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Chalitsios CV, Markozannes G, Papagiannopoulos C, Aglago EK, Berndt SI, Buchanan DD, Campbell PT, Cao Y, Chan AT, Dimou N, Drew DA, French AJ, Georgeson P, Giannakis M, Gruber SB, Gunter MJ, Harrison TA, Hoffmeister M, Hsu L, Huang WY, Hullar MAJ, Huyghe JR, Lynch BM, Moreno V, Newton CC, Nowak JA, Obón-Santacana M, Ogino S, Qu C, Schmit SL, Steinfelder RS, Sun W, Thomas CE, Toland AE, Trinh QM, Ugai T, Um CY, Van Guelpen B, Zaidi SH, Murphy N, Peters U, Phipps AI, Tsilidis KK. Waist Circumference, a Body Shape Index, and Molecular Subtypes of Colorectal Cancer: A Pooled Analysis of Four Cohort Studies. Cancer Epidemiol Biomarkers Prev 2025; 34:568-577. [PMID: 39898780 DOI: 10.1158/1055-9965.epi-24-1534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/27/2024] [Accepted: 01/29/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Waist circumference (WC) and its allometric counterpart, "a body shape index" (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease. METHODS Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively. RESULTS Higher WC (ORper 5 cm = 1.06, 95% confidence interval, 1.04-1.09) and ABSI (ORper 1-SD = 1.07, 95% confidence interval, 1.00-1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis. CONCLUSIONS Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention. IMPACT The proposed results have potential utility in colorectal cancer prevention.
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Affiliation(s)
| | - Georgios Markozannes
- Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | | | - Elom K Aglago
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia
- University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, Australia
- Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Australia
| | - Peter T Campbell
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri
- Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, Missouri
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Niki Dimou
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - David A Drew
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Amy J French
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Peter Georgeson
- Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, Australia
- University of Melbourne Centre for Cancer Research, The University of Melbourne, Parkville, Australia
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Stephen B Gruber
- Department of Medical Oncology and Therapeutics Research and Center for Precision Medicine, City of Hope National Medical Center, Duarte, California
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Biostatistics, University of Washington, Seattle, Washington
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Meredith A J Hullar
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Brigid M Lynch
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
| | - Victor Moreno
- Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Christina C Newton
- Department of Population Science, American Cancer Society, Atlanta, Georgia
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mireia Obón-Santacana
- Unit of Biomarkers and Suceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain
- ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Stephanie L Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
- Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, Ohio
| | - Robert S Steinfelder
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Wei Sun
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Claire E Thomas
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Amanda E Toland
- Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Quang M Trinh
- Ontario Institute for Cancer Research, Toronto, Canada
| | - Tomotaka Ugai
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts
| | - Caroline Y Um
- Department of Population Science, American Cancer Society, Atlanta, Georgia
| | - Bethany Van Guelpen
- Department of Diagnostics and Intervention, Oncology Unit, Umeå University, Umeå, Sweden
- Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Syed H Zaidi
- Ontario Institute for Cancer Research, Toronto, Canada
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
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Razzaq S, Fatima I, Moafian Z, Rahdar A, Fathi-Karkan S, Kharaba Z, Shirzad M, Khan A, Pandey S. Nanomedicine innovations in colon and rectal cancer: advances in targeted drug and gene delivery systems. Med Oncol 2025; 42:113. [PMID: 40097759 DOI: 10.1007/s12032-025-02670-z] [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: 01/01/2025] [Accepted: 03/04/2025] [Indexed: 03/19/2025]
Abstract
Nanotechnology has revolutionized cancer diagnostics and therapy, offering unprecedented possibilities to overcome the constraints of conventional treatments. This study provides a detailed overview of the current progress and difficulties in the creation of nanostructured materials, with a specific emphasis on their use in drug and gene delivery systems. The study examines tactics that attempt to improve the effectiveness and safety of chemotherapeutic drugs such as doxorubicin (Dox) by focusing on the potential of antibody-drug conjugates and functionalized nanoparticles. Moreover, it clarifies the challenges encountered in administering nanoparticles orally for gastrointestinal treatments, emphasizing the crucial physicochemical properties that affect their behavior in the gastrointestinal system. This study highlights the transformational potential of nanostructured materials in precision oncology by examining advanced breakthroughs such cell membrane-camouflaged nanoparticles and inorganic nanoparticles designed for gastrointestinal disorders. The text investigates the processes involved in the absorption of nanoparticles and their destruction in lysosomes, revealing the many methods in which enterocytes take up these particles. This study strongly supports the use of advanced nanoparticle-based methods to reduce the harmful effects on the whole body and improve the effectiveness of therapy, based on a thorough examination of current experiments on animals and humans. The main objective of this paper is to provide a fundamental comprehension that will stimulate more investigation and practical use in the field of cancer nanomedicine, advancing its boundaries.
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Affiliation(s)
- Sobia Razzaq
- School of Pharmacy, University of Management and Technology, Lahore, Punjab, Pakistan
| | - Iqra Fatima
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Zeinab Moafian
- Department of Chemistry and Biochemistry, University of Delaware, Newark, USA
| | - Abbas Rahdar
- Department of Physics, Faculty of Sciences, University of Zabol, Zabol, 538-98615, Iran.
| | - Sonia Fathi-Karkan
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, 94531-55166, Iran.
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, 9414974877, Iran.
| | - Zelal Kharaba
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, UAE
| | - Maryam Shirzad
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ahmad Khan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
| | - Sadanand Pandey
- School of Bioengineering and Food Technology, Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, 173229, Himachal Pradesh, India.
- Department of Chemistry, College of Natural Science, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
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C M, Pasha TY, Rahamathulla M, H P G, B L K, K M G, K N P, Hussain SM, Ahmed MM, Shivanandappa TB, Pasha I. Epidermal growth factor receptors unveiled: a comprehensive survey on mutations, clinical insights of global inhibitors, and emergence of heterocyclic derivatives as EGFR inhibitors. J Drug Target 2025:1-19. [PMID: 39756062 DOI: 10.1080/1061186x.2024.2449495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 12/09/2024] [Accepted: 12/21/2024] [Indexed: 01/07/2025]
Abstract
Mutations that overexpress the epidermal growth factor receptor (EGFR) are linked to cancers like breast (15-20%), head and neck (10-15%), colorectal (5-8%), and non-small cell lung cancer (10-50%), especially in East Asian populations. EGFR activation stimulates 'RAS/RAF/MEK/ERK, PI3K/Akt, and MAPK' pathways, which enhance cell division, survival, angiogenesis, and tumour growth while inhibiting apoptosis and metastasis. Secondary mutations (e.g. 'T790M', 'C797S'), off-target effects, and resistance due to alternate pathway activation reduce the efficacy of currently available EGFR inhibitors. To address these issues, 'novel heterocyclic inhibitors with structural versatility were developed to improve selectivity and binding affinity for mutant EGFR forms'. These new EGFR reduce side effects, enhance pharmacokinetics, and enhance therapeutic efficacy at low concentrations. This review focuses on 'EGFR mutations in various cancers' detailing the biochemical effects, clinical profiles, and binding interactions of globally approved EGFR inhibitors. Furthermore, it focuses into recent progress in nano-formulations and the development of heterocyclic derivatives that can successfully 'target mutant EGFRs' through varied synthesis methods. These inhibitors have the potential to have better binding affinities, selectivity's, and less side-effect. Further research required to refine the structures and develop nanoformulations of EGFR-targeted therapeutics in order to improve therapeutic efficiency and, provide more effective cancer treatments.
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Affiliation(s)
- Manojmouli C
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - T Y Pasha
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Mohamed Rahamathulla
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Al Faraa 62223, Abha, Saudi Arabia
| | - Gagana H P
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Kavya B L
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Gagana K M
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Purushotham K N
- Department of Pharmaceutical Chemistry, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B. G. Nagara, Karnataka, India
| | - Shalam M Hussain
- Department of Clinical Pharmacy, College of Nursing and Health Science. Al-Rayyan Medical College, Madinah, Saudi Arabia
| | - Mohammed Muqtader Ahmed
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Ismail Pasha
- Department of Pharmacology, Orotta College of Medicine and Health Sciences, Asmara University, Asmara, State of Eritrea
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Kong R, Huang J, Wu Y, Yan N, Chen X, Cheng H. Tricomponent immunoactivating nanomedicine to downregulate PD-L1 and polarize macrophage for photodynamic immunotherapy of colorectal cancer. Int J Pharm 2025; 668:124968. [PMID: 39561904 DOI: 10.1016/j.ijpharm.2024.124968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/05/2024] [Accepted: 11/16/2024] [Indexed: 11/21/2024]
Abstract
The unsatisfactory immunotherapeutic responses are primarily attributed to the insufficient immune recognition and the presence of an immunosuppressive tumor microenvironment (ITM). This study focuses on the development of a tricomponent immunoactivating nanomedicine called TIN that combines a photosensitizer, an inhibitor of epidermal growth factor receptor (EGFR) and a CSF-1R inhibitor to enable photodynamic immunotherapy by downregulating PD-L1 expression and repolarizing tumor-associated macrophages (TAMs). TIN is designed to facilitate the drug delivery and target specific pathways involved in tumor progression. By inhibiting the activity of EGFR and CSF-1R, TIN reduces PD-L1 expression on tumor cells and induces the TAMs polarization to M1 phenotype, restoring the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive microenvironment. Additionally, the photodynamic therapy (PDT) of TIN can greatly destroy the primary tumor and trigger immunogenic cell death (ICD). Importantly, the immune checkpoint blockade effect of TIN can enhance the immune response of PDT-induced ICD for metastatic tumor treatment. This study presents a self-assembling strategy for the development of an all-in-one nanomedicine, effectively integrating multiple therapeutic modalities to provide a comprehensive and systemic approach for tumor suppression.
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Affiliation(s)
- Renjiang Kong
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China; School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Jiaqi Huang
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Yeyang Wu
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Ni Yan
- School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China
| | - Xin Chen
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China.
| | - Hong Cheng
- Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, PR China; School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, PR China.
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Krishnan K A, Valavi SG, Joy A. Identification of Novel EGFR Inhibitors for the Targeted Therapy of Colorectal Cancer Using Pharmacophore Modelling, Docking, Molecular Dynamic Simulation and Biological Activity Prediction. Anticancer Agents Med Chem 2024; 24:263-279. [PMID: 38173208 DOI: 10.2174/0118715206275566231206094645] [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: 08/04/2023] [Revised: 10/30/2023] [Accepted: 11/14/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is considered the second deadliest cancer in the world. One of the reasons for the occurrence of this cancer is the deregulation of the Epidermal Growth Factor Receptor (EGFR), which plays a critical role in regulating cell division, persistence, differentiation, and migration. The overexpression of the EGFR protein leads to its dysregulation and causes CRC. OBJECTIVES Hence, this work aims to identify and validate novel EGFR inhibitors for the treatment of colorectal cancer employing various computer aided techniques such as pharmacophore modeling, docking, molecular dynamic simulation and Quantitative Structure-Activity Relationship (QSAR) analysis. METHODS In this work, a shared-featured ligand-based pharmacophore model was generated using the known inhibitors of EGFR. The best model was validated and screened against ZincPharmer and Maybridge databases, and 143 hits were obtained. Pharmacokinetic and toxicological properties of these hits were studied, and the acceptable ligands were docked against EGFR. The best five protein-ligand complexes with binding energy less than -5 kcal/mol were selected. The molecular dynamic simulation studies of these complexes were conducted for 100 nanoseconds (ns), and the results were analyzed. The biological activity of this ligand was calculated using QSAR analysis. RESULTS The best complex with Root Mean Square Deviation (RMSD) 3.429 Å and Radius of Gyration (RoG) 20.181 Å was selected. The Root Mean Square Fluctuations (RMSF) results were also found to be satisfactory. The biological activity of this ligand was found to be 1.38 μM. CONCLUSION This work hereby proposes the ligand 2-((1,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)oxy)-N- (1H-indol-4-yl)acetamide as a potential EGFR inhibitor for the treatment of colorectal cancer. The wet lab analysis must be conducted, however, to confirm this hypothesis.
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Affiliation(s)
- Amrutha Krishnan K
- Department of Applied Science and Humanities, Sahrdaya College of Engineering and Technology, Affiliated to APJ Abdul Kalam Technological University, Kodakara, Thrissur, Kerala, India
| | - Sudha George Valavi
- Department of Applied Science and Humanities, Sahrdaya College of Engineering and Technology, Affiliated to APJ Abdul Kalam Technological University, Kodakara, Thrissur, Kerala, India
| | - Amitha Joy
- Department of Biotechnology, Sahrdaya College of Engineering and Technology, Affiliated to APJ Abdul Kalam Technological University, Kodakara, Thrissur, Kerala, India
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Obaya AA, Mohammed AA, Rashied H, Morsy AM, Osman G, Allam AS, Elsayed AM, Harb OA, Elsayed WSH. Evaluating the value of Amphiregulin, Phosphatase and Tensin Homologue (PTEN) and P21 Expression for Anti-EGFR Treatment in Metastatic Colorectal Carcinoma. Asian Pac J Cancer Prev 2021; 22:1025-1034. [PMID: 33906293 PMCID: PMC8325139 DOI: 10.31557/apjcp.2021.22.4.1025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Despite the significant progress in target therapy for the treatment of metastatic colorectal carcinoma (mCRC), the overall survival isn't satisfactory. METHODS We assessed the expression of Amphiregulin, PTEN, and P21 in sections from 23 paraffin blocks prepared from 23 patients with left-sided mCRC using immunohistochemistry (IHC). The relationship between their level of expressions, clinicopathological parameters, response to anti-EGFR, and prognosis were analyzed. RESULTS High Amphiregulin, PTEN and low P21 expression levels were associated with low tumor grade (p= 0.038 and 0.025 respectively), better response to anti-EGFR treatment (p <0.001), and favorable outcome {progression-free survival (PFS) and overall survival (OS)} (p <0.05). There was a direct relation between Amphiregulin and PTEN expressions (phi coefficient=+0.840), while there was an inverse relation between P21expression and both Amphiregulin (phi coefficient= -0.840) and PTEN expressions (phi coefficient = -1.000), which was statistically significant (P <0.001). CONCLUSION High Amphiregulin and PTEN expression levels and low P21 expression levels were associated with better response to anti-EGFR therapy and improved survival outcome. They might be considered predictive markers of response to anti-EGFR therapy in mCRC.<br /> <br />.
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Affiliation(s)
- Ahmed Ali Obaya
- Department of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Zagazig University, Egypt
| | - Amrallah A Mohammed
- Department of Medical Oncology, Faculty of Medicine, Zagazig University, Egypt
| | - Hanaa Rashied
- Department of Clinical Oncology & Nuclear Medicine, Elmabara Hospital of Zagazig, Health Insurance Organization, Zagazig, Egypt
| | - Adel Mahmoud Morsy
- Department of General Surgery, Faculty of Medicine, Zagazig University, Egypt
| | - Gamal Osman
- Department of General Surgery, Faculty of Medicine, Zagazig University, Egypt
| | - Ahmed S Allam
- Department of Internal Medicine, Faculty of Medicine, Zagazig University, Egypt
| | - Ahmed M Elsayed
- Department of Tropical Medicine, Faculty of Medicine, Zagazig University, Egypt
| | - Ola A Harb
- Department of Pathology, Faculty of Medicine, Zagazig University, Egypt
| | - Walid S H Elsayed
- Department of Pathology, Faculty of Medicine, Zagazig University, Egypt
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Huijberts SC, van Geel RM, Bernards R, Beijnen JH, Steeghs N. Encorafenib, binimetinib and cetuximab combined therapy for patients with BRAFV600E mutant metastatic colorectal cancer. Future Oncol 2020; 16:161-173. [PMID: 32027186 DOI: 10.2217/fon-2019-0748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Approximately 10-15% of colorectal cancers (CRCs) harbor an activating BRAF mutation, leading to tumor growth promotion by activation of the mitogen-activated protein kinases pathway. BRAFV600E mutations are prognostic for treatment failure after first-line systemic therapy in the metastatic setting. In contrast to the efficacy of combined BRAF and MEK inhibition in melanoma, BRAFV600E mutant CRC is intrinsically unresponsive due to upregulation of HER/EGFR. However, combining the EGFR inhibitor cetuximab, the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib improves overall survival. This review discusses the current treatment field for patients with BRAFV600E mutant metastatic CRC and summarizes the pharmacology, efficacy and safety of the novel doublet and triplet therapies consisting of encorafenib and cetuximab with or without binimetinib.
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Affiliation(s)
- Sanne Cfa Huijberts
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
| | - Robin Mjm van Geel
- Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre, Maastricht, 6229 HX, The Netherlands.,Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Rene Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.,Utrecht University, Utrecht, 3508 TC, The Netherlands
| | - Jos H Beijnen
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.,Utrecht University, Utrecht, 3508 TC, The Netherlands.,Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands
| | - Neeltje Steeghs
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.,Division of Medical Oncology, The Netherlands Cancer institute, Amsterdam, 1066 CX, The Netherlands
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khorshid Sofyani E, sharifi R. Synergistic Effect of Docetaxel Combined with Quinacrine on Induction of Apoptosis and Reduction of Cell proliferation in a Lung Cancer Cell Line. MEDICAL LABORATORY JOURNAL 2020. [DOI: 10.29252/mlj.14.4.38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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Phipps AI, Alwers E, Harrison T, Banbury B, Brenner H, Campbell PT, Chang-Claude J, Buchanan D, Chan AT, Farris AB, Figueiredo JC, Gallinger S, Giles GG, Jenkins M, Milne RL, Newcomb PA, Slattery ML, Song M, Ogino S, Zaidi SH, Hoffmeister M, Peters U. Association Between Molecular Subtypes of Colorectal Tumors and Patient Survival, Based on Pooled Analysis of 7 International Studies. Gastroenterology 2020; 158:2158-2168.e4. [PMID: 32088204 PMCID: PMC7282955 DOI: 10.1053/j.gastro.2020.02.029] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 01/31/2020] [Accepted: 02/12/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The heterogeneity among colorectal tumors is probably due to differences in developmental pathways and might associate with patient survival times. We studied the relationship among markers of different subtypes of colorectal tumors and patient survival. METHODS We pooled data from 7 observational studies, comprising 5010 patients with colorectal cancer. All the studies collected information on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in KRAS and BRAF in tumors. Tumors with complete marker data were classified as type 1 (MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 2 (not MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 3 (not MSI-high or CIMP, with pathogenic mutations in KRAS but not BRAF), type 4 (not MSI-high or CIMP, no pathogenic mutations in BRAF or KRAS), or type 5 (MSI-high, no CIMP, no pathogenic mutations in BRAF or KRAS). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations of these subtypes and tumor markers with disease-specific survival (DSS) and overall survival times, adjusting for age, sex, stage at diagnosis, and study population. RESULTS Patients with type 2 colorectal tumors had significantly shorter time of DSS than patients with type 4 tumors (HRDSS 1.66; 95% CI 1.33-2.07), regardless of sex, age, or stage at diagnosis. Patients without MSI-high tumors had significantly shorter time of DSS compared with patients with MSI-high tumors (HRDSS 0.42; 95% CI 0.27-0.64), regardless of other tumor markers or stage, or patient sex or age. CONCLUSIONS In a pooled analysis of data from 7 observational studies of patients with colorectal cancer, we found that tumor subtypes, defined by combinations of 4 common tumor markers, were associated with differences in survival time. Colorectal tumor subtypes might therefore be used in determining patients' prognoses.
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Affiliation(s)
- Amanda I. Phipps
- Epidemiology Department, University of Washington, Seattle, WA,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Elizabeth Alwers
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tabitha Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Barbara Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany,Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Germany
| | - Peter T. Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany,Cancer Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Hamburg, Germany
| | - Daniel Buchanan
- Department of Clinical Pathology, Colorectal Oncogenomics Group, The University of Melbourne, Parkville, Victoria, Australia
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Department of Medicine, and Division of Gastroenterology, Massachusetts General Hospital, Boston, MA,Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | | | - Jane C. Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia,Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Mark Jenkins
- Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Roger L. Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia,Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Polly A. Newcomb
- Epidemiology Department, University of Washington, Seattle, WA,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Department of Medicine, and Division of Gastroenterology, Massachusetts General Hospital, Boston, MA,Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Shuji Ogino
- Departments of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA,Program in Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA,Broad Institute of MIT and Harvard, Cambridge, MA
| | - Syed H. Zaidi
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ulrike Peters
- Epidemiology Department, University of Washington, Seattle, WA,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
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10
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Kim BH, Kim JM, Kang GH, Chang HJ, Kang DW, Kim JH, Bae JM, Seo AN, Park HS, Kang YK, Lee KH, Cho MY, Do IG, Lee HS, Chang HK, Park DY, Kang HJ, Sohn JH, Chang MS, Jung ES, Jin SY, Yu E, Han HS, Kim YW. Standardized Pathology Report for Colorectal Cancer, 2nd Edition. J Pathol Transl Med 2019; 54:1-19. [PMID: 31722452 PMCID: PMC6986966 DOI: 10.4132/jptm.2019.09.28] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 09/26/2019] [Indexed: 02/06/2023] Open
Abstract
The first edition of the 'Standardized Pathology Report for Colorectal Cancer,' which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of "standard data elements" and "conditional data elements." Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as "standard data elements," while other prognostic factors and factors related to adjuvant therapy are classified as "conditional data elements" so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.
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Affiliation(s)
- Baek-Hui Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Jin Chang
- Department of Pathology, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Dong Wook Kang
- Department of Pathology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Ho Sung Park
- Department of Pathology, Chonbuk National University Medical School, Jeonju, Korea
| | - Yun Kyung Kang
- Department of Pathology, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Kyung-Hwa Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
| | - Mee Yon Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In-Gu Do
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University College of Medicine, Busan, Korea
| | - Do Youn Park
- Department of Pathology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Hyo Jeong Kang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Hee Sohn
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Sun Jung
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - So-Young Jin
- Department of Pathology, Soonchunhyang University Seoul Hospital, Soonchunhyang UniversityCollege of Medicine, Seoul, Korea
| | - Eunsil Yu
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye Seung Han
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Youn Wha Kim
- Department of Pathology, Kyung Hee University College of Medicine, Seoul, Korea
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11
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Dai J, Chen A, Zhu M, Qi X, Tang W, Liu M, Li D, Gu Q, Li J. Penicisulfuranol A, a novel C-terminal inhibitor disrupting molecular chaperone function of Hsp90 independent of ATP binding domain. Biochem Pharmacol 2019; 163:404-415. [PMID: 30857829 DOI: 10.1016/j.bcp.2019.03.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 03/07/2019] [Indexed: 12/30/2022]
Abstract
The goal of this study is to explore the mechanism of a heat shock protein 90 (Hsp90) C-terminal inhibitor, Penicisulfuranol A (PEN-A), for cancer therapy. PEN-A was produced by a mangrove endophytic fungus Penicillium janthinellum and had a new structure with a rare 3H-spiro [benzofuran-2, 2'-piperazine] ring system. PEN-A caused depletion of multiple Hsp90 client proteins without induction of heat shock protein 70 (Hsp70). Subsequently, it induced apoptosis and inhibited xerograph tumor growth of HCT116 cells in vitro and in vivo. Mechanism studies showed that PEN-A was bound to C-terminus of Hsp90 at the binding site different from ATP binding domain. Therefore, it inhibited dimerization of Hsp90 C-terminus, depolymerization of ADH protein by C-terminus of Hsp90, and interaction of co-chaperones with Hsp90. These inhibitory effects of PEN-A were similar to those of novobiocin, an inhibitor binding to interaction site for ATP of C-terminus of Hsp90. Furthermore, our study revealed that disulfide bond was essential moiety for inhibition activity of PEN-A on Hsp90. This suggested that PEN-A may be bound to cysteine residues near amino acid region which was responsible for dimerization of Hsp90. All results indicate that PEN-A is a novel C-terminal inhibitor of Hsp90 and worthy for further study in the future not only for drug development but also for unraveling the bioactivities of Hsp90.
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Affiliation(s)
- Jiajia Dai
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China
| | - Ao Chen
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China
| | - Meilin Zhu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China
| | - Xin Qi
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China
| | - Wei Tang
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China
| | - Ming Liu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Dehai Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China
| | - Qianqun Gu
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China
| | - Jing Li
- Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, PR China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, PR China.
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12
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Morgan RG, Mortensson E, Legge DN, Gupta B, Collard TJ, Greenhough A, Williams AC. LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity. Br J Cancer 2017; 118:558-565. [PMID: 29149105 PMCID: PMC5830587 DOI: 10.1038/bjc.2017.412] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/18/2017] [Accepted: 10/19/2017] [Indexed: 12/25/2022] Open
Abstract
Background: LGR5 serves as a co-receptor for Wnt/β-catenin signalling and marks normal intestinal stem cells; however, its role in colorectal cancer (CRC) remains controversial. LGR5+ cells are known to exist outside the stem cell niche during CRC progression, and the requirement for epidermal growth factor (EGF) signalling within early adenomas remains to be fully elucidated. Methods: Epidermal growth factor and gefitinib treatments were performed in EGF-responsive LGR5+ early adenoma RG/C2 cells. 2D growth assays were measured using an IncuCyte. LGR5 or MEK1/2 silencing studies were executed using siRNA and LGR5 expression was assessed by qRT–PCR and immunoblotting. Ki67 level and cell cycle status were analysed by flow cytometry. Results: Epidermal growth factor suppresses expression of LGR5 at both the transcript and protein level in colorectal adenoma and carcinoma cells. Suppression of LGR5 reduces the survival of EGF-treated adenoma cells by increasing detached cell yield but also inducing a proliferative state, as evidenced by elevated Ki67 level and enhanced cell cycle progression. Repression of LGR5 further increases the sensitivity of adenoma cells to EGFR inhibition. Conclusions: LGR5 has an important role in the EGF-mediated survival and proliferation of early adenoma cells and could have clinical utility in predicting response of CRC patients to EGFR therapy.
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Affiliation(s)
- R G Morgan
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - E Mortensson
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - D N Legge
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - B Gupta
- European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - T J Collard
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - A Greenhough
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
| | - A C Williams
- School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, Bristol BS8 1TD, UK
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13
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Oztan A, Fischer S, Schrock AB, Erlich RL, Lovly CM, Stephens PJ, Ross JS, Miller V, Ali SM, Ou SHI, Raez LE. Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib. Lung Cancer 2017; 111:84-87. [PMID: 28838405 DOI: 10.1016/j.lungcan.2017.07.002] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 07/03/2017] [Accepted: 07/05/2017] [Indexed: 11/26/2022]
Abstract
Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment. This study demonstrates the importance of both tissue and blood based hybrid-capture based genomic profiling at disease progression to identifying novel resistance mechanisms in the clinic.
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Affiliation(s)
- A Oztan
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA.
| | - S Fischer
- Providence Medical Institute, 2021 Santa Monica Blvd, Santa Monica, CA 90404, USA
| | - A B Schrock
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA
| | - R L Erlich
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA
| | - C M Lovly
- Vanderbilt Ingram Cancer Center, Nashville, TN 37232, USA
| | - P J Stephens
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA
| | - J S Ross
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA
| | - V Miller
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA
| | - S M Ali
- Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA
| | - S-H I Ou
- Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA 92868, USA
| | - L E Raez
- Memorial Cancer Institute/Memorial Healthcare System, 801 N. Flamingo Road, Pembroke Pines, FL 33028, USA
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14
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Zhu YP, Liu Z, Fu ZX, Li DC. Smad3 mutant mice develop colon cancer with overexpression of COX-2. Oncol Lett 2017; 13:1535-1538. [PMID: 28454287 PMCID: PMC5403702 DOI: 10.3892/ol.2017.5639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 06/29/2016] [Indexed: 01/05/2023] Open
Abstract
Colon cancer is the second most common cause of cancer-associated mortality in human populations. The aim of the present study was to identify the role of cyclooxygenase-2 (COX-2) in Smad3 mutant mice, which are known to develop colon cancer. Homozygous Smad3 (-/-) mutant mice were generated from inbred and hybrid Smad3 mouse strains by intercrossing the appropriate heterozygotes. Immunohistochemistry with COX-2 antibody was performed throughout this experiment and the data was validated and cross-checked with reverse transcription-polymerase chain reaction (RT-PCR). Homozygous mutant Smad3 mice were generated and the overexpression pattern of COX-2 was identified by immunohistochemistry and validated with RT-PCR. The results of the present study demonstrated a link between the Smad3 mutant mice, colon cancer and COX-2. In addition, the overexpression pattern of COX-2 in Smad3 mutant mice that develop colon cancer was identified.
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Affiliation(s)
- Yu-Ping Zhu
- Department of Colorectal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhuo Liu
- Department of Colorectal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhi-Xuan Fu
- Department of Colorectal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - De-Chuan Li
- Department of Colorectal Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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15
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Manne U, Jadhav T, Putcha BDK, Samuel T, Soni S, Shanmugam C, Suswam EA. Molecular Biomarkers of Colorectal Cancer and Cancer Disparities: Current Status and Perspective. CURRENT COLORECTAL CANCER REPORTS 2016. [PMID: 28626361 DOI: 10.1007/s11888-016-0338-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
This review provides updates on the efforts for the development of prognostic and predictive markers in colorectal cancer based on the race/ethnicity of patients. Since the clinical consequences of genetic and molecular alterations differ with patient race and ethnicity, the usefulness of these molecular alterations as biomarkers needs to be evaluated in different racial/ethnic groups. To accomplish personalized patient care, a combined analysis of multiple molecular alterations in DNA, RNA, microRNAs (miRNAs), metabolites, and proteins in a single test is required to assess disease status in a precise way. Therefore, a special emphasis is placed on issues related to utility of recently identified genetic and molecular alterations in genes, miRNAs, and various "-omes" (e.g., proteomes, kinomes, metabolomes, exomes, methylomes) as candidate molecular markers to determine cancer progression (disease recurrence/relapse and metastasis) and to assess the efficacy of therapy in colorectal cancer in relation to patient race and ethnicity. This review will be useful for oncologists, pathologists, and basic and translational researchers.
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Affiliation(s)
- Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, Wallace Tumor Institute, University of Alabama at Birmingham, Room # 420A, 1530 3rd Avenue South, Birmingham, AL 35294, USA
| | - Trafina Jadhav
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Wallace Tumor Institute, University of Alabama at Birmingham, Room # 430A, 1530 3rd Avenue South, Birmingham, AL 35294, USA.,Present address: Division of Cardiovascular Medicine, Vanderbilt University, 1215 21st Avenue South, Medical Center East, Suite 5050, Nashville, TN 37232-8802, USA
| | - Balananda-Dhurjati Kumar Putcha
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Wallace Tumor Institute, University of Alabama at Birmingham, Room # 430A, 1530 3rd Avenue South, Birmingham, AL 35294, USA.,Present address: 2502 East Woodlands, Saint Joseph, MO 64506, USA
| | - Temesgen Samuel
- Department of Pathobiology, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088, USA
| | - Shivani Soni
- Department of Biological Sciences, Alabama State University, Room # 325, Life Science Building, 1627, Hall Street, Montgomery, AL 36104, USA
| | - Chandrakumar Shanmugam
- Wallace Tumor Institute, University of Alabama at Birmingham, Room # 430A, 1530 3rd Avenue South, Birmingham, AL 35294, USA.,Present address: Department of Pathology, ESIC Medical College and Hospital, Sanathnagar, Hyderabad, Telangana 500 038, India
| | - Esther A Suswam
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Pathology, Wallace Tumor Institute, University of Alabama at Birmingham, 1720 2nd Avenue South, # 410C, Birmingham, AL 35294-3300, USA
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16
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Kim SA, Inamura K, Yamauchi M, Nishihara R, Mima K, Sukawa Y, Li T, Yasunari M, Morikawa T, Fitzgerald KC, Fuchs CS, Wu K, Chan AT, Zhang X, Ogino S, Qian ZR. Loss of CDH1 (E-cadherin) expression is associated with infiltrative tumour growth and lymph node metastasis. Br J Cancer 2016; 114:199-206. [PMID: 26742007 PMCID: PMC4815802 DOI: 10.1038/bjc.2015.347] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 08/06/2015] [Accepted: 09/04/2015] [Indexed: 02/07/2023] Open
Abstract
Background: Loss of CDH1 (E-cadherin) expression in cancer cells may promote cell migration and invasion. Therefore, we hypothesised that loss of CDH1 expression in colorectal carcinoma might be associated with aggressive features and clinical outcome. Methods: Utilising molecular pathological epidemiology database of 689 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, we assessed tumour CDH1 expression by immunohistochemistry. Multivariate logistic regression analysis was conducted to assess association of CDH1 loss with tumour growth pattern (expansile-intermediate vs infiltrative) and lymph node metastasis and distant metastasis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and PIK3CA, BRAF and KRAS mutations. Mortality according to CDH1 status was assessed using Cox proportional hazards model. Results: Loss of tumour CDH1 expression was observed in 356 cases (52%), and associated with infiltrative tumour growth pattern (odds ratio (OR), 2.02; 95% confidence interval (CI), 1.23–3.34; P=0.006) and higher pN stage (OR, 1.73; 95% CI, 1.23–2.43; P=0.001). Tumour CDH1 expression was not significantly associated with distant metastasis or prognosis. Conclusions: Loss of CDH1 expression in colorectal cancer is associated with infiltrative tumour growth pattern and lymph node metastasis.
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Affiliation(s)
- Sun A Kim
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA
| | - Kentaro Inamura
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA.,Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Mai Yamauchi
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue Building 2, room 213, Boston, MA 02115, USA
| | - Kosuke Mima
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA
| | - Yasutaka Sukawa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA
| | - Tingting Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA.,Department of Geriatric Gastroenterology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing 100853, China
| | - Mika Yasunari
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA
| | - Teppei Morikawa
- Department of Pathology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Kathryn C Fitzgerald
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA
| | - Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 29 Wigglesworth Street, Boston, MA 02120, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue Building 2, room 213, Boston, MA 02115, USA
| | - Andrew T Chan
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 29 Wigglesworth Street, Boston, MA 02120, USA.,Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, GRJ-722, Boston, MA 02114, USA
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, 29 Wigglesworth Street, Boston, MA 02120, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA.,Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, 29 Wigglesworth Street, Boston, MA 02120, USA
| | - Zhi Rong Qian
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Avenue M420, Boston, MA 02215, USA
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17
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Huang S, Peter Rodemann H, Harari PM. Molecular Targeting of Growth Factor Receptor Signaling in Radiation Oncology. Recent Results Cancer Res 2016; 198:45-87. [PMID: 27318681 DOI: 10.1007/978-3-662-49651-0_3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Ionizing radiation has been shown to activate and interact with multiple growth factor receptor pathways that can influence tumor response to therapy. Among these receptor interactions, the epidermal growth factor receptor (EGFR) has been the most extensively studied with mature clinical applications during the last decade. The combination of radiation and EGFR-targeting agents using either monoclonal antibody (mAb) or small-molecule tyrosine kinase inhibitor (TKI) offers a promising approach to improve tumor control compared to radiation alone. Several underlying mechanisms have been identified that contribute to improved anti-tumor capacity after combined treatment. These include effects on cell cycle distribution, apoptosis, tumor cell repopulation, DNA damage/repair, and impact on tumor vasculature. However, as with virtually all cancer drugs, patients who initially respond to EGFR-targeted agents may eventually develop resistance and manifest cancer progression. Several potential mechanisms of resistance have been identified including mutations in EGFR and downstream signaling molecules, and activation of alternative member-bound tyrosine kinase receptors that bypass the inhibition of EGFR signaling. Several strategies to overcome the resistance are currently being explored in preclinical and clinical models, including agents that target the EGFR T790 M resistance mutation or target multiple EGFR family members, as well as agents that target other receptor tyrosine kinase and downstream signaling sites. In this chapter, we focus primarily on the interaction of radiation with anti-EGFR therapies to summarize this promising approach and highlight newly developing opportunities.
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Affiliation(s)
- Shyhmin Huang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA
- Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, WIMR 3136, 1111 Highland Ave Madison, Madison, WI, 53705, USA
| | - H Peter Rodemann
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tübingen, Röntgenweg, 72076, Tübingen, Germany
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue K4/336 CSC, Madison, WI, 53792, USA.
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18
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Wang L, Zeng H, Wang Q, Zhao Z, Boyer TG, Bian X, Xu W. MED12 methylation by CARM1 sensitizes human breast cancer cells to chemotherapy drugs. SCIENCE ADVANCES 2015; 1:e1500463. [PMID: 26601288 PMCID: PMC4646802 DOI: 10.1126/sciadv.1500463] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 08/10/2015] [Indexed: 05/29/2023]
Abstract
The RNA polymerase II mediator complex subunit 12 (MED12) is frequently mutated in human cancers, and loss of MED12 has been shown to induce drug resistance through activation of transforming growth factor-β receptor (TGF-βR) signaling. We identified MED12 as a substrate for coactivator-associated arginine methyltransferase 1 (CARM1). Not only are the expression levels of CARM1 and MED12 positively correlated, but their high expression also predicts better prognosis in human breast cancers after chemotherapy. MED12 was methylated at R1862 and R1912 by CARM1, and mutation of these sites in cell lines resulted in resistance to chemotherapy drugs. Furthermore, we showed that the methylation-dependent drug response mechanism is distinct from activation of TGF-βR signaling, because methylated MED12 potently suppresses p21/WAF1 transcription. Cells defective in MED12 methylation have up-regulated p21 protein, which correlates with poor prognosis in breast cancer patients treated with chemotherapy. Collectively, this study identifies MED12 methylation as a sensor for predicting response to commonly used chemotherapy drugs in human cancers.
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Affiliation(s)
- Lu Wang
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Hao Zeng
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Graduate Program in Cellular and Molecular Biology, University of Wisconsin–Madison, Madison, WI 53705, USA
| | - Qiang Wang
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China
| | - Zibo Zhao
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Thomas G. Boyer
- Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229–3900, USA
| | - Xiuwu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
- Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China
| | - Wei Xu
- McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Graduate Program in Cellular and Molecular Biology, University of Wisconsin–Madison, Madison, WI 53705, USA
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19
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Serine phosphorylation of vasodilator-stimulated phosphoprotein (VASP) regulates colon cancer cell survival and apoptosis. Life Sci 2014; 123:1-8. [PMID: 25543053 DOI: 10.1016/j.lfs.2014.12.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 09/29/2014] [Accepted: 12/15/2014] [Indexed: 12/16/2022]
Abstract
AIMS In colon cancer, disease recurrence and death are associated with abnormal tumor cell survival. Vasodilator-stimulated phosphoprotein (VASP) is an actin binding protein regulating cell shape and polarity through the F-actin cytoskeleton, whose activity is controlled by cAMP-dependent phosphorylation at Ser157 and cGMP-dependent phosphorylation at Ser239. This study examined the role of differential VASP Ser phosphorylation in regulating cell survival and apoptosis in human colon carcinoma cells. MAIN METHODS Selective inhibition of VASP Ser157 or Ser239 phosphorylation in colon cancer cells was performed with specific phosphomutant constructs. F-actin organization was examined by confocal microscopy, and the balance of cell survival and death assessed by measuring acridine orange and ethidium bromide staining, caspase-3 and BAD-pS112 expression and DNA fragmentation. KEY FINDINGS In human colon carcinoma cells suppression of VASP Ser157 phosphorylation reduced F-actin content and survival and increased apoptosis, while inhibition of VASP Ser239 phosphorylation increased F-actin content and survival and reduced cell death. Also, while 8Br-cAMP induced VASP Ser157 phosphorylation and reduced cell death, treatments with 8CPT-cGMP elevated VASP Ser239 phosphorylation and promoted apoptosis. SIGNIFICANCE These findings suggest that differential VASP Ser phosphorylation represents a unique therapeutic target to control cell survival and death behavior in colon cancer. In particular, pharmacological manipulation of VASP Ser phosphorylation could be exploited to affect the malignant actin cytoskeleton and induce apoptosis in colorectal cancer cells.
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20
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Islam MR, Ellis IR, Macluskey M, Cochrane L, Jones SJ. Activation of Akt at T308 and S473 in alcohol, tobacco and HPV-induced HNSCC: is there evidence to support a prognostic or diagnostic role? Exp Hematol Oncol 2014; 3:25. [PMID: 25352995 PMCID: PMC4210546 DOI: 10.1186/2162-3619-3-25] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 10/07/2014] [Indexed: 01/22/2023] Open
Abstract
Background Tobacco, alcohol and HPV infection are associated with increased risk of HNSCC. However, little is known about the underlying signaling events influencing risk. We aimed to investigate the relationship between these risk factors and Akt phosphorylation, to determine prognostic value. Method VEGF-positive HNSCC biopsies, with known HPV status, were analyzed by immunohistochemistry (IHC) for Akt, phosphorylated at residues S473 and T308. Comparisons between the tissues were carried out using a Mann–Whitney U test. Associations between the variables and continuous immunohistochemical parameters were evaluated with general linear models. Patient characteristics and pAkt IHC score were analyzed for possible association with overall survival by Cox proportional hazard models. Results Immunohistochemistry revealed that cancer patients had significantly higher levels of pAkt T308 than S473 (P < 0.001). Smoking and alcohol were found to be independent risk factors for Akt phosphorylation at T308 (P = 0.022 and 0.027, respectively). Patients with tumors positive for HPV or pAkt S473 had a poorer prognosis (P = 0.005, and 0.004, respectively). Patients who were heavy drinkers were 49 times more likely to die than non-drinkers (P = 0.003). Patients with low pAkt T308 were more likely to be HPV positive (P = 0.028). Non-drinkers were also found to have lower levels of pAkt T308 and were more likely to have tumors positive for HPV than heavy drinkers (P = 0.044 and 0.007, respectively). Conclusion This study suggests different mechanisms of carcinogenesis are initiated by smoking, alcohol and HPV. Our data propose higher phosphorylation of Akt at T308 as a reliable biomarker for smoking and alcohol induced HNSCC progression and higher phosphorylation of Akt at S473 as a prognostic factor for HNSCC.
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Affiliation(s)
- Mohammad R Islam
- Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK
| | - Ian R Ellis
- Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK
| | - Michaelina Macluskey
- Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK
| | - Lynda Cochrane
- Division of Population Health Science, Medical Research Institute, University of Dundee, Dundee, DD2 4BF UK
| | - Sarah J Jones
- Division of Oral and Maxillofacial Clinical Sciences, The Dental School, University of Dundee, Dundee, DD1 4HR UK
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21
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MacConaill LE, Garcia E, Shivdasani P, Ducar M, Adusumilli R, Breneiser M, Byrne M, Chung L, Conneely J, Crosby L, Garraway LA, Gong X, Hahn WC, Hatton C, Kantoff PW, Kluk M, Kuo F, Jia Y, Joshi R, Longtine J, Manning A, Palescandolo E, Sharaf N, Sholl L, van Hummelen P, Wade J, Wollinson BM, Zepf D, Rollins BJ, Lindeman NI. Prospective enterprise-level molecular genotyping of a cohort of cancer patients. J Mol Diagn 2014; 16:660-72. [PMID: 25157968 DOI: 10.1016/j.jmoldx.2014.06.004] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/31/2014] [Accepted: 06/25/2014] [Indexed: 12/22/2022] Open
Abstract
Ongoing cancer genome characterization studies continue to elucidate the spectrum of genomic abnormalities that drive many cancers, and in the clinical arena assessment of the driver genetic alterations in patients is playing an increasingly important diagnostic and/or prognostic role for many cancer types. However, the landscape of genomic abnormalities is still unknown for less common cancers, and the influence of specific genotypes on clinical behavior is often still unclear. To address some of these deficiencies, we developed Profile, a prospective cohort study to obtain genomic information on all patients at a large tertiary care medical center for cancer-related care. We enrolled patients with any cancer diagnosis, and, for each patient (unselected for cancer site or type) we applied mass spectrometric genotyping (OncoMap) of 471 common recurrent mutations in 41 cancer-related genes. We report the results of the first 5000 patients, of which 26% exhibited potentially actionable somatic mutations. These observations indicate the utility of genotyping in advancing the field of precision oncology.
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Affiliation(s)
- Laura E MacConaill
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
| | - Elizabeth Garcia
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Priyanka Shivdasani
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Matthew Ducar
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ravali Adusumilli
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Marc Breneiser
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mark Byrne
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Lawrence Chung
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Jodie Conneely
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Lauren Crosby
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Levi A Garraway
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts
| | - Xin Gong
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - William C Hahn
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts
| | - Charlie Hatton
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Philip W Kantoff
- Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts
| | - Michael Kluk
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Frank Kuo
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Yonghui Jia
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Ruchi Joshi
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Janina Longtine
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Allison Manning
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Emanuele Palescandolo
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Nematullah Sharaf
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Lynette Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Paul van Hummelen
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jacqueline Wade
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Bruce M Wollinson
- Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Dimity Zepf
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Barrett J Rollins
- Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts
| | - Neal I Lindeman
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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22
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Konda K, Konishi K, Yamochi T, Ito YM, Nozawa H, Tojo M, Shinmura K, Kogo M, Katagiri A, Kubota Y, Muramoto T, Yano Y, Kobayashi Y, Kihara T, Tagawa T, Makino R, Takimoto M, Imawari M, Yoshida H. Distinct molecular features of different macroscopic subtypes of colorectal neoplasms. PLoS One 2014; 9:e103822. [PMID: 25093594 PMCID: PMC4122357 DOI: 10.1371/journal.pone.0103822] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 07/01/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). METHODS We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. RESULTS S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). CONCLUSION We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.
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Affiliation(s)
- Kenichi Konda
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kazuo Konishi
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
- * E-mail:
| | - Toshiko Yamochi
- Department of Pathology, Showa University School of Medicine, Tokyo, Japan
| | - Yoichi M. Ito
- Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hisako Nozawa
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Masayuki Tojo
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kensuke Shinmura
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Mari Kogo
- Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Tokyo, Japan
| | - Atsushi Katagiri
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yutaro Kubota
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takashi Muramoto
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yuichiro Yano
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yoshiya Kobayashi
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Toshihiro Kihara
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Teppei Tagawa
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Reiko Makino
- Clinical Collaborating laboratory, Showa University School of Medicine, Tokyo, Japan
| | - Masafumi Takimoto
- Department of Pathology, Showa University School of Medicine, Tokyo, Japan
| | - Michio Imawari
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hitoshi Yoshida
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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23
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Cho J, Bass AJ, Lawrence MS, Cibulskis K, Cho A, Lee SN, Yamauchi M, Wagle N, Pochanard P, Kim N, Park AK, Won J, Hur HS, Greulich H, Ogino S, Sougnez C, Voet D, Tabernero J, Jimenez J, Baselga J, Gabriel SB, Lander ES, Getz G, Eck MJ, Park WY, Meyerson M. Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab. Mol Cancer 2014; 13:141. [PMID: 24894453 PMCID: PMC4072491 DOI: 10.1186/1476-4598-13-141] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 05/23/2014] [Indexed: 12/19/2022] Open
Abstract
Background Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. Findings We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. Conclusion The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy.
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Affiliation(s)
- Jeonghee Cho
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02115, USA.
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Chhatrala R, Thanavala Y, Iyer R. Targeted therapy in gastrointestinal malignancies. J Carcinog 2014; 13:4. [PMID: 24737952 PMCID: PMC3986534 DOI: 10.4103/1477-3163.127639] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Accepted: 12/15/2013] [Indexed: 12/13/2022] Open
Abstract
Increased understanding of cancer pathogenesis has identified several pathways that serve as potential targets for novel targeted agents in development. The selection of targeted cancer therapy based on biomarkers has instigated a new era of personalized medicine and changed the way we practice oncology. Many targeted agents are approved for treatment of gastrointestinal malignancies most targeting tumor angiogenesis, and many more are in different phases of development. Here we briefly summarize nine different targeted agents that are approved currently in the U.S. and several other agents currently being studied in various gastrointestinal cancers.
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Affiliation(s)
- Ravi Chhatrala
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA
| | - Yasmin Thanavala
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Renuka Iyer
- Department of Medicine, Division of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
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25
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Yamaguchi NH, Mayer IA, Malzyner A, de Andrade CJ, Murad AM, Del Giglio A, Alves V. Gefitinib and celecoxib in advanced metastatic gastrointestinal tumors: a pilot feasibility study. J Gastrointest Oncol 2014; 5:57-66. [PMID: 24490043 DOI: 10.3978/j.issn.2078-6891.2013.056] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 11/11/2013] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND This pilot, open-label study examined the safety and tolerability (primary objective) and efficacy (secondary objective) of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in patients with advanced or refractory gastrointestinal (GI) tumors of epithelial origin. METHODS Patients were administered gefitinib (250 mg/day) plus celecoxib (400 mg twice daily). In the event of toxicity, dose interruptions were permitted and a single celecoxib dose reduction was allowed. RESULTS Thirty patients (median age 60 years) with primary colorectal (25 patients), pancreatic (3 patients), esophageal (1 patient), or gall bladder (1 patient) tumors were recruited, 29 of whom had received prior chemotherapy. Adverse events (AEs) were generally mild and consisted mainly of acne, diarrhea, and nausea. Few severe AEs were noted. There were no withdrawals or deaths due to AEs. Dose reductions for celecoxib were reported for five patients, in three cases due to toxicity. Stable disease was confirmed in 12 patients (40%), with progressive disease in 18 patients (60%). CONCLUSIONS After study completion, safety issues relating to the long-term use of COX-2 inhibitors have been raised. However, in this pilot study, the combination of gefitinib and celecoxib was generally well tolerated in patients with advanced GI cancer.
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Affiliation(s)
- Nise H Yamaguchi
- University of São Paulo Medical School and Institute of Advances in Medicine, São Paulo, Brazil
| | | | - Artur Malzyner
- Hospital Israelita Albert Einstein and Heliopolis Hospital and Clínica de Oncologia Médica, São Paulo, Brazil
| | | | - Andre M Murad
- Oncology Department, Hospital das Clinicas, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Venancio Alves
- University of São Paulo School of Medicine, São Paulo, Brazil
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26
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Adams R, Maughan T. Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer. Expert Rev Anticancer Ther 2014; 7:503-18. [PMID: 17428171 DOI: 10.1586/14737140.7.4.503] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The discovery over 20 years ago by the Nobel Laureate Stanley Cohen of epidermal growth factor and its receptor, followed by the recognition that this receptor is overexpressed in multiple cancer types, has been of phenomenal significance. From these events the 'Holy Grail' of targeted therapy has looked increasingly realistic. Over the last 5 years this work has come of age with the licensing of multiple agents targeting this important mitogenic pathway in multiple tumor types. However, these agents and the technology behind them, while impressive, have resulted in lower clinical response rates than anticipated. In this review we will focus on the epidermal growth factor receptor-targeted therapies in colorectal cancer, why our expectations from these therapies have not yet been fulfilled and how we may predict those cancers that are likely to respond or be resistant to these therapies through a greater appreciation of the intricacy, diversity and dynamism of cellular signaling mechanisms.
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Affiliation(s)
- Richard Adams
- Clinical Oncology, Velindre Hospital, South East Wales Cancer Centre, Whitchurch, Cardiff, South Glamorgan, UK.
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Spencer DH, Tyagi M, Vallania F, Bredemeyer AJ, Pfeifer JD, Mitra RD, Duncavage EJ. Performance of common analysis methods for detecting low-frequency single nucleotide variants in targeted next-generation sequence data. J Mol Diagn 2013; 16:75-88. [PMID: 24211364 DOI: 10.1016/j.jmoldx.2013.09.003] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 08/16/2013] [Accepted: 09/04/2013] [Indexed: 12/31/2022] Open
Abstract
Next-generation sequencing (NGS) is becoming a common approach for clinical testing of oncology specimens for mutations in cancer genes. Unlike inherited variants, cancer mutations may occur at low frequencies because of contamination from normal cells or tumor heterogeneity and can therefore be challenging to detect using common NGS analysis tools, which are often designed for constitutional genomic studies. We generated high-coverage (>1000×) NGS data from synthetic DNA mixtures with variant allele fractions (VAFs) of 25% to 2.5% to assess the performance of four variant callers, SAMtools, Genome Analysis Toolkit, VarScan2, and SPLINTER, in detecting low-frequency variants. SAMtools had the lowest sensitivity and detected only 49% of variants with VAFs of approximately 25%; whereas the Genome Analysis Toolkit, VarScan2, and SPLINTER detected at least 94% of variants with VAFs of approximately 10%. VarScan2 and SPLINTER achieved sensitivities of 97% and 89%, respectively, for variants with observed VAFs of 1% to 8%, with >98% sensitivity and >99% positive predictive value in coding regions. Coverage analysis demonstrated that >500× coverage was required for optimal performance. The specificity of SPLINTER improved with higher coverage, whereas VarScan2 yielded more false positive results at high coverage levels, although this effect was abrogated by removing low-quality reads before variant identification. Finally, we demonstrate the utility of high-sensitivity variant callers with data from 15 clinical lung cancers.
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Affiliation(s)
- David H Spencer
- Department of Pathology and Immunology, Washington University, St. Louis, Missouri
| | - Manoj Tyagi
- Department of Genetics, Washington University, St. Louis, Missouri
| | - Francesco Vallania
- Genomics and Pathology Services, Washington University School of Medicine, St. Louis, Missouri
| | | | - John D Pfeifer
- Department of Pathology and Immunology, Washington University, St. Louis, Missouri
| | - Rob D Mitra
- Genomics and Pathology Services, Washington University School of Medicine, St. Louis, Missouri
| | - Eric J Duncavage
- Department of Pathology and Immunology, Washington University, St. Louis, Missouri.
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Chen AS, Solimando DA, Waddell JA. Gefitinib, Fluorouracil, Oxaliplatin, and Leucovorin (IFOX) Regimen for Colorectal Cancer. Hosp Pharm 2013; 48:905-11. [DOI: 10.1310/hpj4811-905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Ma BBY, Chan SL, Ho WM, Lau W, Mo F, Hui EP, Chan C, Poon A, Dattatray RD, Wong SCC, To KF, King AD, Ahuja A, Chan ATC. Intermittent versus continuous erlotinib with concomitant modified “XELOX” (q3W) in first-line treatment of metastatic colorectal cancer. Cancer 2013; 119:4145-53. [DOI: 10.1002/cncr.28327] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 06/09/2013] [Accepted: 07/16/2013] [Indexed: 02/02/2023]
Affiliation(s)
- Brigette B. Y. Ma
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Stephen L. Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Wing M. Ho
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Wilson Lau
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Frankie Mo
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Edwin P. Hui
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Charles Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Annette Poon
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
| | - Rasalkar D. Dattatray
- Department of Imaging and Interventional Radiology; Prince of Wales Hospital; Hong Kong SAR China
| | - S. C. Cesar Wong
- Department of Health Technology and Informatics; the Hong Kong Polytechnic University; Hong Kong SAR China
| | - Ka F. To
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital; Chinese University of Hong Kong; Hong Kong SAR China
| | - Ann D. King
- Department of Imaging and Interventional Radiology; Prince of Wales Hospital; Hong Kong SAR China
| | - Anil Ahuja
- Department of Imaging and Interventional Radiology; Prince of Wales Hospital; Hong Kong SAR China
| | - Anthony T. C. Chan
- Department of Clinical Oncology, Sir Y.K. Pao Centre for Cancer, State Key Laboratory in Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences; Chinese University of Hong Kong; Hong Kong SAR China
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Yewale C, Baradia D, Vhora I, Patil S, Misra A. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials 2013; 34:8690-707. [PMID: 23953842 DOI: 10.1016/j.biomaterials.2013.07.100] [Citation(s) in RCA: 365] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 07/28/2013] [Indexed: 01/03/2023]
Abstract
The epidermal growth factor receptor (EGFR) is a cell-surface receptor belonging to ErbB family of tyrosine kinase and it plays a vital role in the regulation of cell proliferation, survival and differentiation. However; EGFR is aberrantly activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with development of variety of tumors. Therefore, specific EGFR inhibition is one of the key targets for cancer therapy. Two major approaches have been developed and demonstrated benefits in clinical trials for targeting EGFR; monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). EGFR inhibitors like, cetuximab, panitumumab, etc. (mAbs) and gefitinib, erlotinib, lapatinib, etc. (TKIs) are now commercially available for treatment of variety of cancers. Recently, many other agents like peptides, nanobodies, affibodies and antisense oligonucleotide have also shown better efficacy in targeting and inhibiting EGFR. Now a days, efforts are being focused to identify molecular markers that can predict patients more likely to respond to anti-EGFR therapy; to find out combinatorial approaches with EGFR inhibitors and to bring new therapeutic agents with clinical efficacy. In this review we have outlined the role of EGFR in cancer, different types of EGFR inhibitors, preclinical and clinical status of EGFR inhibitors as well as summarized the recent efforts made in the field of molecular EGFR targeting.
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Affiliation(s)
- Chetan Yewale
- Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara 390 001, Gujarat, India
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Boeckx C, Baay M, Wouters A, Specenier P, Vermorken JB, Peeters M, Lardon F. Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist 2013; 18:850-64. [PMID: 23821327 DOI: 10.1634/theoncologist.2013-0013] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Targeted therapy against the epidermal growth factor receptor (EGFR) is one of the most promising molecular therapeutics for head and neck squamous cell carcinoma (HNSCC). EGFR is overexpressed in a wide range of malignancies, including HNSCC, and initiates important signal transduction pathways in HNSCC carcinogenesis. However, primary and acquired resistance are serious problems and are responsible for low single-agent response rate and tumor recurrence. Therefore, an improved understanding of the molecular mechanisms of resistance to EGFR inhibitors may provide valuable indications to identify biomarkers that can be used clinically to predict response to EGFR blockade and to establish new treatment options to overcome resistance. To date, no predictive biomarker for HNSCC is available in the clinic. Therapeutic resistance to anti-EGFR therapy may arise from mechanisms that can compensate for reduced EGFR signaling and/or mechanisms that can modulate EGFR-dependent signaling. In this review, we will summarize some of these molecular mechanisms and describe strategies to overcome that resistance.
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Affiliation(s)
- Carolien Boeckx
- Center for Oncological Research Antwerp, Laboratory of Cancer Research and Clinical Oncology, University of Antwerp, Wilrijk, Belgium
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Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M, College of American Pathologists International Association for the Study of Lung Cancer and Association for Molecular Pathology. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 2013; 15:415-53. [PMID: 23562183 DOI: 10.1016/j.jmoldx.2013.03.001] [Citation(s) in RCA: 343] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 02/12/2013] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. PARTICIPANTS Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. EVIDENCE Three unbiased literature searches of electronic databases were performed to capture published articles from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. EVIDENCE was formally graded for each recommendation. CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). CONCLUSIONS The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115-6110, USA.
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33
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Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8:823-59. [PMID: 23552377 PMCID: PMC4159960 DOI: 10.1097/jto.0b013e318290868f] [Citation(s) in RCA: 624] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. PARTICIPANTS Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. EVIDENCE Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). CONCLUSIONS The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts 02115-6110, USA.
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Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 2013; 137:828-60. [PMID: 23551194 PMCID: PMC4162344 DOI: 10.5858/arpa.2012-0720-oa] [Citation(s) in RCA: 335] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. PARTICIPANTS Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. EVIDENCE Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). CONCLUSIONS The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115-6110, USA.
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Kriegshäuser G, Auner V, Zeillinger R. New and potential clinical applications of KRAS as a cancer biomarker. ACTA ACUST UNITED AC 2013; 4:383-95. [PMID: 23496197 DOI: 10.1517/17530059.2010.510512] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
IMPORTANCE OF THE FIELD KRAS mutation is the most common oncogenic alteration in various human cancers. Recently, KRAS has emerged as an important predictive biomarker in common malignancies such as metastatic colorectal cancer (mCRC) and non-small cell lung cancer (NSCLC). This work aims to discuss the clinical impact of the KRAS mutation status on state-of-the-art treatment approaches, including epidermal growth factor receptor (EGFR)-targeted therapies. AREAS COVERED IN THIS REVIEW This review considers the potential of KRAS to serve as a diagnostic, prognostic or predictive biomarker in various cancers, including those of the lung, colon/rectum, pancreas, ovary and endometrium. WHAT THE READER WILL GAIN KRAS mutations in mCRC and NSCLC primary tumors predict resistance to EGFR-targeted therapy. In pancreatic cancer, KRAS may prove useful as a diagnostic biomarker to screen for early neoplasia. Furthermore, quantitative KRAS mutation analysis could have the potential to distinguish pancreatic cancer from other conditions such as chronic pancreatitis. With respect to ovarian and endometrial cancer, further studies should focus on determining reliable biomarkers for predicting response to EGFR-targeted therapy. Besides EGFR inhibition, KRAS may also serve as a diagnostic and predictive biomarker for evolving therapies directed against mutant RAS proteins. TAKE HOME MESSAGE KRAS has been recognized as an outstanding predictive biomarker to select mCRC and NSCLC patients for EGFR-targeted therapies; however, multi-determinant approaches including other molecular markers should facilitate the identification of patients likely to respond to such therapies.
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Affiliation(s)
- Gernot Kriegshäuser
- ViennaLab Diagnostics GmbH, Gaudenzdorfer Gürtel 43-45, 1120 Vienna, Austria +43 1 812015642 ; +43 1 812015619 ;
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Lin JH, Morikawa T, Chan AT, Kuchiba A, Shima K, Nosho K, Kirkner G, Zhang SM, Manson JE, Giovannucci E, Fuchs CS, Ogino S. Postmenopausal hormone therapy is associated with a reduced risk of colorectal cancer lacking CDKN1A expression. Cancer Res 2012; 72:3020-8. [PMID: 22511578 DOI: 10.1158/0008-5472.can-11-2619] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle-related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (P(heterogeneity) = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46-0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A.
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Affiliation(s)
- Jennifer H Lin
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
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Laborde RR, Wang VW, Smith TM, Olson NE, Olsen SM, García JJ, Olsen KD, Moore EJ, Kasperbauer JL, Tombers NM, Smith DI. Transcriptional profiling by sequencing of oropharyngeal cancer. Mayo Clin Proc 2012; 87:226-32. [PMID: 22386177 PMCID: PMC3538409 DOI: 10.1016/j.mayocp.2011.10.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Revised: 09/21/2011] [Accepted: 10/21/2011] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To compare full transcriptome expression levels of matched tumor and normal samples from patients with oropharyngeal carcinoma stratified by known tumor etiologic factors. PATIENTS AND METHODS Full transcriptome sequencing was analyzed for 10 matched tumor and normal tissue samples from patients with previously untreated oropharyngeal carcinoma. Transcriptomes were analyzed using massively parallel messenger RNA sequencing and validated using the NanoString nCounter system. Global gene expression levels were compared in samples grouped by smoking status and human papillomavirus status. This study was completed between June 10, 2010, and June 30, 2011. RESULTS Global gene expression analysis indicated tumor tissue from former smokers grouped more closely to the never smokers than the current smokers. Pathway analysis revealed alterations in the expression of genes involved in the p53 DNA damage-repair pathway, including CHEK2 and ATR, which display patterns of increased expression that is associated with human papillomavirus-negative current smokers rather than former or never smokers. CONCLUSION These findings support the application of messenger RNA sequencing technology as an important clinical tool for more accurately stratifying patients based on individual tumor biology with the goal of improving our understanding of tumor prognosis and treatment response, ultimately leading to individualized patient care strategies.
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Affiliation(s)
- Rebecca R. Laborde
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Vivian W. Wang
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | | | | | - Steven M. Olsen
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | | | - Kerry D. Olsen
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Eric J. Moore
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Jan L. Kasperbauer
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - Nicole M. Tombers
- Department of Otorhinolaryngology–Head and Neck Surgery, Mayo Clinic, Rochester, MN
| | - David I. Smith
- Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
- Correspondence: Address to David I. Smith, PhD, Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Ogino S, Shima K, Meyerhardt JA, McCleary NJ, Ng K, Hollis D, Saltz LB, Mayer RJ, Schaefer P, Whittom R, Hantel A, Benson AB, Spiegelman D, Goldberg RM, Bertagnolli MM, Fuchs CS. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res 2012; 18:890-900. [PMID: 22147942 PMCID: PMC3271172 DOI: 10.1158/1078-0432.ccr-11-2246] [Citation(s) in RCA: 228] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. METHODS We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. RESULTS Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). CONCLUSIONS BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.
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Affiliation(s)
- Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02215, USA.
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Folic acid supplementary reduce the incidence of adenocarcinoma in a mouse model of colorectal cancer: microarray gene expression profile. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:116. [PMID: 22206623 PMCID: PMC3259116 DOI: 10.1186/1756-9966-30-116] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Accepted: 12/29/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND Whether Folic acid is a potential drug that may prevent the progression of colorectal carcinoma and when to use are important healthy issues we focus on. Our study is to examine the effect of folic acid on the development of the CRC and the optimal time folic acid should be provided in a mouse-ICR model induced by 1, 2-Dimethylhydrazine. Also, we investigated the gene expression profile of this model related to folic acid. METHOD Female ICR mouse (n=130) were divided into 7 groups either with the treatment of 1, 2-Dimethylhydrazine (20 mg/kg bodyweight) weekly or folic acid (8 mg/kg bodyweight) twice a week for 12 or 24 weeks. Using a 4 x 44 K Agilent whole genome oligo microarray assay, different gene expression among groups (NS, DMH, FA2, FA3) were identified and selected genes were validated by real-time polymerase chain reaction. RESULTS Animals with a supplementary of folic acid showed a significant decrease in the incidence, the maximum diameter and multiplicity of adenocarcinomas (P<0.05). Furthermore, there were fewer adenomas or adenocarcinomas developed in the group of folic acid supplementation in pre-adenoma stage compared to group of post-adenoma stage. Meanwhile, about 1070 genes that were changed by 1, 2-Dimethylhydrazine can be reversed by folic acid and 172 differentially genes were identified between the groups of pre- and post- adenoma stage using microarray gene expression analysis. CONCLUSION Our study demonstrated that folic acid supplementary was significantly associated with the decrease risk of CRC. And the subgroup of providing folic acid without precancerous lesions was more effective than that with precancerous lesions.
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Matallanas D, Romano D, Al-Mulla F, O'Neill E, Al-Ali W, Crespo P, Doyle B, Nixon C, Sansom O, Drosten M, Barbacid M, Kolch W. Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Mol Cell 2011; 44:893-906. [PMID: 22195963 DOI: 10.1016/j.molcel.2011.10.016] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 08/29/2011] [Accepted: 10/10/2011] [Indexed: 01/14/2023]
Abstract
K-Ras mutations are frequent in colorectal cancer (CRC), albeit K-Ras is the only Ras isoform that can elicit apoptosis. Here, we show that mutant K-Ras directly binds to the tumor suppressor RASSF1A to activate the apoptotic MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase Mdm2 causing stabilization of the tumor suppressor p53 and apoptosis. However, mutant Ras also stimulates autocrine activation of the EGF receptor (EGFR) which counteracts mutant K-Ras-induced apoptosis. Interestingly, this protection requires the wild-type K-Ras allele, which inhibits the MST2 pathway in part via AKT activation. Confirming the pathophysiological relevance of the molecular findings, we find a negative correlation between K-Ras mutation and MST2 expression in human CRC patients and CRC mouse models. The small number of tumors with co-expression of mutant K-Ras and MST2 has elevated apoptosis rates. Thus, in CRC, mutant K-Ras transformation is supported by the wild-type allele.
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Affiliation(s)
- David Matallanas
- Systems Biology Ireland, University College Dublin, Dublin 4, Ireland
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Huang S, Benavente S, Armstrong EA, Li C, Wheeler DL, Harari PM. p53 modulates acquired resistance to EGFR inhibitors and radiation. Cancer Res 2011; 71:7071-9. [PMID: 22068033 DOI: 10.1158/0008-5472.can-11-0128] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.
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Affiliation(s)
- Shyhmin Huang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA
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Oh BY, Lee RA, Chung SS, Kim KH. Epidermal growth factor receptor mutations in colorectal cancer patients. JOURNAL OF THE KOREAN SOCIETY OF COLOPROCTOLOGY 2011; 27:127-32. [PMID: 21829767 PMCID: PMC3145883 DOI: 10.3393/jksc.2011.27.3.127] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 06/06/2011] [Indexed: 01/13/2023]
Abstract
Purpose The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor progression of colorectal cancer and leads to the activation of intracellular signaling pathways. The use of anti-EGFR-targeted therapy has increased for patients with colorectal cancer, but patients with EGFR mutations will be resistant to anti-EGFR-targeted therapy. The identification of gene mutations is critical in cancer treatment; therefore, the aim of this study is to investigate the incidences of EGFR mutations in colorectal cancer patients in Korea. Methods We retrospectively reviewed 58 colorectal cancer patients who underwent surgery between 2003 and 2006. We analyzed their EGFR mutations in four loci by DNA sequencing. In addition, we analyzed the correlation between the presence of EGFR mutation and patients' clinicopathologic features. Results Of the 58 patients, 35 patients were male and 23 were female. Their mean age was 63.28 ± 11.18 years. Two patients (3.45%) were diagnosed as stage Tis, 7 patients (12.07%) as stage I, 24 patients (41.38%) as stage II, 20 patients (34.48%) as stage III, and 5 patients (8.62%) as stage IV. As a result of mutational analysis, EGFR mutations on exon 20 were detected in 13 patients (22.41%, G→A transitions). No EGFR mutations were detected on exons 18, 19, and 21. EGFR mutation was increased in the earlier stage and in the absence of lymph node metastasis (P = 0.028). Conclusion The incidence of EGFR mutation in Korean colorectal cancer patients is 22.41%. In addition, EGFR mutation was significantly increased in the earlier stage and in the absence of lymph node metastasis.
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Affiliation(s)
- Bo-Young Oh
- Department of Surgery, Ewha Womans University School of Medicine, Seoul, Korea
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Lee WS, Jeong Heum Baek, Jung Nam Lee, Woon Kee Lee. Mutations in K-ras and Epidermal Growth Factor Receptor Expression in Korean Patients With Stages III and IV Colorectal Cancer. Int J Surg Pathol 2011; 19:145-51. [DOI: 10.1177/1066896911400411] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
K-Ras somatic mutations in advanced colorectal cancer (CRC) can predict resistance to mAbs that target the epidermal growth factor receptor (EGFR). The relationships between K-ras mutations and the EGFR status have not yet been examined, especially in Korean patients. A total of 82 colorectal tumors (stage III-IV) were analyzed. K-Ras mutations at codons 12 and 13 were detected by polymerase chain reaction—single strand conformational polymorphism. The EGFR expressions were examined by immunohistochemistry, and these were graded according to a modified EGFR expression scoring system. The relationships between the patients’ characteristics and the survival time and the gene mutation status were analyzed. The EGFR expression was positive in 69 patients (84.1%) and negative in 13 patients (15.9%). The K-ras mutation rate was 35.4%. In all, 20 (68.9%) cases were mutated at codon 12 and 9 (31.1%) cases were mutated at codon 13. No relationship was observed between the EGFR status and K-ras mutation. The median overall survival (OS) was 68.1 months. There was no difference between the K-ras mutant group and the wild type group for overall survival (30.3% vs 21.0%, respectively, at 36 months, P = .777). K-ras mutation and the EGFR status were not independent prognostic factors for OS ( P = .105 and P = .499, respectively). For the Korean patients with CRC, the rate of an EGFR protein expression was greater than that for the patients in Western countries, and the rate of K-ras mutations was lower than that for patients in Western countries. This study found no correlation between the EGFR status and K-ras mutations in colorectal tumors.
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Affiliation(s)
- Won-Suk Lee
- Gachon University of Medicine and Science, Incheon, Korea,
| | | | - Jung Nam Lee
- Gachon University of Medicine and Science, Incheon, Korea
| | - Woon Kee Lee
- Gachon University of Medicine and Science, Incheon, Korea
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Abstract
Microsatellite instability (MSI) occurs in about 15% of gastrointestinal cancers and it is associated with specific clinic, pathologic, and molecular features of the tumors. MSI-high (MSI-H) carcinomas also follow specific tumor development pathways. This review is focused on the molecular profile of alterations in members of the KRAS signaling pathway (EGFR, KRAS, BRAF, PIK3CA, RASSF1A, and MLK3 genes) in MSI gastrointestinal carcinomas. Alterations in these genes characterize more than half of gastrointestinal cancers and frequently occur simultaneously in the same tumor, pinpointing the KRAS signaling pathway as one of the most frequently altered pathways in this subset of cancers. Nowadays, many and novel inhibitors targeting molecules of this signaling pathway are being described; therefore, it is worthwhile to test their efficacy in MSI gastrointestinal cancers in order to develop new and more directed targeted therapies for patients affected by this disease.
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Analysis of KRAS Mutations of Exon 2 Codons 12 and 13 by SNaPshot Analysis in Comparison to Common DNA Sequencing. Gastroenterol Res Pract 2010; 2010:789363. [PMID: 21197450 PMCID: PMC3010661 DOI: 10.1155/2010/789363] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2010] [Revised: 11/10/2010] [Accepted: 11/10/2010] [Indexed: 01/25/2023] Open
Abstract
Due to the call for fast KRAS mutation status analysis for treatment of patients with monoclonal antibodies for metastatic colorectal cancer, sensitive, economic, and easily feasible methods are required. Under this aspect, the sensitivity and specificity of the SNaPshot analysis in comparison to the commonly used DNA sequencing was checked. We examined KRAS mutations in exon 2 codons 12 and 13 with DNA sequencing and SNaPshot analysis in 100 formalin-fixed paraffin-embedded tumor tissue samples of pancreatic carcinoma, colorectal carcinoma, and nonsmall cell lung cancer specimens of the primary tumor or metastases. 40% of these samples demonstrated mutated KRAS genes using sequencing and SNaPshot-analysis; additional five samples (45/100) were identified only with the SNaPshot. KRAS mutation detection is feasible with the reliable SNaPshot analysis method. The more frequent mutation detection by the SNaPshot analysis shows that this method has a high probability of accuracy in the detection of KRAS mutations compared to sequencing.
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De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S. KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 2010; 12:594-603. [PMID: 21163703 DOI: 10.1016/s1470-2045(10)70209-6] [Citation(s) in RCA: 464] [Impact Index Per Article: 30.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The discovery of mutant KRAS as a predictor of resistance to epidermal growth-factor receptor (EGFR) monoclonal antibodies brought a major change in the treatment of metastatic colorectal cancer. This seminal finding also highlighted our sparse knowledge about key signalling pathways in colorectal tumours. Drugs that inhibit oncogenic alterations such as phospho-MAP2K (also called MEK), phospho-AKT, and mutant B-RAF seem promising as single treatment or when given with EGFR inhibitors. However, our understanding of the precise role these potential drug targets have in colorectal tumours, and the oncogenic dependence that tumours might have on these components, has not progressed at the same rate. As a result, patient selection and prediction of treatment effects remain problematic. We review the role of mutations in genes other than KRAS on the efficacy of anti-EGFR therapy, and discuss strategies to target these oncogenic alterations alone or in combination with receptor tyrosine-kinase inhibition.
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Affiliation(s)
- Wendy De Roock
- Centre for Human Genetics, Catholic University of Leuven, Leuven, Belgium
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MacConaill LE, Garraway LA. Clinical implications of the cancer genome. J Clin Oncol 2010; 28:5219-28. [PMID: 20975063 PMCID: PMC3020694 DOI: 10.1200/jco.2009.27.4944] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Accepted: 08/11/2010] [Indexed: 01/06/2023] Open
Abstract
Cancer is a disease of the genome. Most tumors harbor a constellation of structural genomic alterations that may dictate their clinical behavior and treatment response. Whereas elucidating the nature and importance of these genomic alterations has been the goal of cancer biologists for several decades, ongoing global genome characterization efforts are revolutionizing both tumor biology and the optimal paradigm for cancer treatment at an unprecedented scope. The pace of advance has been empowered, in large part, through disruptive technological innovations that render complete cancer genome characterization feasible on a large scale. This article highlights cardinal biologic and clinical insights gleaned from systematic cancer genome characterization. We also discuss how the convergence of cancer genome biology, technology, and targeted therapeutics articulates a cohesive framework for the advent of personalized cancer medicine.
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Affiliation(s)
- Laura E. MacConaill
- From the Center for Cancer Genome Discovery; Dana-Farber Cancer Institute and Harvard Medical School, Boston; and The Broad Institute, Cambridge, MA
| | - Levi A. Garraway
- From the Center for Cancer Genome Discovery; Dana-Farber Cancer Institute and Harvard Medical School, Boston; and The Broad Institute, Cambridge, MA
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Abstract
Activating mutations in members of the RAS oncogene family (KRAS, HRAS, and NRAS) have been found in a variety of human malignancies, suggesting a dominant role in carcinogenesis. In colon cancers, KRAS mutations are common and clearly contribute to malignant progression. The frequency of NRAS mutations and their relationship with clinical, pathologic, and molecular features remains uncertain. We developed and validated a Pyroseqencing assay to detect NRAS mutations at codons 12, 13, and 61. Using a collection of 225 colorectal cancers from 2 prospective cohort studies, we examined the relationship between NRAS mutations, clinical outcome, and other molecular features, including mutation of KRAS, BRAF, and PIK3CA, microsatellite instability, and the CpG island methylator phenotype. Finally, we examined whether NRAS mutation was associated with patient survival or prognosis. NRAS mutations were detected in 5 (2.2%) of the 225 colorectal cancers and tended to occur in left-sided cancers arising in women, but did not seem to be associated with any of the molecular features that were examined.
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Messersmith WA, Jimeno A, Jacene H, Zhao M, Kulesza P, Laheru DA, Kahn Y, Spira A, Dancey J, Iacobuzio-Donahue C, Donehower RC, Carducci M, Rudek MA, Hidalgo M. Phase I trial of oxaliplatin, infusional 5-fluorouracil, and leucovorin (FOLFOX4) with erlotinib and bevacizumab in colorectal cancer. Clin Colorectal Cancer 2010; 9:297-304. [PMID: 21208844 PMCID: PMC3033228 DOI: 10.3816/ccc.2010.n.043] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
RATIONALE This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD. PATIENTS AND METHODS Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans. RESULTS Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease. CONCLUSION The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.
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An B, Kondo Y, Okamoto Y, Shinjo K, Kanemitsu Y, Komori K, Hirai T, Sawaki A, Tajika M, Nakamura T, Yamao K, Yatabe Y, Fujii M, Murakami H, Osada H, Tani T, Matsuo K, Shen L, Issa JPJ, Sekido Y. Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers. Int J Cancer 2010; 127:2095-105. [PMID: 20131317 DOI: 10.1002/ijc.25225] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Aberrant DNA methylation is involved in colon carcinogenesis. Although the CpG island methylator phenotype (CIMP) is defined as a subset of colorectal cancers (CRCs) with remarkably high levels of DNA methylation, it is not known whether epigenetic processes are also involved in CIMP-negative tumors. We analyzed the DNA methylation profiles of 94 CRCs and their corresponding normal-appearing colonic mucosa with 11 different markers, including the five classical CIMP markers. The CIMP markers were frequently methylated in proximal CRCs (p < 0.01); however, RASSF1A methylation levels were significantly higher in distal CRCs, the majority of which are CIMP-negative (p < 0.05). Similarly, methylation levels of RASSF1A and SFRP1 in the normal-appearing mucosae of distal CRC cases were significantly higher than those in the proximal CRC cases (p < 0.05). They were also positively correlated with age (RASSF1A, p < 0.01; SFRP1, p < 0.01). Microarray-based genome-wide DNA methylation analysis of 18 CRCs revealed that 168 genes and 720 genes were preferentially methylated in CIMP-negative distal CRCs and CIMP-positive CRCs, respectively. Interestingly, more than half of the hypermethylated genes in CIMP-negative distal CRCs were also methylated in the normal-appearing mucosae, indicating that hypermethylation in CIMP-negative distal CRCs is more closely associated with age-related methylation. By contrast, more than 60% of the hypermethylated genes in CIMP-positive proximal CRCs were cancer specific (p < 0.01). These data altogether suggest that CpG island promoters appear to be methylated in different ways depending on location, a finding which may imply the presence of different mechanisms for the acquisition of epigenetic changes during colon tumorigenesis.
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Affiliation(s)
- Byonggu An
- Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa-Ku, Nagoya 464-8681, Japan
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