/04/2020] [Accepted: 11/04/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Recent studies have demonstrated benefits from adjuvant tyrosine-kinase inhibitors (TKIs) compared with chemotherapy in non-small cell lung cancer. We launched a multi-center retrospective study to evaluate the efficacy and toxicity of adjuvant TKIs with or without chemotherapy in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma. METHODS Two hundred and seventy-four consecutive cases with stage III-pN2 lung adenocarcinoma and complete resection have been investigated. Clinic-pathologic characteristics, adjuvant treatments, long-term survivals, and toxicities were documented. Risk factors of distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated. RESULTS There were 52 (19.0%) patients treated with adjuvant TKIs alone, 199 (72.6%) with adjuvant chemotherapy alone, and 23 (8.4%) with both. After a median follow-up time of 29 months, the two-year DMFS, DFS, and OS was 61.2%, 54.1%, and 91.2%, respectively. According to univariable analyses, the risk factors were lymphovascular invasion (p < 0.001), extranodal extension (p = 0.005), and adjuvant systemic therapy (p = 0.006) for DMFS, EGFR mutation type (p = 0.025), lymphovascular invasion (p = 0.013), extranodal extension (p = 0.004), and adjuvant systemic therapy (p < 0.001) for DFS, and EGFR mutation type (p < 0.001) for OS. Multivariable analyses indicated that the independent prognostic factors were adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, Harzard ratio (HR) = 0.40; p = 0.036; TKIs vs. chemotherapy, HR = 0.38; p = 0.004), lymphovascular invasion (yes vs. no, HR = 2.22; p = 0.001) for DMFS, and adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, HR = 0.42; p = 0.034; TKIs vs. chemotherapy, HR = 0.33; p < 0.001) for DFS. No significant difference was found in the incidence of Grade 3-4 toxicities between groups (p = 0.445). CONCLUSIONS Adjuvant TKIs might be a beneficial choice compared with adjuvant chemotherapy or combination systemic treatments.
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Affiliation(s)
- Qiwen Li
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Q.L.); (B.Q.); (Y.W.); (N.C.); (J.G.)
| | - Li Ma
- Department of Radiation Oncology, National Cancer Center, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China;
| | - Bo Qiu
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Q.L.); (B.Q.); (Y.W.); (N.C.); (J.G.)
| | - Yuzhi Wen
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Q.L.); (B.Q.); (Y.W.); (N.C.); (J.G.)
| | - Wenhua Liang
- State Key Laboratory of Respiratory Disease, Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center of Respiratory Disease, Guangzhou 510060, China; (W.L.); (M.G.); (Y.Z.)
| | - Wanming Hu
- State Key Laboratory of Oncology in South China, Department of Pathology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.H.); (S.L.)
| | - Naibin Chen
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Q.L.); (B.Q.); (Y.W.); (N.C.); (J.G.)
| | - Tian Zhang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; (T.Z.); (Q.P.)
| | - Shuangbing Xu
- Union Hospital Cancer Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (S.X.); (L.C.)
| | - Lingjuan Chen
- Union Hospital Cancer Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (S.X.); (L.C.)
| | - Minzhang Guo
- State Key Laboratory of Respiratory Disease, Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center of Respiratory Disease, Guangzhou 510060, China; (W.L.); (M.G.); (Y.Z.)
| | - Yi Zhao
- State Key Laboratory of Respiratory Disease, Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center of Respiratory Disease, Guangzhou 510060, China; (W.L.); (M.G.); (Y.Z.)
| | - Songran Liu
- State Key Laboratory of Oncology in South China, Department of Pathology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.H.); (S.L.)
| | - Jinyu Guo
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Q.L.); (B.Q.); (Y.W.); (N.C.); (J.G.)
| | - Junye Wang
- State Key Laboratory of Oncology in South China, Department of Thoracic Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (J.W.); (S.W.); (X.W.); (H.L.)
| | - Siyu Wang
- State Key Laboratory of Oncology in South China, Department of Thoracic Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (J.W.); (S.W.); (X.W.); (H.L.)
| | - Xin Wang
- State Key Laboratory of Oncology in South China, Department of Thoracic Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (J.W.); (S.W.); (X.W.); (H.L.)
| | - Qingsong Pang
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; (T.Z.); (Q.P.)
| | - Hao Long
- State Key Laboratory of Oncology in South China, Department of Thoracic Surgery, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (J.W.); (S.W.); (X.W.); (H.L.)
| | - Hui Liu
- State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (Q.L.); (B.Q.); (Y.W.); (N.C.); (J.G.)
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30
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Lauko A, Thapa B, Sharma M, Muhsen B, Barnett A, Rauf Y, Borghei-Razavi H, Tatineni V, Patil P, Mohammadi A, Chao S, Murphy ES, Angelov L, Suh J, Barnett GH, Nowacki AS, Pennell N, Ahluwalia MS. Neutrophil to lymphocyte ratio influences impact of steroids on efficacy of immune checkpoint inhibitors in lung cancer brain metastases. Sci Rep 2021; 11:7490. [PMID: 33820922 PMCID: PMC8021556 DOI: 10.1038/s41598-021-85328-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/06/2021] [Indexed: 11/12/2022] Open
Abstract
Steroids are often utilized to manage patients with non-small cell lung cancer brain metastases (NSCLCBM). Steroids and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with decreased overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI). We retrospectively investigated patients treated with ICI after the diagnosis of NSCLCBM at a single tertiary care institution examing the impact of steroids and NLR. Overall survival (OS) and intracranial progression-free survival (PFS) were analyzed. 171 patients treated with ICI for NSCLCBM were included. Thirty-six received steroids within 30 days of the start of ICI, and 53 patients had an NLR ≥ 5 before the start of ICI. Upfront steroids was associated with decreased OS on multivariable analysis (median OS 10.5 vs. 17.9 months, p = .03) and intracranial PFS (5.0 vs. 8.7 months, p = .045). NLR ≥ 5 was indicative of worse OS (10.5 vs. 18.4 months, p = .04) but not intracranial PFS (7.2 vs. 7.7 months, p = .61). When NLR and upfront steroids are modeled together, there is a strong interaction (p = .0008) indicating that the impact of steroids depended on the patient’s NLR. In a subgroup analysis, only in patients with NLR < 4 was there a significant difference in OS with upfront steroids (26.1 vs. 15.6 months, p = .032). The impact of steroids on the efficacy of ICI in patients with NSCLCBM is dependent on the patient's NLR underscoring its importance in these patients. Patients with a low NLR, steroid use decreases the efficacy of ICI. These results can inform clinicians about the impact of steroids in patients treated with ICI.
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Affiliation(s)
- Adam Lauko
- Cleveland Clinic Lerner College of Medicine At Case Western Reserve University, 9500 Euclid Ave, CA-51, Cleveland, OH, 44195, USA
| | - Bicky Thapa
- Foedtert and Medical College of Wisconsin, Milwaukee, WI, USA
| | - Mayur Sharma
- Department of Neurological Surgery, University of Louisville, Louisville, KY, USA
| | - Baha'eddin Muhsen
- Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Addison Barnett
- Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Yasmeen Rauf
- Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | | | | | - Pradnya Patil
- Department of Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Alireza Mohammadi
- Cleveland Clinic Lerner College of Medicine At Case Western Reserve University, 9500 Euclid Ave, CA-51, Cleveland, OH, 44195, USA.,Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Samuel Chao
- Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Erin S Murphy
- Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Lilyana Angelov
- Cleveland Clinic Lerner College of Medicine At Case Western Reserve University, 9500 Euclid Ave, CA-51, Cleveland, OH, 44195, USA.,Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - John Suh
- Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gene H Barnett
- Cleveland Clinic Lerner College of Medicine At Case Western Reserve University, 9500 Euclid Ave, CA-51, Cleveland, OH, 44195, USA.,Rosa Ella Burkhart Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.,Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Amy S Nowacki
- Cleveland Clinic Lerner College of Medicine At Case Western Reserve University, 9500 Euclid Ave, CA-51, Cleveland, OH, 44195, USA.,Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Nathan Pennell
- Department of Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Manmeet S Ahluwalia
- Department of Medical Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
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31
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Overcoming therapy resistance in EGFR-mutant lung cancer. NATURE CANCER 2021; 2:377-391. [PMID: 35122001 DOI: 10.1038/s43018-021-00195-8] [Citation(s) in RCA: 292] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 03/11/2021] [Indexed: 02/01/2023]
Abstract
Tyrosine kinase inhibitors (TKIs) have dramatically changed the clinical prospects of patients with non-small cell lung cancer harboring epidermal growth factor receptor (EGFR)-activating mutations. Despite prolonged disease control and high tumor response rates, all patients eventually progress on EGFR TKI treatment. Here, we review the mechanisms of acquired EGFR TKI resistance, the methods for monitoring its appearance, as well as current and future efforts to define treatment strategies to overcome resistance.
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Abstract
The deployment of molecular biomarkers that are indicative of sensitivity to tumor-targeted or immune-targeted cancer therapies improves the outcome of individual patients and increases the chances of successful drug approval. However, for many lethal malignancies, the majority of clinical trials are conducted with patients who do not have biomarkers and hence they miss the target.
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Affiliation(s)
- Jacob J Adashek
- Department of Internal Medicine, University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Alexey Goloubev
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Shumei Kato
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
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33
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Greenhalgh J, Boland A, Bates V, Vecchio F, Dundar Y, Chaplin M, Green JA. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer. Cochrane Database Syst Rev 2021; 3:CD010383. [PMID: 33734432 PMCID: PMC8092455 DOI: 10.1002/14651858.cd010383.pub3] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours. OBJECTIVES To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life. SEARCH METHODS We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.
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Affiliation(s)
- Janette Greenhalgh
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Angela Boland
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Victoria Bates
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Fabio Vecchio
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Yenal Dundar
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
- Central Queensland Hospital and Health Service, Rockhampton, Australia
| | - Marty Chaplin
- Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
| | - John A Green
- Institute of Translational Medicine, University of Liverpool, Bebington, UK
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34
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Validation of a multicellular tumor microenvironment system for modeling patient tumor biology and drug response. Sci Rep 2021; 11:5535. [PMID: 33692370 PMCID: PMC7946945 DOI: 10.1038/s41598-021-84612-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 02/09/2021] [Indexed: 02/06/2023] Open
Abstract
Lung cancer rates are rising globally and non-small cell lung cancer (NSCLC) has a five year survival rate of only 24%. Unfortunately, the development of drugs to treat cancer is severely hampered by the inefficiency of translating pre-clinical studies into clinical benefit. Thus, we sought to apply a tumor microenvironment system (TMES) to NSCLC. Using microvascular endothelial cells, lung cancer derived fibroblasts, and NSCLC tumor cells in the presence of in vivo tumor-derived hemodynamic flow and transport, we demonstrate that the TMES generates an in-vivo like biological state and predicts drug response to EGFR inhibitors. Transcriptomic and proteomic profiling indicate that the TMES recapitulates the in vivo and patient molecular biological state providing a mechanistic rationale for the predictive nature of the TMES. This work further validates the TMES for modeling patient tumor biology and drug response indicating utility of the TMES as a predictive tool for drug discovery and development and potential for use as a system for patient avatars.
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35
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Roeper J, Kurz S, Grohé C, Griesinger F. Optimizing therapy sequence to prevent patient attrition in EGFR mutation-positive advanced or metastatic NSCLC. Future Oncol 2020; 17:471-486. [PMID: 33094641 DOI: 10.2217/fon-2020-0854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Clinical trial and real-world data in non-small-cell lung cancer indicate that 10-60% of patients that progressed on first- or second-generation EGFR-targeting tyrosine kinase inhibitors (TKI) do not receive systemic second-line therapy. In our article, we discuss efficacy, safety and treatment duration with different EGFR-TKIs and stress the need for delivery of the most efficacious therapy in the first-line. We also provide our perspective on analysis of circulating tumor DNA and the role of EGFR-TKI in combined therapies. Finally, we review new therapeutic options to overcome resistance to EGFR-TKI. We believe that overall treatment duration and access to different medications in subsequent lines of therapy should be considered when planning the optimal treatment strategy.
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Affiliation(s)
- Julia Roeper
- Department of Hematology & Oncology, University Department Internal Medicine-Oncology, Pius-Hospital, Medical Campus University of Oldenburg, Oldenburg, Germany
| | - Sylke Kurz
- Department of Respiratory Medicine, Evangelische Lungenklinik Berlin, Berlin, Germany
| | - Christian Grohé
- Department of Respiratory Medicine, Evangelische Lungenklinik Berlin, Berlin, Germany
| | - Frank Griesinger
- Department of Hematology & Oncology, University Department Internal Medicine-Oncology, Pius-Hospital, Medical Campus University of Oldenburg, Oldenburg, Germany
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36
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Lee CS, Sharma S, Miao E, Mensah C, Sullivan K, Seetharamu N. A Comprehensive Review of Contemporary Literature for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer and Their Toxicity. LUNG CANCER (AUCKLAND, N.Z.) 2020; 11:73-103. [PMID: 33117017 PMCID: PMC7548332 DOI: 10.2147/lctt.s258444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/26/2020] [Indexed: 01/10/2023]
Abstract
Mutations in the epidermal growth factor receptor (EGFR) are common amongst those with non-small cell lung cancer and represent a major factor in treatment decisions, most notably in the advanced stages. Small molecule tyrosine kinase inhibitors (TKIs) that target the EGFR, such as erlotinib, gefitinib, icotinib, afatinib, dacomitinib and osimertinib, have all shown to be effective in this setting. Osimertinib, a third-generation EGFR TKI, is a favorable option, but almost all patients develop resistance at some time point. There are no effective treatment options for patients who progress on osimertinib, but ongoing trials will hopefully address this unmet need. The aim of this review is to provide a comprehensive review of the data with EGFR TKIs, management of the toxicities and the ongoing trials with this class of agents.
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Affiliation(s)
- Chung-Shien Lee
- Department of Clinical Health Professions, St. John’s University, College of Pharmacy and Health Sciences, Queens, NY11439, USA
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY11042, USA
| | - Sandhya Sharma
- Department of Hematology and Oncology, Denver Health, Denver, CO80204, USA
| | - Emily Miao
- Albert Einstein College of Medicine, Bronx, NY, USA
| | - Cheryl Mensah
- Weil Cornell School of Medicine, Department of Hematology and Oncology, Weill Cornell of Medicine, New York, NY, USA
| | - Kevin Sullivan
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY11042, USA
| | - Nagashree Seetharamu
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY11042, USA
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37
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Shu Y, Weng S, Zheng S. Metronomic chemotherapy in non-small cell lung cancer. Oncol Lett 2020; 20:307. [PMID: 33093916 DOI: 10.3892/ol.2020.12170] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 07/15/2020] [Indexed: 12/17/2022] Open
Abstract
Metronomic chemotherapy (MCT) is defined as the rhythmic chemotherapy of low-dose cytotoxic drugs with short or no drug-free breaks over prolonged periods. MCT affects tumor cells and the tumor microenvironment. Particularly, the low-dose schedule impairs the repair process of endothelial cells, resulting in an anti-angiogenesis effect. By stimulating the immune system to eliminate tumor cells, MCT induces immunological activation. Furthermore, combined with targeted therapy, anti-angiogenic drugs enhance the efficacy of MCT. The present review is an overview of phase I, II and III clinical trials focusing on the efficacy, toxicity and mechanism of MCT in patients with non-small cell lung cancer (NSCLC). Furthermore, the prospects of MCT in NSCLC have been discussed. The present review indicated that MCT is an efficacious treatment for selected patients with NSCLC, with acceptable systemic side effects and economic viability for public health.
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Affiliation(s)
- Yefei Shu
- Department of Medical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China
| | - Shanshan Weng
- Department of Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Song Zheng
- Department of Medical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, P.R. China.,Department of Medical Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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38
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Santos ES, Hart L. Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib. Onco Targets Ther 2020; 13:9305-9321. [PMID: 33061419 PMCID: PMC7519820 DOI: 10.2147/ott.s250446] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 08/20/2020] [Indexed: 12/28/2022] Open
Abstract
Options for the treatment of squamous cell lung carcinoma expanded in recent years with the introduction of the immune checkpoint inhibitors into routine clinical practice in both the first- and second-line settings but are still limited. As a result, pembrolizumab, given either alone or in combination with platinum-based chemotherapy, is now a standard first-line treatment for squamous cell lung cancer. However, few options exist once patients have progressed on immune checkpoint inhibitors and chemotherapy. In this setting, the irreversible ErbB family blocker, afatinib, has a potential role as second or subsequent therapy for some patients. The Phase III LUX-Lung 8 study demonstrated that afatinib significantly prolonged progression-free and overall survival compared with erlotinib in patients with squamous cell lung carcinoma. Notably, retrospective, ad-hoc biomarker analyses of a subset of patients from LUX-Lung 8 suggested that patients with ErbB family mutations derived particular benefit from afatinib, especially those with ErbB2 (HER2) mutations. Afatinib has a manageable and predictable safety profile, and adverse events can be managed with the use of a tolerability-guided dose modification protocol. Until more data are available, afatinib could be considered as a potential second-line treatment option for patients who have progressed on combined pembrolizumab and platinum-based chemotherapy and are ineligible for more established second-line options, or as a third-line option in patients who have received first-line immunotherapy, and second-line chemotherapy or chemotherapy and antiangiogenesis therapy. However, further data are required to support the use of afatinib following immunotherapy. Given that treatment options are limited in both of these settings, investigating an agent with an entirely new mechanism of action is warranted. If available, molecular analysis to identify ErbB family mutations or the use of proteomic profiling could help to further isolate patients who are likely to derive the most benefit from afatinib.
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Affiliation(s)
- Edgardo S Santos
- Florida Precision Oncology/A Division of 21st Century Oncology, Florida Atlantic University, Aventura, FL, USA
| | - Lowell Hart
- Drug Development Unit, Florida Cancer Specialists, Fort Myers, FL, USA.,Wake Forest School of Medicine, Winston-Salem, NC, USA
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He ZX, Zhao TQ, Gong YP, Zhang X, Ma LY, Liu HM. Pyrimidine: A promising scaffold for optimization to develop the inhibitors of ABC transporters. Eur J Med Chem 2020; 200:112458. [PMID: 32497962 DOI: 10.1016/j.ejmech.2020.112458] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/30/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022]
Abstract
The multidrug resistance (MDR) phenomenon in cancer cells is the major obstacle leading to failure of chemotherapy accompanied by the feature of intractable and recurrence of cancers. As significant contributors that cause MDR, ABC superfamily proteins can transport the chemotherapeutic drugs out of the tumor cells by the energy of adenosine triphosphate (ATP) hydrolysis, thereby reducing their intracellular accumulation. The ABC transports like ABCB1, ABCC1 and ABCG2 have been extensively studied to develop modulators for overcoming MDR. To date, no reversal agents have been successfully marketed for clinical application, and little information about the ABC proteins bound to specific inhibitors is known, which make the design of MDR inhibitors with potency, selectivity and low toxicity a major challenge. In recent years, it has been increasingly recognized that pyrimidine-based derivatives have the potential for reversing ABC-mediated MDR. In this review, we summarized the pyrimidine-based inhibitors of ABC transporters, and mainly focused on their structure optimizations, development strategies and structure-activity relationship studies in hope of providing a reference for medicinal chemists to develop new modulators of MDR with highly potency and fewer side effects.
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Affiliation(s)
- Zhang-Xu He
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Tao-Qian Zhao
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Yun-Peng Gong
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Xin Zhang
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Li-Ying Ma
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
| | - Hong-Min Liu
- Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China.
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Abstract
The development of brain metastases occurs in 10–20% of all patients with cancer. Brain metastases portend poor survival and contribute to increased cancer mortality and morbidity. Despite multimodal treatment options, which include surgery, radiotherapy, and chemotherapy, 5-year survival remains low. Besides, our current treatment modalities can have significant neurological comorbidities, which result in neurocognitive decline and a decrease in a patient’s quality of life. However, innovations in technology, improved understanding of tumor biology, and new therapeutic options have led to improved patient care. Novel approaches in radiotherapy are minimizing the neurocognitive decline while providing the same therapeutic benefit. In addition, advances in targeted therapies and immune checkpoint inhibitors are redefining the management of lung and melanoma brain metastases. Similar approaches to brain metastases from other primary tumors promise to lead to new and effective therapies. We are beginning to understand the appropriate combination of these novel approaches with our traditional treatment options. As advances in basic and translational science and innovative technologies enter clinical practice, the prognosis of patients with brain metastases will continue to improve.
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Affiliation(s)
- Adam Lauko
- Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Yasmeen Rauf
- Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
| | - Manmeet S Ahluwalia
- Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA
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Zhao Q, Sun K, Lei X, Cai L. A meta-analysis of the therapeutic effect of gefitinib combined with chemotherapy and chemotherapy alone in treating non-small cell lung cancer. Medicine (Baltimore) 2020; 99:e21490. [PMID: 32756179 PMCID: PMC7402902 DOI: 10.1097/md.0000000000021490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Whether the combination of gefitinib and chemotherapy is beneficial for advanced non-small cell lung cancer (NSCLC) remains controversial. This study aimed to summarize the currently available evidence and compare the efficacy and safety of gefitinib combined with chemotherapy versus chemotherapy alone for treating advanced NSCLC. METHODS Literature on comparing the effects of gefitinib combined with chemotherapy and chemotherapy alone in treating NSCLC was retrieved from the PubMed, EMBASE and Cochrane Database. The primary outcome measures included progression-free survival (PFS) and overall survival (OS). Revman 5.3 was used for data processing. RESULTS Seven randomized controlled trials were included, involving a total of 1418 patients. There appeared a significant improvement in PFS (hazard ratio (HR) = 0.60 [95% CI 0.43, 0.82], P = .001) after treatment with gefitinib combined with chemotherapy when compared with chemotherapy alone. The subgroup analysis showed a significant advantage of sequential administration (HR = 0.67 [95% CI 0.57, 0.79], P < .00001). There was no significant improvement in OS (HR = 0.92 [95% CI 0.71, 1.20], P = .54), and no significant improvement in overall response rate (ORR) (HR = 0.98 [95% CI 0.67, 1.44], P = .93). The risks of rash and diarrhea (odds ratios) were higher in gefitinib combined with chemotherapy group when compared with chemotherapy alone, and there were significant differences on grade 3/4 rash and thrombocytopenia between 2 groups. CONCLUSION Gefitinib combined with chemotherapy is superior to chemotherapy alone in PFS, sequential administration prolongs the patients' PFS, however, a survival advantage is not shown in OS or ORR. Gefitinib combined with chemotherapy aggravates rash, diarrhea and thrombocytopenia.
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Affiliation(s)
- Qingda Zhao
- Department of Traditional Chinese Medicine, First Medical Center, Chinese PLA General Hospital, Beijing
| | - Kai Sun
- Penglai Traditional Chinese Medicine Hospital, Penglai
| | - Xuemei Lei
- Laibin Traditional Chinese Medicine Hospital, Laibin
| | - Le Cai
- Department of Pharmacy, Medical Supplies Center, Chinese PLA General Hospital, Beijing, China
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Kiss E, Abdelwahab EHMM, Steib A, Papp E, Torok Z, Jakab L, Smuk G, Sarosi V, Pongracz JE. Cisplatin treatment induced interleukin 6 and 8 production alters lung adenocarcinoma cell migration in an oncogenic mutation dependent manner. Respir Res 2020; 21:120. [PMID: 32434541 PMCID: PMC7238555 DOI: 10.1186/s12931-020-01389-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 05/08/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The predominant metastatic site of lung cancer (LC) is the brain. Although outdated, conventional cisplatin treatment is still the main therapeutic approach for patients with advanced non-small cell lung cancer (NSCLC), since targeted therapy that offers better tumor control is not always possible. In the present study brain metastasis associated cytokine expression was investigated in primary NSCLC adenocarcinoma (AC) tissues with known oncogenic mutations in the presence or absence of platina based and tyrosine kinase inhibitor (TKI) drugs. METHODS Primary lung tumor samples were isolated, DNA was sequenced and then the samples were grouped based on mutation. Experiments were also performed using KRAS mutant A549 and EGFR mutant PC-9 cells. Drug response was analyzed in three dimensional (3D) tissue cultures. We assessed drug response and IL-6 and IL-8 cytokine expression in relation to cellular invasion using ATP dependent cell viability, qRT-PCR analysis, cytokine bead array, and migration assay. RESULTS In 3D co-cultures, primary NSCLC derived cells harboring EGFR mutation responded better to erlotinib treatment than KRAS mutant or KRAS/EGFR wild type (WT) cancer cells. In contrast, under the same culture conditions KRAS/EGFR WT or KRAS mutant cancer cells are more sensitive to cisplatin than EGFR mutant cells. Drug response and pro-inflammatory cytokine production varied depending on the driver mutations. Cisplatin but not erlotinib increased both IL-6 and IL-8 secretion and only IL-6 increased cellular migration and proliferation. CONCLUSION In vitro assays are available to determine the response to planned therapeutic approach of lung cancer subtypes. The sequence of administration of therapeutic drugs determines cytokine production and therefore therapeutic response.
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Affiliation(s)
- Edit Kiss
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, Pecs, Hungary
- Humeltis Ltd, 20 Ifjusag Str, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, Pecs, Hungary
| | - El Husseiny Mohamed Mahmud Abdelwahab
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, Pecs, Hungary
| | | | - Emoke Papp
- Department of Internal Medicine, Medical School and Clinical Centre, University of Pecs, 13 Ifjusag Str, Pecs, Hungary
| | - Zsofia Torok
- Department of Internal Medicine, Medical School and Clinical Centre, University of Pecs, 13 Ifjusag Str, Pecs, Hungary
| | - Laszlo Jakab
- Department of Surgery, Medical School and Clinical Centre, University of Pecs, 13 Ifjusag Str, Pecs, Hungary
| | - Gabor Smuk
- Department of Pathology, Medical School and Clinical Centre, University of Pecs, 13 Ifjusag Str, Pecs, Hungary
| | - Veronika Sarosi
- Department of Internal Medicine, Medical School and Clinical Centre, University of Pecs, 13 Ifjusag Str, Pecs, Hungary
| | - Judit Erzsebet Pongracz
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, Pecs, Hungary
- Humeltis Ltd, 20 Ifjusag Str, Pecs, Hungary
- Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, Pecs, Hungary
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First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients. Clin Lung Cancer 2020; 21:e572-e582. [PMID: 32605893 DOI: 10.1016/j.cllc.2020.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/25/2020] [Accepted: 05/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND We aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma. PATIENTS AND METHODS Never-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib. RESULTS Between June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms. CONCLUSIONS Intercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.
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Liu J, Zuo Z, Wu G. Link Prediction Only With Interaction Data and its Application on Drug Repositioning. IEEE Trans Nanobioscience 2020; 19:547-555. [PMID: 32340956 DOI: 10.1109/tnb.2020.2990291] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
To assist drug development, many computational methods have been proposed to identify potential drug-disease treatment associations before wet experiments. Based on the assumption that similar drugs may treat similar diseases, most methods calculate the similarities of drugs and diseases by using various chemical or biological features. However, since these features may be unknown or hard to collect, such methods will not work in the face of incomplete data. Besides, due to the lack of validated negative samples in the drug-disease associations data, most methods have no choice but to simply select some unlabeled samples as negative ones, which may introduce noises and decrease the reliability of prediction. Herein, we propose a new method (TS-SVD) which only uses those known drug-protein, disease-protein and drug-disease interactions to predict the potential drug-disease associations. In a constructed drug-protein-disease heterogeneous network, assuming that drugs/diseases relating to some common proteins or diseases/drugs may be similar, we get the common neighbors count matrix of drugs/diseases, then convert it to a topological similarity matrix. After that, we get low dimensional embedding representations of drug-disease pairs by using topological features and singular value decomposition. Finally, a Random Forest classifier is trained to do the prediction. To train a more reasonable model, we select out some reliable negative samples based on the k -step neighbors relationships between drugs and diseases. Compared with some state-of-the-art methods, we use less information but achieve better or comparable performance. Meanwhile, our strategy for selecting reliable negative samples can improve the performances of these methods. Case studies have further shown the practicality of our method in discovering novel drug-disease associations.
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Han J, Xu Y, Zhou Y, Yang A, Cui J, Chen P, Zhao H, Zhou X, Shen C, Yu J, Lu H. The effect of TKI therapy and chemotherapy treatment delivery sequence on total progression-free survival in patients with advanced EGFR-mutated NSCLC. Oncol Lett 2020; 20:391-400. [PMID: 32565965 DOI: 10.3892/ol.2020.11535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 01/21/2020] [Indexed: 12/25/2022] Open
Abstract
The present study aimed to evaluate the total progression-free survival (PFS) time of the 1st-line chemotherapy (CHT)/2nd-line tyrosine kinase inhibitor (TKI) and 1st-line TKI/2nd-line CHT therapeutic regimens. Data from patients with non-small-cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor (EGFR) mutations, who had received both TKI and platinum CHT were retrieved from the Shandong Cancer Hospital (Jinan, China) database. A total of 89 patients were included, 50 of whom were treated with the 1st-line CHT/2nd-line TKI regimen and the remaining 39 patients underwent a 1st-line TKI/2nd-line CHT regimen. The differences in total PFS time between the two regimens were analyzed. The median total PFS time was 14.28 months with the 1st-line CHT/2nd-line TKI regimen and 17.77 months with the 1st-line TKI/2nd-line CHT regimen (adjusted hazard ratio, 0.96; 95% confidence interval (CI), 0.56-1.66; P=0.886). A significant difference in PFS time was revealed between the two strategies when comparing only the 1st-line or 2nd-line treatments (all P<0.001). The objective response rate (RR) was 52.0% for those treated with 1st-line CHT/2nd-line TKI and 38.5% for the reverse regimen. After adjusting for associated factors, the odds ratio for the RR was 2.77 (95% CI: 0.77-9.90; P=0.117). The current results revealed that there was no significant difference between the total PFS time of patients with NSCLC undergoing the 1st-line CHT/2nd-line TKI regimen compared with patients with NSCLC undergoing the 1st-line TKI/2nd-line CHT regimen.
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Affiliation(s)
- Jie Han
- Department of Radiation Oncology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
| | - Yan Xu
- Department of Oncology, Rizhao City Hospital of Traditional Chinese Medicine, Rizhao, Shandong 276800, P.R. China
| | - Yumei Zhou
- Department of Oncology, The People's Hospital of Rizhao City, Jinan, Shandong 250117, P.R. China
| | - Aiju Yang
- Department of Nursing, Shandong Cancer Hospital and Institute Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China
| | - Jianfeng Cui
- Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong 250000, P.R. China
| | - Pengxiang Chen
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong 250000, P.R. China
| | - Hongyu Zhao
- Department of Radiation Oncology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
| | - Xingqin Zhou
- Department of Radiation Oncology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
| | - Chaoyan Shen
- Department of Radiation Oncology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China
| | - Heng Lu
- Department of Pathology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
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Scodes S, Cappuzzo F. Determining the appropriate treatment for different EGFR mutations in non-small cell lung cancer patients. Expert Rev Respir Med 2020; 14:565-576. [PMID: 32233809 DOI: 10.1080/17476348.2020.1746646] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Epidermal growth factor receptor (EGFR) mutations occur in a significant fraction of non-small cell lung cancer (NSCLC) patients. Most common activating mutations are in-frame deletion in exon 19 and point mutation in exon 21. EGFR tyrosine kinase inhibitors (TKIs) represent standard of care of EGFR mutated patients bearing common mutations. Therapy for individuals carrying uncommon mutations, such as G719X, L861Q, S768I, is less defined and few options exist for individuals harboring EGFR exon 20 mutations. In all mutated patients, drug resistance remains the most critical clinical problem and new agents and strategies are under investigation.Areas covered: We have reviewed the current status of NSCLC EGFR mutated treatment by analyzing data from preclinical studies, clinical prospective and retrospective trials in order to analyze current and future options for patients harboring different EGFR mutations.Expert opinion: At the present time, available data demonstrated that osimertinib is the best EGFR-TKI for front-line therapy. Other agents, such as dacomitinib, and new drug combinations, such as regimens including anti-angiogenic agents or chemotherapy, demonstrated to significantly prolong progression-free survival or overall survival, representing potential alternative to osimertinib. Many questions remain opened, including best drug sequencing and needing of new therapeutic approaches extending patient survival and cure rate.
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Affiliation(s)
- Simona Scodes
- Department of Oncology and Hematology, AUSL Romagna, Ravenna, Italy
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The top 100 cited articles in lung cancer - a bibliometric analysis. Contemp Oncol (Pozn) 2020; 24:17-28. [PMID: 32514234 PMCID: PMC7265956 DOI: 10.5114/wo.2020.94725] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 01/05/2020] [Indexed: 12/19/2022] Open
Abstract
Aim of the study To analyze the 100 most cited lung cancer articles published in biomedical literature in the last 44 years. We pointed out developments in lung cancer and aimed to create convenient access for the researchers of this dynamic field. Material and methods We accessed the WoS database (accessed: 15.07.2019) using the keyword “lung cancer” between 1975 and 2019. The top 100 cited articles were analyzed by topic, journal, author, year, institution, level of evidence, adjusted citation index and also the correlations between citation, adjusted citation index, impact factor and length of time since publication. Results A total of 240,701 eligible articles were identified and we chose the top 100 articles cited in the field of lung cancer. The mean number of citations for these articles was 1879.82 ±1264.78. The most cited article was (times cited: 7751) a study by Lynch et al. The New England Journal of Medicine (NEJM) made the greatest contribution to the top 100 list with 32 articles, and the most cited article also originated from NEJM. The highest number of citations was seen in 2017 with 18,393 citations while the highest number of publications was seen in 2005 with 12 publications. Conclusions Oncology is a developing field and we have seen the evolution in this area through the treatment of lung cancer in recent years. The first 100 articles in our analysis not only reflect the landmark articles with the greatest impact on lung cancer research, but also acknowledge the most productive authors and institutions that have contributed to the list with their articles.
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Arunmanee W, Ecoy GAU, Khine HEE, Duangkaew M, Prompetchara E, Chanvorachote P, Chaotham C. Colicin N Mediates Apoptosis and Suppresses Integrin-Modulated Survival in Human Lung Cancer Cells. Molecules 2020; 25:E816. [PMID: 32069989 PMCID: PMC7070259 DOI: 10.3390/molecules25040816] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/06/2020] [Accepted: 02/12/2020] [Indexed: 01/26/2023] Open
Abstract
The inherent limitations, including serious side-effects and drug resistance, of current chemotherapies necessitate the search for alternative treatments especially for lung cancer. Herein, the anticancer activity of colicin N, bacteria-produced antibiotic peptide, was investigated in various human lung cancer cells. After 24 h of treatment, colicin N at 5-15 µM selectively caused cytotoxicity detected by MTT assay in human lung cancer H460, H292 and H23 cells with no noticeable cell death in human dermal papilla DPCs cells. Flow cytometry analysis of annexin V-FITC/propidium iodide indicated that colicin N primarily induced apoptosis in human lung cancer cells. The activation of extrinsic apoptosis evidenced with the reduction of c-FLIP and caspase-8, as well as the modulation of intrinsic apoptosis signaling proteins including Bax and Mcl-1 were observed via Western blot analysis in lung cancer cells cultured with colicin N (10-15 µM) for 12 h. Moreover, 5-15 µM of colicin N down-regulated the expression of activated Akt (p-Akt) and its upstream survival molecules, integrin β1 and αV in human lung cancer cells. Taken together, colicin N exhibits selective anticancer activity associated with suppression of integrin-modulated survival which potentiate the development of a novel therapy with high safety profile for treatment of human lung cancer.
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Affiliation(s)
- Wanatchaporn Arunmanee
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (W.A.); (G.A.U.E.); (H.E.E.K.); (M.D.)
- Vaccines and Therapeutic Proteins Research Group, the Special Task Force for Activating Research (STAR), Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Gea Abigail U. Ecoy
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (W.A.); (G.A.U.E.); (H.E.E.K.); (M.D.)
- Department of Pharmacy, School of Health Care Professions, University of San Carlos, Cebu 6000, Philippines
| | - Hnin Ei Ei Khine
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (W.A.); (G.A.U.E.); (H.E.E.K.); (M.D.)
| | - Methawee Duangkaew
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (W.A.); (G.A.U.E.); (H.E.E.K.); (M.D.)
- Vaccines and Therapeutic Proteins Research Group, the Special Task Force for Activating Research (STAR), Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
| | - Eakachai Prompetchara
- Vaccines and Therapeutic Proteins Research Group, the Special Task Force for Activating Research (STAR), Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand;
- Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Center of Excellence in Vaccine Research and Development (Chula Vaccine Research Center-Chula VRC), Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Chatchai Chaotham
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (W.A.); (G.A.U.E.); (H.E.E.K.); (M.D.)
- Cell-based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
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Rotow JK, Jänne PA. What's Old Is New Again: Revisiting Up-Front Chemotherapy in EGFR-Mutated Non-Small-Cell Lung Cancer. J Clin Oncol 2020; 38:107-110. [PMID: 31774706 DOI: 10.1200/jco.19.02724] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Wang X, Yeo RX, Hogg PJ, Goldstein D, Crowe P, Dilda PJ, Yang JL. The synergistic inhibitory effect of combining therapies targeting EGFR and mitochondria in sarcomas. Oncotarget 2020; 11:46-61. [PMID: 32002123 PMCID: PMC6967775 DOI: 10.18632/oncotarget.27416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
Our group previously demonstrated that sarcoma cell lines were insensitive to epidermal growth factor receptor (EGFR) inhibitor gefitinib monotherapy. PENAO, an anti-tumour metabolic compound created in our laboratory, is currently in clinical trials. Considering the positive regulation of tumour energy production by both the EGFR signalling and tumour metabolism pathways, this study aimed to investigate the effect and mechanisms of combination therapy using gefitinib and PENAO in sarcoma cell lines in vitro and in vivo. PENAO monotherapy reduced proliferation in 12 sarcoma cell lines. Combining gefitinib and PENAO resulted in synergistic inhibition in both a time- and dose-dependent manner in 3 sarcoma cell lines with less prominent monotherapy effects. Combined treatment significantly enhanced cell death and perturbed mitochondrial function. In vivo combination therapy with PENAO and gefitinib was non-toxic to mice and significantly delayed tumour growth and prolonged survival. At 20 days after treatment, tumours from the combination treated mice were significantly smaller than those from untreated and single drug treated mice. The survival curves also showed significant difference across and between groups. The combination of PENAO and gefitinib in vitro and in vivo, shows promise as a treatment pathway in this poor outcome tumour.
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Affiliation(s)
- Xiaochun Wang
- Sarcoma and Nano-oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Department of Surgery, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,These authors contributed equally to this work
| | - Reichelle X Yeo
- Sarcoma and Nano-oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Sydney, Australia.,These authors contributed equally to this work
| | - Philip J Hogg
- The Centenary Institute, NHMRC Clinical Trials Centre, Sydney Medical School, University of Sydney, Sydney, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Philip Crowe
- Sarcoma and Nano-oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Department of Surgery, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Pierre J Dilda
- Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Jia-Lin Yang
- Sarcoma and Nano-oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.,Department of Surgery, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
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