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Zhu W, Pei J, Lu X. A patent review of small molecular inhibitors targeting EGFR exon 20 insertion (Ex20ins) (2019-present). Expert Opin Ther Pat 2025; 35:91-110. [PMID: 39708287 DOI: 10.1080/13543776.2024.2446220] [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: 07/28/2024] [Revised: 10/24/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
INTRODUCTION Mutations in epidermal growth factor receptor (EGFR) kinase domain consistently activate downstream signaling pathways, such as the PI3K/AKT/mTOR and RAS/RAF/MEK, thereby promoting tumor growth. Although the majority of non-small cell lung cancer (NSCLC) patients harboring EGFR mutations are sensitive to existing EGFR tyrosine kinase inhibitors (EGFR-TKIs), there remains an unmet clinical need for effective therapies targeting EGFR Ex20ins mutations, making direct targeting EGFR Ex20ins mutations a promising therapeutic strategy. AREAS COVERED This review covers the progress of clinical studies targeting EGFR Ex20ins inhibitors and summarizes recent (1 January 2019 - 30 April 2024) patents disclosing EGFR Ex20ins inhibitors available in the Espacenet and CAS SciFinder databases. EXPERT OPINION An increasing number of EGFR Ex20ins inhibitors are being developed and reported. Existing inhibitors are focused on enhancing the efficacy of EGFR Ex20ins inhibitors and addressing the challenge of targeted resistance by optimizing the second - or third-generation EGFR inhibitors and developing innovative skeleton molecules. Moreover, the development of targeted protein degraders, allosteric inhibitors, and combination therapies provide additional approaches to address EGFR Ex20ins mutations. However, bypass resistance, selectivity, and drug sensitivity still pose challenges in this field.
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Affiliation(s)
- Wenjian Zhu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China
| | - Junping Pei
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China
| | - Xiaoyun Lu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, China
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Fatani WK, Aleanizy FS, Alqahtani FY, Alanazi MM, Aldossari AA, Shakeel F, Haq N, Abdelhady H, Alkahtani HM, Alsarra IA. Erlotinib-Loaded Dendrimer Nanocomposites as a Targeted Lung Cancer Chemotherapy. Molecules 2023; 28:3974. [PMID: 37175381 PMCID: PMC10180382 DOI: 10.3390/molecules28093974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/04/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Lung cancer is the main cause of cancer-related mortality globally. Erlotinib is a tyrosine kinase inhibitor, affecting both cancerous cell proliferation and survival. The emergence of oncological nanotechnology has provided a novel drug delivery system for erlotinib. The aims of this current investigation were to formulate two different polyamidoamine (PAMAM) dendrimer generations-generation 4 (G4) and generation 5 (G5) PAMAM dendrimer-to study the impact of two different PAMAM dendrimer formulations on entrapment by drug loading and encapsulation efficiency tests; to assess various characterizations, including particle size distribution, polydispersity index, and zeta potential; and to evaluate in vitro drug release along with assessing in situ human lung adenocarcinoma cell culture. The results showed that the average particle size of G4 and G5 nanocomposites were 200 nm and 224.8 nm, with polydispersity index values of 0.05 and 0.300, zeta potential values of 11.54 and 4.26 mV of G4 and G5 PAMAM dendrimer, respectively. Comparative in situ study showed that cationic G4 erlotinib-loaded dendrimer was more selective and had higher antiproliferation activity against A549 lung cells compared to neutral G5 erlotinib-loaded dendrimers and erlotinib alone. These conclusions highlight the potential effect of cationic G4 dendrimer as a targeting-sustained-release carrier for erlotinib.
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Affiliation(s)
- Wafa K. Fatani
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Fadilah S. Aleanizy
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Fulwah Y. Alqahtani
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammed M. Alanazi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdullah A. Aldossari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Faiyaz Shakeel
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nazrul Haq
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Hosam Abdelhady
- Department of Physiology & Pharmacology, College of Osteopathic Medicine, Sam Houston State University, 925 City Central Avenue, Conroe, TX 77304, USA
| | - Hamad M. Alkahtani
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ibrahim A. Alsarra
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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3
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Myacheva K, Walsh A, Riester M, Pelos G, Carl J, Diederichs S. CRISPRi screening identifies CASP8AP2 as an essential viability factor in lung cancer controlling tumor cell death via the AP-1 pathway. Cancer Lett 2023; 552:215958. [PMID: 36252816 DOI: 10.1016/j.canlet.2022.215958] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 02/09/2023]
Abstract
Since lung cancer remains the leading cause of cancer death globally, there is an urgent demand for novel therapeutic targets. We carried out a CRISPR interference (CRISPRi) loss-of-function screen for human lung adenocarcinoma (LUAD) targeting 2098 deregulated genes using a customized algorithm to comprehensively probe the functionality of every resolvable transcriptional start site (TSS). CASP8AP2 was identified as the only hit that significantly affected the viability of all eight screened LUAD cell lines while the viability of non-transformed lung cells was only moderately impacted. Knockdown (KD) of CASP8AP2 induced both autophagy and apoptotic cell death pathways. Systematic expression profiling linked the AP-1 transcription factor to the CASP8AP2 KD-induced cancer cell death. Furthermore, inhibition of AP-1 reverted the CASP8AP2 silencing-induced phenotype. Overall, the tailored CRISPRi screen profiled the impact of over 2000 genes on the survival of eight LUAD cell lines and identified the CASP8AP2 - AP-1 axis mediating lung cancer viability.
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Affiliation(s)
- Ksenia Myacheva
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) - Partner Site Freiburg, Germany; Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andrew Walsh
- siTOOLs Biotech GmbH, Lochhamerstr. 29A, Planegg, Martinsried, Germany
| | - Marisa Riester
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) - Partner Site Freiburg, Germany
| | - Giulia Pelos
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) - Partner Site Freiburg, Germany
| | - Jane Carl
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) - Partner Site Freiburg, Germany
| | - Sven Diederichs
- Division of Cancer Research, Department of Thoracic Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, German Cancer Consortium (DKTK) - Partner Site Freiburg, Germany; Division of RNA Biology & Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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4
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Anandu KR, Jayan AP, Aneesh TP, Saiprabha VN. Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in NSCLC: - A comprehensive review. Chem Biol Drug Des 2022; 100:599-621. [PMID: 35883248 DOI: 10.1111/cbdd.14124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/11/2022] [Accepted: 07/17/2022] [Indexed: 11/30/2022]
Abstract
EGFR positive NSCLC due to primary mutation (EGFR DEL19 & L858R) has been recognized as a crucial mediator of tumor progression. This led to the development and approval of EGFR tyrosine kinase inhibitors which addresses EGFR mediated NSCLC but fail to show potency after initial months of therapy due to acquired resistance (EGFR T790M, EGFR C797S). Extensive research allowed identification of drugs for EGFR positive NSCLC, wherein the majority of compounds have a pyrimidine substructure offering marked therapeutic benefits compared to chemotherapy. This current review outlines the diverse pyrimidine derivatives with amino-linked and fused pyrimidine scaffolds such as furo-pyrimidine, pyrimido-pyrimidine, thieno-pyrimidine, highlighting pyrimidine EGFR TK inhibitors reported in research emphasizing structural aspects, design approaches, inhibition potential. selectivity profile towards mutant EGFR conveyed through biological evaluation studies. Furthermore, mentioning the in-silico interaction profile of synthesized compounds for evaluating the binding affinity with key amino acids. The epilogue of review focuses on the recent research that drives forward to aid in the discovery and development of substituted amino and fused scaffolds of pyrimidine that can counteract the mutations and effectively manage EGFR positive NSCLC.
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Affiliation(s)
- K R Anandu
- Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - Ajay P Jayan
- Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - T P Aneesh
- Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
| | - V N Saiprabha
- Amrita School of Pharmacy, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala, 682041, India
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5
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Huang K, Yang L, Wang Y, Huang L, Zhou X, Zhang W. Identification of non-small-cell lung cancer subtypes by unsupervised clustering of CT image features with distinct prognoses and gene pathway activities. Biomed Signal Process Control 2022. [DOI: 10.1016/j.bspc.2022.103643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Dai J, Jiang M, He K, Wang H, Chen P, Guo H, Zhao W, Lu H, He Y, Zhou C. DNA Damage Response and Repair Gene Alterations Increase Tumor Mutational Burden and Promote Poor Prognosis of Advanced Lung Cancer. Front Oncol 2021; 11:708294. [PMID: 34604048 PMCID: PMC8479169 DOI: 10.3389/fonc.2021.708294] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 08/06/2021] [Indexed: 01/10/2023] Open
Abstract
DNA damage response and repair (DDR) gene alterations increase tumor-infiltrating lymphocytes, genomic instability, and tumor mutational burden (TMB). Whether DDR-related alterations relate to therapeutic response and prognosis in lung cancer lacking oncogenic drivers remains unknown. Pretherapeutic cancer samples of 122 patients [86 non-small cell lung cancer and 36 small cell lung cancer (SCLC)] harboring no EGFR/ALK alterations were collected. Through whole-exome sequencing, we outlined DDR mutational landscape and determined relationships between DDR gene alterations and TMB or intratumoral heterogeneity. Then, we evaluated the impacts of DDR gene alterations on therapeutic response and prognosis and established a DDR-based model for prognosis prediction. In addition, we investigated somatic interactions of DDR genes and immunomodulatory genes, immune expression patterns, immune microenvironment, and immune infiltration characteristics between DDR-deficient and DDR-proficient samples. Samples from cBioportal datasets were utilized for verification. We found that deleterious DDR gene alterations were closely associated with higher TMB than proficient-types (p < 0.001). DDR mechanisms attach great importance to the determination of patients’ prognosis after chemotherapy, and alterations of base excision repair pathway in adenocarcinoma, nucleotide excision repair in squamous carcinoma, and homologous recombination pathway in SCLC tend to associate with worse progression-free survival to first-line chemotherapy (all p < 0.05). A predictive nomogram model was constructed incorporating DDR-related alterations, clinical stage, and smoking status, with the area under curve values of 0.692–0.789 for 1- and 2-year receiver operating characteristic curves in training and testing cohorts. Furthermore, DDR-altered tumors contained enhanced frequencies of alterations in various genes of human leukocyte antigen (HLA) class I pathway including TAP1 and TAP2 than DDR-proficient samples. DDR-deficient types had lower expressions of STING1 (p = 0.01), CD28 (p = 0.020), HLA-DRB6 (p = 0.014) in adenocarcinoma, lower TNFRSF4 (p = 0.017), and TGFB1 expressions (p = 0.033) in squamous carcinoma, and higher CD40 (p = 0.012) and TNFRSF14 expressions (p = 0.022) in SCLC. DDR alteration enhanced activated mast cells in adenocarcinoma (p = 0.044) and M2 macrophage in squamous carcinoma (p = 0.004) than DDR-proficient types. Collectively, DDR gene alterations in lung cancer without oncogenic drivers are positively associated with high TMB. Specific DDR gene alterations tend to associate with worse progression-free survival to initial chemotherapy.
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Affiliation(s)
- Jiawei Dai
- SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Minlin Jiang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Kan He
- SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Peixin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Haoyue Guo
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Wencheng Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Hui Lu
- SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China.,Medical School, Tongji University, Shanghai, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, China
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7
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He Y, Song L, Wang H, Chen P, Liu Y, Sun H, Li X, Dang S, Liu G, Liu X, Chen S, Zhang X, Hofman P, Uchino J, Park HS, Pacheco JM, Tabbò F, Xu M, Dai J, He K, Yang Y, Zhou C, written on behalf of the AME Lung Cancer Collaborative Group. Mutational Profile Evaluates Response and Survival to First-Line Chemotherapy in Lung Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003263. [PMID: 33643802 PMCID: PMC7887584 DOI: 10.1002/advs.202003263] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/04/2020] [Indexed: 05/06/2023]
Abstract
Evaluating the therapeutic response and survival of lung cancer patients receiving first-line chemotherapy has always been difficult. Limited biomarkers for evaluation exist and as a result histology represents an empiric tool to guide therapeutic decision making. In this study, molecular signatures associated with response and long-term survival of lung cancer patients receiving first-line chemotherapy are discovered. Whole-exome sequencing is performed on pretherapeutic tissue samples of 186 patients [145 non-small cell lung cancer (NSCLC) and 41 small cell lung cancer (SCLC)]. On the basis of genomic alteration characteristics, NSCLC patients can be classified into four subtypes (C1-C4). The long-term survival is similar among different subtypes. SCLC patients are also divided into four subtypes and significant difference in their progression free survival is revealed (P < 0.001). NSCLC patients can be divided into three subtypes (S1-S3) based on TMB. A trend of worse survival associated with higher TMB in subtype S3 than in S1+S2 is found. In contrast, no significant correlations between molecular subtype and therapeutic response are observed. In conclusion, this study identifies several molecular signatures associated with response and survival to first-line chemotherapy in lung cancer.
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Affiliation(s)
- Yayi He
- Department of Medical OncologyShanghai Pulmonary Hospital and Thoracic Cancer InstituteTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
| | - Lele Song
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
- Department of Radiotherapythe eighth medical center of the Chinese PLA General HospitalNo. 17, Heishanhu Road, Haidian DistrictBeijing100091P. R. China
| | - Hao Wang
- Department of Medical OncologyShanghai Pulmonary Hospital and Thoracic Cancer InstituteTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
| | - Peixin Chen
- Department of Medical OncologyShanghai Pulmonary Hospital and Thoracic Cancer InstituteTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
| | - Yu Liu
- Department of Medical OncologyShanghai Pulmonary Hospital and Thoracic Cancer InstituteTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
| | - Hui Sun
- Department of Medical OncologyShanghai Pulmonary Hospital and Thoracic Cancer InstituteTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
| | - Xiaobin Li
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Shiying Dang
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Guifeng Liu
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Xinyi Liu
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Shifu Chen
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Xiaoni Zhang
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
- Shenzhen HaploX Medical Laboratory1106 South Block of Yuanxing Science and Technology Building, No. 1 Songpingshan Road, Xili Street, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Paul Hofman
- Laboratory of Clinical and Experimental PathologyFHU OncoAgeBB‐0033‐00025Pasteur HospitalUniversity Côte d'Azur30 avenue de la voie romaine, Nice cedex 01Nice06001France
| | - Junji Uchino
- Department of Pulmonary MedicineKyoto Prefectural University of MedicineKyoto602‐8566Japan
| | - Henry S. Park
- Department of Therapeutic RadiologyYale University School of MedicineNew HavenCT06511USA
| | - Jose M. Pacheco
- Thoracic Oncology ProgramDivision of Medical OncologyDepartment of Internal MedicineUniversity of Colorado Cancer CenterAuroraCO80045USA
| | - Fabrizio Tabbò
- Department of OncologyUniversity of TurinSan Luigi HospitalOrbassanoTurin10043Italy
| | - Mingyan Xu
- HaploX Biotechnology, Co., Ltd.8th floor, Auto Electric Power Building, Songpingshan Road, Nanshan DistrictShenzhenGuangdong518057P. R. China
| | - Jiawei Dai
- SJTU‐Yale Joint Center for Biostatistics and Data ScienceDepartment of Bioinformatics and BiostatisticsSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai200240China
| | - Kan He
- SJTU‐Yale Joint Center for Biostatistics and Data ScienceDepartment of Bioinformatics and BiostatisticsSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai200240China
| | - Yang Yang
- Department of Surgery, Shanghai Pulmonary HospitalTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
| | - Caicun Zhou
- Department of Medical OncologyShanghai Pulmonary Hospital and Thoracic Cancer InstituteTongji University School of MedicineNo. 507, Zhengmin Road, Yangpu DistrictShanghai200433P. R. China
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Rai A, Noor S, Ahmad SI, Alajmi MF, Hussain A, Abbas H, Hasan GM. Recent Advances and Implication of Bioengineered Nanomaterials in Cancer Theranostics. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:91. [PMID: 33494239 PMCID: PMC7909769 DOI: 10.3390/medicina57020091] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/28/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
Cancer is one of the most common causes of death and affects millions of lives every year. In addition to non-infectious carcinogens, infectious agents contribute significantly to increased incidence of several cancers. Several therapeutic techniques have been used for the treatment of such cancers. Recently, nanotechnology has emerged to advance the diagnosis, imaging, and therapeutics of various cancer types. Nanomaterials have multiple advantages over other materials due to their small size and high surface area, which allow retention and controlled drug release to improve the anti-cancer property. Most cancer therapies have been known to damage healthy cells due to poor specificity, which can be avoided by using nanosized particles. Nanomaterials can be combined with various types of biomaterials to make it less toxic and improve its biocompatibility. Based on these properties, several nanomaterials have been developed which possess excellent anti-cancer efficacy potential and improved diagnosis. This review presents the latest update on novel nanomaterials used to improve the diagnostic and therapeutic of pathogen-associated and non-pathogenic cancers. We further highlighted mechanistic insights into their mode of action, improved features, and limitations.
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Affiliation(s)
- Ayushi Rai
- Department of Nanoscience, Central University of Gujarat, Sector 29, Gandhinagar 382030, India;
| | - Saba Noor
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India;
| | - Syed Ishraque Ahmad
- Department of Chemistry, Zakir Husain Delhi College, University of Delhi, New Delhi 110002, India;
| | - Mohamed F. Alajmi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (A.H.)
| | - Afzal Hussain
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (M.F.A.); (A.H.)
| | - Hashim Abbas
- Department of Medicine, Nottingham University Hospitals, NHS Trust, Nottingham NG7 2UH, UK;
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
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9
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Oaknin A, Friedman CF, Roman LD, D'Souza A, Brana I, Bidard FC, Goldman J, Alvarez EA, Boni V, ElNaggar AC, Passalacqua R, Do KTM, Santin AD, Keyvanjah K, Xu F, Eli LD, Lalani AS, Bryce RP, Hyman DM, Meric-Bernstam F, Solit DB, Monk BJ. Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial. Gynecol Oncol 2020; 159:150-156. [PMID: 32723675 PMCID: PMC8336424 DOI: 10.1016/j.ygyno.2020.07.025] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/15/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors. METHODS Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety. RESULTS Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations. CONCLUSIONS Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population. TRIAL REGISTRATION NUMBER NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
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Affiliation(s)
- Ana Oaknin
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Lynda D Roman
- USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Anishka D'Souza
- USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Irene Brana
- Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Jonathan Goldman
- The David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | | | - Valentina Boni
- START Madrid Centro Oncologico Clara Campal (CIOCC), Madrid, Spain
| | | | | | | | | | | | - Feng Xu
- Puma Biotechnology Inc, Los Angeles, CA, USA
| | - Lisa D Eli
- Puma Biotechnology Inc, Los Angeles, CA, USA
| | | | | | - David M Hyman
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - David B Solit
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Bradley J Monk
- Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, AZ, USA.
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10
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Jin PC, Gou B, Qian W. Urinary markers in treatment monitoring of lung cancer patients with bone metastasis. Int J Biol Markers 2019; 34:243-250. [PMID: 31113273 DOI: 10.1177/1724600819848762] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Bone metastasis remains critical for advanced stage non-small cell lung cancer (NSCLC)-a disease that is challenging to manage. Urinary markers present opportunities for non-invasive testing. METHODS Urine specimens were collected from patients prior to treatment. Urinary cell-free DNA was subsequently purified from these samples. To address the specificity of the test, driver mutations in epidermal growth factor receptor L858R and L861Q were analyzed. Clinical specificity was established by comparison with healthy volunteers. Regular monitoring was established during treatment with tyrosine kinase inhibitors. The overall survival of patients was correlated with changes in circulating tumor DNA (ctDNA). RESULTS Baseline clinical correlation of urinary ctDNA and matched tumor specimens achieved 89% concordance. The clinical specificity was 100%. The average background level of urinary ctDNA was 20.7 ng/mL. Comparing patients with and without bone metastasis, the latter had significantly lower baseline levels. During treatment, more pronounced decline in urinary ctDNA was observed in patients without bone metastasis. In our Kaplan-Meier estimator, we observed that patients with a more significant reduction in ctDNA had a better overall survival outcome. CONCLUSION Our study demonstrates clear benefits and allows better risk profiling for NSCLC patients with bone metastasis. The non-invasive specimen collection is attractive and complements existing cancer management tools.
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Affiliation(s)
- Pei Cheng Jin
- Department of Orthopaedics, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei,441000 P.R. China
| | - Bo Gou
- Department of Orthopaedics, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Wei Qian
- Department of Orthopaedics, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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11
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Inno A, Di Noia V, Martini M, D'Argento E, Di Salvatore M, Arena V, Schinzari G, Orlandi A, Larocca LM, Cassano A, Barone C. Erlotinib for Patients with EGFR Wild-Type Metastatic NSCLC: a Retrospective Biomarkers Analysis. Pathol Oncol Res 2018; 25:513-520. [PMID: 29557085 DOI: 10.1007/s12253-018-0404-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 03/07/2018] [Indexed: 12/14/2022]
Abstract
Erlotinib is approved for the treatment of patients with EGFR mutation positive, metastatic NSCLC. It is also approved as second/third line therapy for EGFR mutation negative patients, but in this setting the benefit of erlotinib is modest and there is no validated biomarker for selecting EGFR wild-type patients who may benefit the most from the treatment. We retrospectively assessed EGFR and K-RAS mutational status, and EGFR, c-MET and IGF1-R expression in tumor samples of 72 patients with metastatic NSCLC treated with erlotinib after at least one prior line of chemotherapy, from 2008 to 2012. We analyzed the association between biomarkers and outcome (RR, PFS, and OS). EGFR mutated patients achieved a better RR (56% vs 8%, p = .002), PFS (10 vs 3 months, HR 0.53, p = 0.48) and OS (20 vs 6 months, HR 0.55, p = .07), compared to EGFR wild-type patients. Among 63 EGFR wild-type patients, those with EGFR high-expression had a better outcome in terms of RR (40% vs 2%, p = .002), PFS (7.5 vs 2 months, HR 0.45, p = .007) and OS (30 vs 5 months, HR 0.34, p < .001) compared to patients with EGFR intermediate or low/negative-expression. IGF1-R expression, c-MET expression and K-RAS mutational status did not significantly affect the outcome; however, no patients with K-RAS mutation or c-MET high-expression achieved an objective response. In patients with metastatic, chemo-refractory EGFR wild-type NSCLC, EGFR high-expression may represent a positive predictor of activity for erlotinib, whereas K-RAS mutation and c-MET high-expression may predict lack of activity. These findings deserve further prospective evaluation.
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Affiliation(s)
- Alessandro Inno
- Medical Oncology Unit, Cancer Care Center, Ospedale Sacro Cuore Don Calabria, Via don A. Sempreboni 5, 37024 Negrar, Verona, Italy.
| | - Vincenzo Di Noia
- Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maurizio Martini
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ettore D'Argento
- Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Vincenzo Arena
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giovanni Schinzari
- Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Armando Orlandi
- Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Alessandra Cassano
- Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Carlo Barone
- Department of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
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12
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Ng Kee Kwong F, Nicholson AG, Harrison CL, Hansbro PM, Adcock IM, Chung KF. Is mitochondrial dysfunction a driving mechanism linking COPD to nonsmall cell lung carcinoma? Eur Respir Rev 2017; 26:170040. [PMID: 29070578 PMCID: PMC9488999 DOI: 10.1183/16000617.0040-2017] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 07/17/2017] [Indexed: 11/05/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) patients are at increased risk of developing nonsmall cell lung carcinoma, irrespective of their smoking history. Although the mechanisms behind this observation are not clear, established drivers of carcinogenesis in COPD include oxidative stress and sustained chronic inflammation. Mitochondria are critical in these two processes and recent evidence links increased oxidative stress in COPD patients to mitochondrial damage. We therefore postulate that mitochondrial damage in COPD patients leads to increased oxidative stress and chronic inflammation, thereby increasing the risk of carcinogenesis.The functional state of the mitochondrion is dependent on the balance between its biogenesis and degradation (mitophagy). Dysfunctional mitochondria are a source of oxidative stress and inflammasome activation. In COPD, there is impaired translocation of the ubiquitin-related degradation molecule Parkin following activation of the Pink1 mitophagy pathway, resulting in excessive dysfunctional mitochondria. We hypothesise that deranged pathways in mitochondrial biogenesis and mitophagy in COPD can account for the increased risk in carcinogenesis. To test this hypothesis, animal models exposed to cigarette smoke and developing emphysema and lung cancer should be developed. In the future, the use of mitochondria-based antioxidants should be studied as an adjunct with the aim of reducing the risk of COPD-associated cancer.
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Affiliation(s)
- Francois Ng Kee Kwong
- Experimental Studies, National Heart and Lung Institute, Imperial College London, London, UK
- Dept of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - Andrew G Nicholson
- Experimental Studies, National Heart and Lung Institute, Imperial College London, London, UK
- Dept of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | | | - Philip M Hansbro
- School of Biomedical Sciences and Pharmacy, Newcastle, Australia
| | - Ian M Adcock
- Airways Disease, National Heart and Lung Institute, Imperial College London, London, UK
| | - Kian Fan Chung
- Experimental Studies, National Heart and Lung Institute, Imperial College London, London, UK
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13
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Inoue Y, Shiihara J, Miyazawa H, Ohta H, Higo M, Nagai Y, Kobayashi K, Saijo Y, Tsuchida M, Nakayama M, Hagiwara K. A highly specific and sensitive massive parallel sequencer-based test for somatic mutations in non-small cell lung cancer. PLoS One 2017; 12:e0176525. [PMID: 28448556 PMCID: PMC5407820 DOI: 10.1371/journal.pone.0176525] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 03/21/2017] [Indexed: 01/14/2023] Open
Abstract
Molecular targeting therapy for non-small cell lung cancer (NSCLC) has clarified the importance of mutation testing when selecting treatment regimens. As a result, multiple-gene mutation tests are urgently needed. We developed a next-generation sequencer (NGS)-based, multi-gene test named the MINtS for investigating driver mutations in both cytological specimens and snap-frozen tissue samples. The MINtS was used to investigate the EGFR, KRAS, BRAF genes from DNA, and the ERBB2, and the ALK, ROS1, and RET fusion genes from RNA. We focused on high specificity and sensitivity (≥0.99) and even included samples with a cancer cell content of 1%. The MINtS enables testing of more than 100 samples in a single run, making it possible to process a large number of samples submitted to a central laboratory, and reducing the cost for a single sample. We investigated 96 cytological samples and 190 surgically resected tissues, both of which are isolated in daily clinical practice. With the cytological samples, we compared the results for the EGFR mutation between the MINtS and the PNA-LNA PCR clamp test, and their results were 99% consistent. In the snap-frozen tissue samples, 188/190 (99%) samples were successfully analyzed for all genes investigated using both DNA and RNA. Then, we used 200 cytological samples that were serially isolated in clinical practice to assess RNA quality. Using our procedure, 196 samples (98%) provided high-quality RNA suitable for analysis with the MINtS. We concluded that the MINtS test system is feasible for analyzing “druggable” genes using cytological samples and snap-frozen tissue samples. The MINtS will fill a needs for patients for whom only cytological specimens are available for genetic testing.
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Affiliation(s)
- Yoshiaki Inoue
- Graduate School, Saitama Medical University, Moroyama, Saitama, Japan
- Department of General Thoracic Surgery, Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Jun Shiihara
- Department of Respiratory Medicine, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Hitoshi Miyazawa
- Department of Respiratory Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Hiromitsu Ohta
- Department of Respiratory Medicine, Jichi Medical University, Saitama, Saitama, Japan
| | - Megumi Higo
- Clinical Laboratories for Cardiovascular Diseases, Jichi Medical University, Saitama, Saitama, Japan
| | - Yoshiaki Nagai
- Department of Respiratory Medicine, Jichi Medical University, Saitama, Saitama, Japan
| | - Kunihiko Kobayashi
- Department of Respiratory Medicine, Saitama International Medical Center, Hidaka, Saitama, Japan
| | - Yasuo Saijo
- Department of Medical Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan
| | - Masanori Tsuchida
- Department of Thoracic and Cardiovascular Surgery, Graduate School of Medical and Dental Sceinces, Niigata University, Niigata, Niigata, Japan
| | - Mitsuo Nakayama
- Department of General Thoracic Surgery, Saitama Medical Center, Kawagoe, Saitama, Japan
| | - Koichi Hagiwara
- Clinical Laboratories for Cardiovascular Diseases, Jichi Medical University, Saitama, Saitama, Japan
- Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
- * E-mail:
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14
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Bakhtiary Z, Barar J, Aghanejad A, Saei AA, Nemati E, Ezzati Nazhad Dolatabadi J, Omidi Y. Microparticles containing erlotinib-loaded solid lipid nanoparticles for treatment of non-small cell lung cancer. Drug Dev Ind Pharm 2017; 43:1244-1253. [PMID: 28323493 DOI: 10.1080/03639045.2017.1310223] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Non-small cell lung cancer (NSCLC) patients with sensitizing mutations in the exons 18-21 of the epithelial growth factor receptor (EGFR) gene show increased kinase activity of EGFR. Hence, tyrosine kinase inhibitors (TKIs) such as erlotinib (ETB) have commonly been used as the second line therapeutic option for the treatment of metastatic NSCLC. While the ETB is available as an oral dosage form, the local delivery of this TKI to the diseased cells of the lung may ameliorate its therapeutic impacts. In the current study, we report on the development of ETB-loaded solid lipid nanoparticle (SLN) based formulation of dry powder inhaler (ETB-SLN DPI). ETB-SLNs were formulated using designated amount of compritol/poloxamer 407. The engineered ETB-SLNs showed sub-100 nm spherical shape with an encapsulation efficiency of 78.21%. MTT assay and DAPI staining revealed that the ETB-SLNs enhanced the cytotoxicity of cargo drug molecules in the human alveolar adenocarcinoma epithelial A549 cells as a model for NSCLC. To attain the ETB-SLN DPI, the ETB-SLNs were efficiently spray dried into microparticles (1-5 μm) along with mannitol. The ETB-SLN DPI powder displayed suitable flowability and aerodynamic traits. The Carr's Index, Hausner ratio and Next Generation Impactor (NGI) analyses confirmed deep inhalation pattern of the formulation. Based on these findings, we propose the ETB-SLN DPI as a promising treatment modality for the NSCLC patients.
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Affiliation(s)
- Zahra Bakhtiary
- a Student Research Committee, Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Jaleh Barar
- b Research Center for Pharmaceutical Nanotechnology , Tabriz University of Medical Sciences , Tabriz , Iran.,c Department of Pharmaceutics, Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Ayuob Aghanejad
- b Research Center for Pharmaceutical Nanotechnology , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Amir Ata Saei
- d Division of Physiological Chemistry, Department of Medical Biochemistry and Biophysics , KarolinskaInstitutet , Stockholm , Sweden
| | - Elhameh Nemati
- b Research Center for Pharmaceutical Nanotechnology , Tabriz University of Medical Sciences , Tabriz , Iran
| | | | - Yadollah Omidi
- b Research Center for Pharmaceutical Nanotechnology , Tabriz University of Medical Sciences , Tabriz , Iran.,c Department of Pharmaceutics, Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran
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15
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Tian Y, Yu Y, Shen Y, Wan H, Chang S, Zhang T, Wan S, Zhang J. Molecular Simulation Studies on the Binding Selectivity of Type-I Inhibitors in the Complexes with ROS1 versus ALK. J Chem Inf Model 2017; 57:977-987. [PMID: 28318251 DOI: 10.1021/acs.jcim.7b00019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
ROS1 and ALK are promising targets of anticancer drugs for non-small-cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, the selective ROS1 inhibitor is relatively rare. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear. In order to disclose the binding preference toward ROS1 over ALK and to aid the design of selective ROS1 inhibitors, the specific interactions and difference of conformational changes in the dual and selective ROS1/ALK inhibitors systems were investigated by molecular dynamics (MD) simulation and principle component analysis (PCA) in our work. Afterward, binding free energies (MM/GBSA) and binding free energies decomposition analysis indicated that the dominating effect of Van der Waals interaction drives the specific binding process of the type-I inhibitor, and residues of the P-loop and the DFG motif would play an important role in selectivity. On the basis of the modeling results, the new designed compound 14c was verified as a selective ROS1 inhibitor versus ALK, and SMU-B was a dual ROS1/ALK inhibitor by the kinase inhibitory study. These results are expected to facilitate the discovery and rational design of novel and specific ROS1 inhibitors.
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Affiliation(s)
- Yuanxin Tian
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, 510515, People's Republic of China
| | - Yonghuan Yu
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, 510515, People's Republic of China
| | - Yudong Shen
- College of Food Sciences, South China Agricultural University , Guangzhou, 510642, People's Republic of China
| | - Hua Wan
- College of Mathematics and Informatics, South China Agricultural University , Guangzhou, 510642, People's Republic of China
| | - Shan Chang
- Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology , Changzhou, 213001, People's Republic of China
| | - Tingting Zhang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, 510515, People's Republic of China
| | - Shanhe Wan
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, 510515, People's Republic of China
| | - Jiajie Zhang
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, 510515, People's Republic of China
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16
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Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy. Surg Today 2017; 48:1-8. [PMID: 28280984 DOI: 10.1007/s00595-017-1497-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 02/07/2017] [Indexed: 12/11/2022]
Abstract
Lung adenocarcinoma (LADC) is a cancer treatable using targeted therapies against driver gene aberrations. EGFR mutations and ALK fusions are frequent gene aberrations in LADC, and personalized therapies against those aberrations have become a standard therapy. These targeted therapies have shown significant positive efficacy and tolerable toxicity compared to conventional chemotherapy, so it is necessary to identify additional druggable genetic aberrations. Other than EGFR mutations and ALK fusions, mutations in KRAS, HER2, and BRAF, and driver fusions involving RET and ROS1, have also been identified in LADC. Interestingly, the frequency of driver gene aberrations differs according to ethnicity, sex, and smoking, which leads to differences in treatment efficacy. To date, several molecular-targeted drugs against driver genes have been developed, and several clinical trials have been conducted to evaluate the efficacy. However, targeted therapies against driver-gene-negative cases have not yet been well developed. Efforts to identify a new druggable target for such cases are currently underway. Furthermore, immune checkpoint blockade therapy might be effective for driver-negative cases, especially those with accumulated mutations.
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17
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Men X, Wang L, Yu W, Ju Y. Cullin7 is required for lung cancer cell proliferation and is overexpressed in lung cancer. Oncol Res 2017; 22:123-8. [PMID: 25706399 PMCID: PMC7838442 DOI: 10.3727/096504014x14198596979742] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Ubiquitin ligase Cullin7 has been identified as an oncogene in some malignant diseases such as choriocarcinoma and neuroblastoma. However, the role of Cullin7 in lung cancer carcinogenesis remains unclear. In this study, we explored the functional role of Cullin7 in lung cancer cell proliferation and tumorigenesis and determined its expression profile in lung cancer. Knocking down Cullin7 expression by small interfering RNA (siRNA) in lung cancer cells inhibited cell proliferation and elevated the expression of p53, p27, and p21 proteins. The enhanced p53 expression resulted from activation of the DNA damage response pathway. Cullin7 knockdown markedly suppressed xenograft tumor growth in vivo in mice. Moreover, Cullin7 expression was increased in primary lung cancer tissues of humans. Thus, Cullin7 is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of lung cancer. Thus, our study provided evidence that Cullin7 functions as a novel oncogene in lung cancer and may be a potential therapeutic target for lung cancer management.
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Affiliation(s)
- Xuelin Men
- Department of Respiratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
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18
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19
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Chen Y, Huang W, Chen F, Hu G, Li F, Li J, Xuan A. Pregnane X receptors regulate CYP2C8 and P-glycoprotein to impact on the resistance of NSCLC cells to Taxol. Cancer Med 2016; 5:3564-3571. [PMID: 27878971 PMCID: PMC5224856 DOI: 10.1002/cam4.960] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 08/24/2016] [Accepted: 09/04/2016] [Indexed: 12/19/2022] Open
Abstract
Cytochrome P450 2C8 (CYP2C8) is one of the enzymes that primarily participate in producing metabolisms of medications and P‐glycoprotein (P‐gp) has been regarded as one of the important molecules in chemotherapeutically induced multidrug resistance (MDR). In addition, the pregnane X receptor (PXR) is involved in regulating both CYP2C8 and P‐gp. We aim to research the effect of PXR on Taxol‐resistant non–small‐cell lung cancer (NSCLC cells) via regulating CYP2C8 and P‐gp. NSCLC cells were treated with SR12813, LY335979, or PXR siRNA. Cell counting kit (CCK‐8) assay was used to detect cell vitality. Colony formation assay was used to observe cell proliferation. Western blotting, real‐time polymerase chain reaction (RT‐PCR), and immunofluorescence staining were conducted to analyze the expressions of PXR, CYP2C8, and P‐gp. Taxol and its metabolic products were detected by high‐performance liquid chromatography (HPLC). The expression of PXR in A549 cell line was higher than that in other cell lines. The accumulation of PXR was observed in the nucleus after cells were treated with SR12813. Besides, SR12813 induced higher expressions of CYP2C8 and P‐gp proteins. We also discovered that pretreatment with SR12813 reversed the inhibition of cell viability and proliferation after the Taxol treatment in comparison to the SR12813 untreated group. Furthermore, the hydroxylation products of Taxol analyzed by HPLC were increased in comparison to the SR12813 untreated group, indicating that high expressions of CYP2C8 and P‐gp enhanced the resistance of A549 cells to Taxol. For cells treated with PXR siRNA, cell viability, cell proliferation, and Taxol metabolites were significantly reduced after the Taxol treatment in comparison to the siRNA‐negative group. The cell viability, cell proliferation, and Taxol metabolites were regulated by the expressions of PXR, P‐gp, and CYP2C8. That is, PXR expression has an important effect on the resistance of NSCLC cells to Taxol via upregulating P‐gp and CYP2C8.
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Affiliation(s)
- Yan Chen
- Department of Respiratory, Liwan Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510170, China
| | - Wandan Huang
- Department of Anatomy, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Feiyu Chen
- Department of Anatomy, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Guoping Hu
- Department of Respiratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510170, China
| | - Fenglei Li
- Department of Respiratory, Liwan Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510170, China
| | - Jianhua Li
- Department of Physiology, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Aiguo Xuan
- Department of Anatomy, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.,Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Collaborative Innovation Center for Neurogenetics and Channelopathies, Guangzhou, Guangdong, 510260, China
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20
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Schildgen V, Lüsebrink J, Schildgen O, Stoelben E, Brockmann M. Epidemiology of driver mutations in lung cancer in a German tertiary hospital in patients with testing indication. Per Med 2016; 13:315-323. [PMID: 29749816 DOI: 10.2217/pme.16.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND KRAS, BRAF, EGFR and ALK-mutation testing is a prerequisite for non-small-cell lung cancer treatments, but there remains limited epidemiological information about such mutations in German cohorts. MATERIALS & METHODS Between February 2010 and June 2015, a total of 1080 tumor samples from 1019 non-small-cell lung cancer patients were analyzed for KRAS, BRAF, EGFR and ALK-mutations by Therascreen-pyrosequencing and FISH. RESULTS Mutation patterns differed dependent on the histological subtype and sex. Mainly, adenocarcinomas were mutated and formed the major histological group. Double mutations were observed also not explicitly screened for. In our German cohort, female adenocarcinoma patients had statistically significantly higher rates EGFR mutations than male patients. DISCUSSION The different mutation patterns dependent on histological phenotypes warrant further epidemiological studies while suggesting different mechanisms of cancerogenesis.
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Affiliation(s)
- Verena Schildgen
- Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke mit Sitz in Köln Ostmerheimer Str 200., Institut für Pathologie, D-51109 Köln (Cologne) Germany
| | - Jessica Lüsebrink
- Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke mit Sitz in Köln Ostmerheimer Str 200., Institut für Pathologie, D-51109 Köln (Cologne) Germany
| | - Oliver Schildgen
- Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke mit Sitz in Köln Ostmerheimer Str 200., Institut für Pathologie, D-51109 Köln (Cologne) Germany
| | - Erich Stoelben
- Klinikum der Privaten Universität Witten/Herdecke mit Sitz in Köln Ostmerheimer Str. 200, Kliniken der Stadt Köln gGmbH, Lungenklinik/Thoraxchirurgie, D-51109 Köln (Cologne) Germany
| | - Michael Brockmann
- Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke mit Sitz in Köln Ostmerheimer Str 200., Institut für Pathologie, D-51109 Köln (Cologne) Germany
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21
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Bhardwaj B, Revannasiddaiah S, Bhardwaj H, Balusu S, Shwaiki A. Molecular targeted therapy to improve radiotherapeutic outcomes for non-small cell lung carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:50. [PMID: 26904572 DOI: 10.3978/j.issn.2305-5839.2015.10.35] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Effective treatments for non-small cell lung carcinoma (NSCLC) remain elusive. The use of concurrent chemotherapy with radiotherapy (RT) has improved outcomes, but a significant proportion of NSCLC patients are too frail to be able to tolerate an intense course of concurrent chemoradiotherapy. The development of targeted therapies ignited new hope in enhancing radiotherapeutic outcomes. The use of targeted therapies against the epidermal growth factor receptor (EGFR) has offered slight but significant benefits in concurrent use with RT for certain patients in certain situations. However, despite theoretical promise, the use of anti-angiogenics, such as bevacizumab and endostatin, has not proven clinically safe or useful in combination with RT. However, many new targeted agents against new targets are being experimented for combined use with RT. It is hoped that these agents may provide a significant breakthrough in the radiotherapeutic management of NSCLC. The current review provides a brief discussion about the targets, the targeted therapies, the rationale for the use of targeted therapies in combination with RT, and a brief review of the existing data on the subject.
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Affiliation(s)
- Bhaskar Bhardwaj
- 1 Department of Internal medicine, University of Missouri, Kansas City, MO, USA ; 2 Department of Radiation Oncology, Government Medical College, Haldwani, Nanital, India ; 3 Department of Pulmonary Medicine and Critical Care, University of Oklahoma, Norman, OK, USA ; 4 Department of Internal Medicine, University of Missouri, Kansas City, MO, USA ; 5 Department of Hematology and Oncology, Saint Luke's Hospital, Kansas City, MO, USA
| | - Swaroop Revannasiddaiah
- 1 Department of Internal medicine, University of Missouri, Kansas City, MO, USA ; 2 Department of Radiation Oncology, Government Medical College, Haldwani, Nanital, India ; 3 Department of Pulmonary Medicine and Critical Care, University of Oklahoma, Norman, OK, USA ; 4 Department of Internal Medicine, University of Missouri, Kansas City, MO, USA ; 5 Department of Hematology and Oncology, Saint Luke's Hospital, Kansas City, MO, USA
| | - Himanshu Bhardwaj
- 1 Department of Internal medicine, University of Missouri, Kansas City, MO, USA ; 2 Department of Radiation Oncology, Government Medical College, Haldwani, Nanital, India ; 3 Department of Pulmonary Medicine and Critical Care, University of Oklahoma, Norman, OK, USA ; 4 Department of Internal Medicine, University of Missouri, Kansas City, MO, USA ; 5 Department of Hematology and Oncology, Saint Luke's Hospital, Kansas City, MO, USA
| | - Sree Balusu
- 1 Department of Internal medicine, University of Missouri, Kansas City, MO, USA ; 2 Department of Radiation Oncology, Government Medical College, Haldwani, Nanital, India ; 3 Department of Pulmonary Medicine and Critical Care, University of Oklahoma, Norman, OK, USA ; 4 Department of Internal Medicine, University of Missouri, Kansas City, MO, USA ; 5 Department of Hematology and Oncology, Saint Luke's Hospital, Kansas City, MO, USA
| | - Ali Shwaiki
- 1 Department of Internal medicine, University of Missouri, Kansas City, MO, USA ; 2 Department of Radiation Oncology, Government Medical College, Haldwani, Nanital, India ; 3 Department of Pulmonary Medicine and Critical Care, University of Oklahoma, Norman, OK, USA ; 4 Department of Internal Medicine, University of Missouri, Kansas City, MO, USA ; 5 Department of Hematology and Oncology, Saint Luke's Hospital, Kansas City, MO, USA
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22
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Kanthala S, Pallerla S, Jois S. Current and future targeted therapies for non-small-cell lung cancers with aberrant EGF receptors. Future Oncol 2015; 11:865-78. [PMID: 25757687 DOI: 10.2217/fon.14.312] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Expression of the EGF receptors (EGFRs) is abnormally high in many types of cancer, including 25% of lung cancers. Successful treatments target mutations in the EGFR tyrosine kinase domain with EGFR tyrosine kinase inhibitors (TKIs). However, almost all patients develop resistance to this treatment, and acquired resistance to first-generation TKI has prompted the clinical development of a second generation of EGFR TKI. Because of the development of resistance to treatment of TKIs, there is a need to collect genomic information about EGFR levels in non-small-cell lung cancer patients. Herein, we focus on current molecular targets that have therapies available as well as other targets for which therapies will be available in the near future.
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Affiliation(s)
- Shanthi Kanthala
- Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA
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23
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Lin CC, Chen JT, Lin MW, Chan CH, Wen YF, Wu SB, Chung TW, Lyu KW, Chou HC, Chan HL. Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance. Toxicol Appl Pharmacol 2015; 288:359-73. [PMID: 26298006 DOI: 10.1016/j.taap.2015.08.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/27/2015] [Accepted: 08/14/2015] [Indexed: 10/23/2022]
Abstract
Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12-18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC.
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Affiliation(s)
- Chi-Chen Lin
- Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan; Institute of Biomedical Science, and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taiwan; Department of Medical Research and Education, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Jing-Ting Chen
- Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Meng-Wei Lin
- Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan
| | - Chia-Hao Chan
- Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital, Hsinchu 30071, Taiwan
| | - Yueh-Feng Wen
- Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
| | - Shin-Bei Wu
- Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan
| | - Ting-Wen Chung
- Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Kevin W Lyu
- Lutheran Medical Center, Brooklyn, NY, USA; Global Scholars Program, St. George's University/Northumbria University, Newcastle upon Tyne, United Kingdom
| | - Hsiu-Chuan Chou
- Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan.
| | - Hong-Lin Chan
- Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.
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25
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Cummings CT, Linger RMA, Cohen RA, Sather S, Kirkpatrick GD, Davies KD, DeRyckere D, Earp HS, Graham DK. Mer590, a novel monoclonal antibody targeting MER receptor tyrosine kinase, decreases colony formation and increases chemosensitivity in non-small cell lung cancer. Oncotarget 2015; 5:10434-45. [PMID: 25372020 PMCID: PMC4279384 DOI: 10.18632/oncotarget.2142] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 06/24/2014] [Indexed: 01/04/2023] Open
Abstract
The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC) have demonstrated the substantial survival gains made possible by precision therapy. However, the majority of patients do not have tumors with genetic alterations responsive to these therapies, and therefore identification of new targets is needed. Our laboratory previously identified MER receptor tyrosine kinase as one such potential target. We now report our findings targeting MER with a clinically translatable agent – Mer590, a monoclonal antibody specific for MER. Mer590 rapidly and robustly reduced surface and total MER levels in multiple cell lines. Treatment reduced surface MER levels by 87%, and this effect was maximal within four hours. Total MER levels were also dramatically reduced, and this persisted for at least seven days. Mechanistically, MER down-regulation was mediated by receptor internalization and degradation, leading to inhibition of downstream signaling through STAT6, AKT, and ERK1/2. Functionally, this resulted in increased apoptosis, increased chemosensitivity to carboplatin, and decreased colony formation. In addition to carboplatin, Mer590 interacted cooperatively with shRNA-mediated MER inhibition to augment apoptosis. These data demonstrate that MER inhibition can be achieved with a monoclonal antibody in NSCLC. Optimization toward a clinically available anti-MER antibody is warranted.
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Affiliation(s)
- Christopher T Cummings
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rachel M A Linger
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Department of Biomedical Sciences, Rocky Vista University College of Osteopathic Medicine, Parker, CO, USA
| | - Rebecca A Cohen
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Susan Sather
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Gregory D Kirkpatrick
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kurtis D Davies
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Deborah DeRyckere
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - H Shelton Earp
- Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Douglas K Graham
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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26
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Cummings CT, Zhang W, Davies KD, Kirkpatrick GD, Zhang D, DeRyckere D, Wang X, Frye SV, Earp HS, Graham DK. Small Molecule Inhibition of MERTK Is Efficacious in Non-Small Cell Lung Cancer Models Independent of Driver Oncogene Status. Mol Cancer Ther 2015; 14:2014-22. [PMID: 26162689 DOI: 10.1158/1535-7163.mct-15-0116] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 06/25/2015] [Indexed: 12/20/2022]
Abstract
Treatment of non-small cell lung cancer (NSCLC) has been transformed by targeted therapies directed against molecular aberrations specifically activated within an individual patient's tumor. However, such therapies are currently only available against a small number of such aberrations, and new targets and therapeutics are needed. Our laboratory has previously identified the MERTK receptor tyrosine kinase (RTK) as a potential drug target in multiple cancer types, including NSCLC. We have recently developed UNC2025--the first-in-class small molecule inhibitor targeting MERTK with pharmacokinetic properties sufficient for clinical translation. Here, we utilize this compound to further validate the important emerging biologic functions of MERTK in lung cancer pathogenesis, to establish that MERTK can be effectively targeted by a clinically translatable agent, and to demonstrate that inhibition of MERTK is a valid treatment strategy in a wide variety of NSCLC lines independent of their driver oncogene status, including in lines with an EGFR mutation, a KRAS/NRAS mutation, an RTK fusion, or another or unknown driver oncogene. Biochemically, we report the selectivity of UNC2025 for MERTK, and its inhibition of oncogenic downstream signaling. Functionally, we demonstrate that UNC2025 induces apoptosis of MERTK-dependent NSCLC cell lines, while decreasing colony formation in vitro and tumor xenograft growth in vivo in murine models. These findings provide further evidence for the importance of MERTK in NSCLC, and demonstrate that MERTK inhibition by UNC2025 is a feasible, clinically relevant treatment strategy in a wide variety of NSCLC subtypes, which warrants further investigation in clinical trials.
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Affiliation(s)
- Christopher T Cummings
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Weihe Zhang
- Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kurtis D Davies
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Gregory D Kirkpatrick
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Dehui Zhang
- Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Deborah DeRyckere
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Xiaodong Wang
- Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Stephen V Frye
- Center for Integrative Chemical Biology and Drug Discovery and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
| | - H Shelton Earp
- Department of Medicine, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Douglas K Graham
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and can be further classified as nonsquamous carcinoma (including adenocarcinoma, which accounts for 40 % of NSCLCs) and squamous NSCLC, which makes up 30 % of NSCLC cases. The emergence of inhibitors of epidermal growth factor receptors, anaplastic lymphoma kinase, and vascular endothelial growth factors (VEGF) in the last decade has resulted in steady improvement in clinical outcomes for patients with advanced lung adenocarcinoma. However, improvements in the survival of patients with squamous NSCLC have remained elusive, presenting an urgent need for understanding and investigating therapeutically relevant molecular targets, specifically in squamous NSCLC. Although anti-VEGF therapy has been studied in squamous NSCLC, progress has been slow, in part due to issues related to pulmonary hemorrhage. In addition to these safety concerns, several phase III trials that initially included patients with squamous NSCLC failed to demonstrate improved overall survival (primary endpoint) with the addition of antiangiogenic therapy to chemotherapy compared with chemotherapy alone. Angiogenesis is an established hallmark of tumor progression and metastasis, and the role of VEGF signaling in angiogenesis is well established. However, some studies suggest that, while inhibiting VEGF signaling may be beneficial, prolonged exposure to VEGF/VEGF receptor (VEGFR) inhibitors may allow tumor cells to utilize alternative angiogenic mechanisms and become resistant. As a result, agents that target multiple angiogenic pathways simultaneously are also under evaluation. This review focuses on current and investigational antiangiogenic targets in squamous NSCLC, including VEGF/VEGFRs, fibroblast growth factor receptors, platelet-derived growth factor receptors, and angiopoietin. Additionally, clinical trials investigating VEGF- and multi-targeted antiangiogenic therapies are discussed.
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Affiliation(s)
- Bilal Piperdi
- Montefiore Medical Center, 1300 Morris Park Avenue, Mazur Building, Room 616, Bronx, NY, 10461, USA,
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28
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Nicoś M, Krawczyk P, Jarosz B, Sawicki M, Szumiłło J, Trojanowski T, Milanowski J. Analysis of KRAS and BRAF genes mutation in the central nervous system metastases of non-small cell lung cancer. Clin Exp Med 2015; 16:169-76. [PMID: 25902737 PMCID: PMC4844634 DOI: 10.1007/s10238-015-0349-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 04/02/2015] [Indexed: 12/24/2022]
Abstract
KRAS mutations are associated with tumor resistance to EGFR TKIs (erlotinib, gefitinib) and to monoclonal antibody against EGFR (cetuximab). Targeted treatment of mutated RAS patients is still considered as a challenge. Inhibitors of c-Met (onartuzumab or tiwantinib) and MEK (selumetinib—a dual inhibitor of MEK1 and MEK2) signaling pathways showed activity in patients with mutations in KRAS that can became an effective approach in carriers of such disorders. BRAF mutation is very rare in patients with NSCLC, and its presence is associated with sensitivity of tumor cells to BRAF inhibitors (vemurafenib, dabrafenib). In the present study, the frequency and type of KRAS and BRAF mutation were assessed in 145 FFPE tissue samples from CNS metastases of NSCLC. In 30 patients, material from the primary tumor was simultaneously available. Real-time PCR technique with allele-specific molecular probe (KRAS/BRAF Mutation Analysis Kit, Entrogen, USA) was used for molecular tests. KRAS mutations were detected in 21.4 % of CNS metastatic lesions and in 23.3 % of corresponding primary tumors. Five mutations were identified both in primary and in metastatic lesions, while one mutation only in primary tumor and one mutation only in the metastatic tumor. Most of mutations were observed in codon 12 of KRAS; however, an individual patient had diagnosed a rare G13D and Q61R substitutions. KRAS mutations were significantly more frequent in adenocarcinoma patients and smokers. Additional analysis indicated one patient with rare coexistence of KRAS and DDR2 mutations. BRAF mutation was not detected in the examined materials. KRAS frequency appears to be similar in primary and CNS.
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Affiliation(s)
- Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland. .,Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091, Warsaw, Poland.
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland
| | - Bożena Jarosz
- Pathological Laboratory, Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, 20-954, Lublin, Poland
| | - Marek Sawicki
- Department of Thoracic Surgery, Medical University of Lublin, 20-954, Lublin, Poland
| | - Justyna Szumiłło
- Department of Pathomorphology, Medical University of Lublin, 20-954, Lublin, Poland
| | - Tomasz Trojanowski
- Pathological Laboratory, Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, 20-954, Lublin, Poland
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland
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29
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Song M. Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small-Cell Lung Cancer. J Med Chem 2015; 58:3672-81. [DOI: 10.1021/jm501464c] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Minsoo Song
- New Drug
Development Center (NDDC), Daegu-Gyeongbuk
Medical Innovation Foundation (DGMIF), 80 Cheombok-ro, Dong-gu, Daegu 701-310, Korea
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30
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Jurmeister P, Lenze D, Berg E, Mende S, Schäper F, Kellner U, Herbst H, Sers C, Budczies J, Dietel M, Hummel M, von Laffert M. Parallel screening for ALK, MET and ROS1 alterations in non-small cell lung cancer with implications for daily routine testing. Lung Cancer 2014; 87:122-9. [PMID: 25534130 DOI: 10.1016/j.lungcan.2014.11.018] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/08/2014] [Accepted: 11/30/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVES ALK, MET and ROS1 are prognostic and predictive markers in NSCLC, which need to be implemented in daily routine. To evaluate different detection approaches and scoring systems for optimal stratification of patients eligible for mutation testing in the future, we screened a large and unselected cohort of NSCLCs for all three alterations. MATERIAL AND METHODS Using tissue microarrays, 473 surgically resected NSCLCs were tested for ALK and MET expression by IHC and genomic alterations in the ALK, MET and ROS1 gene by FISH. For MET IHC, two different criteria (MetMAb and H-score), for MET FISH, three different scoring systems (UCCC, Cappuzzo, PathVysion) were investigated. RESULTS ALK and ROS1 positivity was seen in 2.6% and 1.3% of all ADCs, respectively, but not in pure SCCs. One ROS1 translocated tumor showed additional ROS1 amplification. MET IHC+/FISH+ cases were found in both histological subtypes (8.6% in all NSCLCs; 10.6% in ADCs; 5.0% in SCCs) and were associated with pleural invasion, lymphatic vessel invasion and lymph node metastasis. MET altered ADCs more frequently showed a papillary growth pattern. Whereas ALK testing revealed homogenous results in IHC and FISH, we saw discordant results for MET in about 10% of cases. Both METIHC scoring systems revealed almost identical results. We did not encounter any combined FISH positivity for ALK, MET or ROS1. However, three ALK positive cases harbored MET overexpression. CONCLUSION In daily routine, IHC could support FISH in the identification of ALK altered NSCLCs. Further research is needed to assess the role of discordant MET results by means of IHC and FISH as well as the relevance of tumors with an increased ROS1 gene copy number.
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Affiliation(s)
- Philipp Jurmeister
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Dido Lenze
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Erika Berg
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Stefanie Mende
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Frank Schäper
- Pathology-Berlin, Bioptisches Institut Gemeinschaftspraxis für Pathologie, Lindenberger Weg 27, 13125 Berlin, Germany
| | - Udo Kellner
- Institute of Pathology, Johannes Wesling Klinikum Minden, Hans-Nolte-Straße 1, 32429 Minden, Germany
| | - Hermann Herbst
- Institute of Pathology, Vivantes Klinikum Berlin, Oranienburger Straße 285, 13437 Berlin, Germany
| | - Christine Sers
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Jan Budczies
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Manfred Dietel
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Michael Hummel
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Maximilian von Laffert
- Institute of Pathology, Campus Charité Mitte, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
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Revannasiddaiah S, Thakur P, Bhardwaj B, Susheela SP, Madabhavi I. Pulmonary adenocarcinoma: implications of the recent advances in molecular biology, treatment and the IASLC/ATS/ERS classification. J Thorac Dis 2014; 6:S502-25. [PMID: 25349702 DOI: 10.3978/j.issn.2072-1439.2014.05.19] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 05/16/2014] [Indexed: 12/13/2022]
Abstract
A decade ago, lung cancer could conveniently be classified into two broad categories-either the small cell lung carcinoma (SCLC), or the non-small cell lung carcinoma (NSCLC), mainly to assist in further treatment related decision making. However, the understanding regarding the eligibility of adenocarcinoma histology for treatments with agents such as pemetrexed and bevacizumab made it a necessity for NSCLC to be classified into more specific sub-groups. Then, the availability of molecular targeted therapy with oral tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib not only further emphasized the need for accurate sub-classification of lung cancer, but also heralded the important role of molecular profiling of lung adenocarcinomas. Given the remarkable advances in molecular biology, oncology and radiology, a need for felt for a revised classification for lung adenocarcinoma, since the existing World Health Organization (WHO) classification of lung cancer, published in the year 2004 was mainly a pathological system of classification. Thus, there was a combined effort by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) with an effort to inculcate newly established perspectives from clinical, molecular and radiological aspects in evolving a modern classification for lung adenocarcinomas. This review provides a summary of the recent advances in molecular biology and molecular targeted therapy with respect to lung adenocarcinoma. Also, a brief summation of the salient recommendations provided in the IASLC/ATS/ERS classification of lung adenocarcinomas is provided. Lastly, a discussion regarding the future prospects with lung adenocarcinoma is included.
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Affiliation(s)
- Swaroop Revannasiddaiah
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Priyanka Thakur
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Bhaskar Bhardwaj
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Sridhar Papaiah Susheela
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Irappa Madabhavi
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
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Jacobsen B, Kriegbaum MC, Santoni-Rugiu E, Ploug M. C4.4A as a biomarker in pulmonary adenocarcinoma and squamous cell carcinoma. World J Clin Oncol 2014; 5:621-632. [PMID: 25302166 PMCID: PMC4129527 DOI: 10.5306/wjco.v5.i4.621] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 03/10/2014] [Accepted: 06/16/2014] [Indexed: 02/06/2023] Open
Abstract
The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uPAR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasive carcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.
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Cohen RL, Settleman J. From cancer genomics to precision oncology--tissue's still an issue. Cell 2014; 157:1509-14. [PMID: 24949964 DOI: 10.1016/j.cell.2014.05.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 05/21/2014] [Indexed: 10/25/2022]
Abstract
Rapidly evolving genome technology has enabled extensive molecular analysis of limited tumor biopsy material, thereby facilitating the broader implementation of personalized cancer medicine. However, genomics-based patient stratification across diverse tumor types is unlikely to supplant tissue-of-origin considerations in addressing clinical needs, including the development and application of novel "rationally targeted" cancer therapies.
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Affiliation(s)
- Robert L Cohen
- Calico Life Sciences, Suite 1200, 601 Gateway Boulevard, South San Francisco, CA 94080, USA
| | - Jeff Settleman
- Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol Oncol 2014; 8:1495-507. [PMID: 24962792 DOI: 10.1016/j.molonc.2014.06.001] [Citation(s) in RCA: 132] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 05/23/2014] [Accepted: 06/03/2014] [Indexed: 12/16/2022] Open
Abstract
The NTRK1 gene encodes Tropomyosin-related kinase A (TRKA), the high-affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3-NTRK1) resulting in expression of the oncogenic chimeric protein TPM3-TRKA, but there has been no subsequent report regarding the relevance of this oncogene in CRC. The KM12 human CRC cell line expresses the chimeric TPM3-TRKA protein and is hypersensitive to TRKA kinase inhibition. We report the detailed characterization of the TPM3-NTRK1 genomic rearrangement in KM12 cells and through a cellular screening approach, the identification of NMS-P626, a novel highly potent and selective TRKA inhibitor. NMS-P626 suppressed TPM3-TRKA phosphorylation and downstream signaling in KM12 cells and showed remarkable antitumor activity in mice bearing KM12 tumors. Finally, using quantitative reverse transcriptase PCR and immunohistochemistry (IHC) we identified the TPM3-NTRK1 rearrangement in a CRC clinical sample, therefore suggesting that this chromosomal translocation is indeed a low frequency recurring event in CRC and that such patients might benefit from therapy with TRKA kinase inhibitors.
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Vansteenkiste JF. Ceritinib for treatment of ALK-rearranged advanced non-small-cell lung cancer. Future Oncol 2014; 10:1925-39. [PMID: 24856155 DOI: 10.2217/fon.14.94] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The anaplastic lymphoma kinase (ALK) gene plays a key role in the pathogenesis of selected tumors, including non-small-cell lung cancer (NSCLC). Patients with ALK-rearranged NSCLC are initially sensitive to the ALK inhibitor crizotinib but eventually become resistant, limiting its therapeutic potential. Ceritinib is an oral second-generation ALK inhibitor with greater preclinical antitumor potency than crizotinib in ALK-positive NSCLC. A Phase I trial of ceritinib in ALK-positive tumors demonstrated good activity in patients with advanced NSCLC, including those who had progressed on crizotinib. Adverse events are similar to those seen with other ALK tyrosine kinase inhibitors and are generally manageable. Ongoing trials are evaluating ceritinib in patients with ALK-rearranged NSCLC treated with prior chemotherapy and/or crizotinib.
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Affiliation(s)
- Johan F Vansteenkiste
- University Hospital KU Leuven, Respiratory Oncology Unit (Pulmonology), Herestraat 49, Leuven B-3000, Belgium.
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