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Liu J, Liu Z, Hu J, Fan B, Zhang S, Chang K, Mao X, Huang G, Liu Z, Ma L. Anti-breast cancer activity of a novel genetically engineered fusion protein composed of HER2 affibody and proapoptotic peptide R8-KLA. Med Oncol 2025; 42:155. [PMID: 40205290 DOI: 10.1007/s12032-025-02707-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/29/2025] [Indexed: 04/11/2025]
Abstract
HER2-positive breast cancer is an aggressive subtype with unfavorable prognoses. Although HER2-targeted agents represented by monoclonal antibodies have achieved remarkable success in the clinic, there are still a substantial number of patients with disease relapse. Recently, multifunctional fusion proteins obtained via genetic engineering technology have received much attention in targeted tumor therapy, especially in breast cancer. In this study, we genetically engineered a novel recombinant fusion protein, named HMK, which was designed as a bifunctional construct including the HER2-specific affibody ZHER2:342 for targeted receptor recognition, and a proapoptotic module featuring a cell-penetrating octa-arginine (R8) motif conjugated to an antimicrobial peptide KLA. High-purity HMK proteins were successfully obtained using E. coli expression system and Ni-Nitrilotriacetic acid affinity purification method. HMK exhibited higher cytotoxicity in HER2-positive breast cancer cells SK-BR-3 (IC50 of 8.36 ± 0.62 μM) compared to normal breast epithelial cells MCF-10A (IC50 of 32.40 ± 2.93 μM), demonstrating favorable selectivity. HMK induced apoptosis in SK-BR-3 cells via activating both endogenous and exogenous apoptotic pathways, as evidenced by the cleavage of Caspase 8, Caspase 9, Caspase 3, and PARP. Caspase inhibitor Z-VAD significantly reversed the function of HMK in SK-BR-3 cells, suggesting that caspase-dependent apoptosis was crucial for the anti-breast cancer activity of HMK. Our results suggested that HMK protein may have the potential to become a candidate molecule for HER2-positive breast cancer treatment.
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Affiliation(s)
- Jian Liu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Zi Liu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China.
| | - Junfeng Hu
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Binru Fan
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Shizhun Zhang
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Kaili Chang
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Xiuping Mao
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Guozheng Huang
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China
| | - Zhi Liu
- Department of Pathology, Ma'anshan Municipal People's Hospital, Ma'anshan, Anhui, 243000, China
| | - Liang Ma
- Department of Chemical Biology and Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan, Anhui, 243002, China.
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Yan HC, Liu Y, Feng Y, Li JM, Sheng LM, Chen X, Xie YP, Li N. Efficacy of disitamab vedotin-containing therapy in metastatic colorectal cancer: A case report. World J Clin Oncol 2025; 16:99527. [PMID: 40130050 PMCID: PMC11866092 DOI: 10.5306/wjco.v16.i3.99527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/10/2024] [Accepted: 12/30/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. In cases of metastatic CRC (mCRC) that are resistant to conventional chemotherapy-based treatments, the efficacy of available therapeutic options is typically low. CRC exhibiting overexpression or amplification of the human epidermal growth factor receptor 2 (HER2) gene has shown responsiveness to HER2-targeted therapies. CASE SUMMARY We present the case of a 69-year-old woman diagnosed with mCRC with an NRAS p.G12V mutation and microsatellite stability, identified through tumor sequencing, along with HER2 overexpression detected by immunohistochemistry. She exhibited an excellent response to disitamab vedotin-containing therapy. To our knowledge, this is the first reported case of mCRC with HER2 overexpression and an NRAS p.G12V mutation achieving a remarkable clinical response to anti-HER2 therapy. CONCLUSION Disitamab vedotin demonstrates promising anti-tumor effects in HER2-overexpressing mCRC, offering patients an additional treatment option.
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Affiliation(s)
- Hu-Cheng Yan
- Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan Province, China
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Liu
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - You Feng
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jun-Ming Li
- Department of Radiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei-Ming Sheng
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Chen
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Ping Xie
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Na Li
- Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Alkhatabi HA, Alatyb HN. In Silico Design of Peptide Inhibitors Targeting HER2 for Lung Cancer Therapy. Cancers (Basel) 2024; 16:3979. [PMID: 39682166 DOI: 10.3390/cancers16233979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/16/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND/OBJECTIVES Human epidermal growth factor receptor 2 (HER2) is overexpressed in several malignancies, such as breast, gastric, ovarian, and lung cancers, where it promotes aggressive tumor proliferation and unfavorable prognosis. Targeting HER2 has thus emerged as a crucial therapeutic strategy, particularly for HER2-positive malignancies. The present study focusses on the design and optimization of peptide inhibitors targeting HER2, utilizing machine learning to identify and enhance peptide candidates with elevated binding affinities. The aim is to provide novel therapeutic options for malignancies linked to HER2 overexpression. METHODS This study started with the extraction and structural examination of the HER2 protein, succeeded by designing the peptide sequences derived from essential interaction residues. A machine learning technique (XGBRegressor model) was employed to predict binding affinities, identifying the top 20 peptide possibilities. The candidates underwent further screening via the FreeSASA methodology and binding free energy calculations, resulting in the selection of four primary candidates (pep-17, pep-7, pep-2, and pep-15). Density functional theory (DFT) calculations were utilized to evaluate molecular and reactivity characteristics, while molecular dynamics simulations were performed to investigate inhibitory mechanisms and selectivity effects. Advanced computational methods, such as QM/MM simulations, offered more understanding of peptide-protein interactions. RESULTS Among the four principal peptides, pep-7 exhibited the most elevated DFT values (-3386.93 kcal/mol) and the maximum dipole moment (10,761.58 Debye), whereas pep-17 had the lowest DFT value (-5788.49 kcal/mol) and the minimal dipole moment (2654.25 Debye). Molecular dynamics simulations indicated that pep-7 had a steady binding free energy of -12.88 kcal/mol and consistently bound inside the HER2 pocket during a 300 ns simulation. The QM/MM simulations showed that the overall total energy of the system, which combines both QM and MM contributions, remained around -79,000 ± 400 kcal/mol, suggesting that the entire protein-peptide complex was in a stable state, with pep-7 maintaining a strong, well-integrated binding. CONCLUSIONS Pep-7 emerged as the most promising therapeutic peptide, displaying strong binding stability, favorable binding free energy, and molecular stability in HER2-overexpressing cancer models. These findings suggest pep-7 as a viable therapeutic candidate for HER2-positive cancers, offering a potential novel treatment strategy against HER2-driven malignancies.
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Affiliation(s)
- Heba Ahmed Alkhatabi
- Faculty of Applied Medical Science, King Abdulaziz University, Jeddah 22254, Saudi Arabia
- Hematology Research Unit (HRU), King Fahd Medical Research Center (KFMRC), Jeddah 22252, Saudi Arabia
- Center of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 22254, Saudi Arabia
| | - Hisham N Alatyb
- Center of Artificial Intelligence in Precision Medicines, King Abdulaziz University, Jeddah 22254, Saudi Arabia
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 22254, Saudi Arabia
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Cotan HT, Emilescu RA, Iaciu CI, Orlov-Slavu CM, Olaru MC, Popa AM, Jinga M, Nitipir C, Schreiner OD, Ciobanu RC. Prognostic and Predictive Determinants of Colorectal Cancer: A Comprehensive Review. Cancers (Basel) 2024; 16:3928. [PMID: 39682117 DOI: 10.3390/cancers16233928] [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: 11/06/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes. This systematic review aims to comprehensively evaluate prognostic and predictive determinants in CRC, encompassing both traditional and emerging biomarkers. A systematic search of major electronic databases was conducted to identify relevant studies published from 1995 up to 2024. Eligible articles were critically appraised, and data extraction was performed according to predefined criteria. The prognostic determinants examined included clinicopathological features such as tumor stage, grade, and lymph node involvement, as well as molecular biomarkers including RAS, BRAF, and MSI status. Predictive determinants encompassed biomarkers influencing response to targeted therapies and immunotherapy, such as HER2 and Immunoscore. The review also explores novel prognostic and predictive markers, including tumor microenvironment characteristics and liquid biopsy-based biomarkers. Synthesizing evidence from diverse studies, this review provides insights into the prognostic and predictive landscape of CRC, highlighting the potential clinical implications of identified determinants. Understanding the multifaceted nature of prognostic and predictive factors in CRC is imperative for the advancement of personalized treatment strategies and improvement of patient outcomes.
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Affiliation(s)
- Horia T Cotan
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Radu A Emilescu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cristian I Iaciu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cristina M Orlov-Slavu
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Mihaela C Olaru
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Ana M Popa
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Mariana Jinga
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Cornelia Nitipir
- General Medicine Faculty, Carol Davila University of Medicine and Pharmacy, 8 Sanitary Heroes Boulevard, 050474 Bucharest, Romania
| | - Oliver Daniel Schreiner
- Regional Institute of Oncology Iasi, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania
- Department 3-Medical Sciences, Grigore T. Popa University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
- Department of Electrical Measurements and Materials, Gheorghe Asachi Technical University, 700050 Iasi, Romania
| | - Romeo Cristian Ciobanu
- Department of Electrical Measurements and Materials, Gheorghe Asachi Technical University, 700050 Iasi, Romania
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Bhamidipati D, Schram AM. Emerging Tumor-Agnostic Molecular Targets. Mol Cancer Ther 2024; 23:1544-1554. [PMID: 39279103 PMCID: PMC11908425 DOI: 10.1158/1535-7163.mct-23-0725] [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: 04/24/2024] [Revised: 07/30/2024] [Accepted: 09/06/2024] [Indexed: 09/18/2024]
Abstract
Advances in tumor molecular profiling have uncovered shared genomic and proteomic alterations across tumor types that can be exploited therapeutically. A biomarker-driven, disease-agnostic approach to oncology drug development can maximize the reach of novel therapeutics. To date, eight drug-biomarker pairs have been approved for the treatment of patients with advanced solid tumors with specific molecular profiles. Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK and mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors.
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Affiliation(s)
| | - Alison M. Schram
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA
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Bhagyalalitha M, Handattu Shankaranarayana A, Arun Kumar S, Singh M, Pujar KG, Bidye D, Veeranna Pujar G. Advances in HER2-Targeted Therapies: From monoclonal antibodies to dual inhibitors developments in cancer treatment. Bioorg Chem 2024; 151:107695. [PMID: 39137598 DOI: 10.1016/j.bioorg.2024.107695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 07/28/2024] [Accepted: 08/04/2024] [Indexed: 08/15/2024]
Abstract
HER2 receptors, overexpressed in certain human cancers, have drawn significant attention in cancer research due to their correlation with poor survival rates. Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer. However, ongoing research is investigating their potential use in other types of cancer, often in combination with other medications. EGFR/HER2 dual-targeted drugs have overcome drug resistance associated with HER2-targeted monotherapy. This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.
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Affiliation(s)
- Meduri Bhagyalalitha
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Akshatha Handattu Shankaranarayana
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Sethu Arun Kumar
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Manisha Singh
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Karthik G Pujar
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Durgesh Bidye
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Gurubasavaraj Veeranna Pujar
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India.
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Verma S, Chapman A, Pickard LA, Porplycia D, McConkey H, Jarosz P, Sinfield J, Lauzon-Young C, Cecchini MJ, Howlett C, Grindrod N, Sadikovic B, Welch SA, Breadner D. Evaluation of HER2 immunohistochemistry expression in non-standard solid tumors from a Single-Institution Prospective Cohort. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:1100-1109. [PMID: 39351438 PMCID: PMC11438559 DOI: 10.37349/etat.2024.00265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 07/29/2024] [Indexed: 10/04/2024] Open
Abstract
Aim Human epidermal growth factor receptor-2 (HER2) is a well-established prognostic and predictive biomarker. It is an FDA-approved therapeutic target for HER2 positive breast, gastroesophageal, and more recently, lung and colon cancers. It is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian, and pancreatic cancers. The emergence of new indications warrants further characterization of HER2 expression in diverse cancer populations. This study investigated HER2 expression in solid tumour samples and the feasibility of obtaining these results. Methods Prospective consent was obtained at a Canadian tertiary academic cancer center from adult oncology patients who were referred for molecular genetic testing of malignant tissue samples. Standard HER2-targeted malignancies were considered breast and gastroesophageal, and were excluded from this study. Between July 2020 and November 2023, 499 samples of solid tumors underwent immunohistochemistry (IHC) HER2 staining. A median turnaround time (TAT) of 14 days would be considered feasible for clinical decision making. Results The mean age (± SD) of participants was 67 ± 12.5 years, with 270 (54%) male and 229 (46%) female. HER2 protein expression was measured in 42 unique cancer types. IHC levels of 0, 1+, 2+, and 3+ were reported and were 43%, 12%, 35%, and 10% of all analyzable samples respectively (tissue inadequate in 3% of samples). The median TAT for HER2 expression results from time of request to result in release was 18 (interquartile range, 11 to 30) days. Conclusions HER2 protein expression varies widely between different cancer types. TAT for HER2 IHC results was a median of 18 days, which is close to our feasibility cut-off.
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Affiliation(s)
- Saurav Verma
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Amanda Chapman
- Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Lee-Anne Pickard
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Danielle Porplycia
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Haley McConkey
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Patricia Jarosz
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - James Sinfield
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Carolyn Lauzon-Young
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Matthew J Cecchini
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Christopher Howlett
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Natalie Grindrod
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON N6A 5W9, Canada
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
| | - Stephen A Welch
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Daniel Breadner
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
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Nipper AJ, Warren EAK, Liao KS, Liu HC, Michikawa C, Porter CE, Wells GA, Villanueva M, Brasil da Costa FH, Veeramachaneni R, Villanueva H, Suzuki M, Sikora AG. Chick Embryo Chorioallantoic Membrane as a Platform for Assessing the In Vivo Efficacy of Chimeric Antigen Receptor T-cell Therapy in Solid Tumors. Immunohorizons 2024; 8:598-605. [PMID: 39225630 PMCID: PMC11374747 DOI: 10.4049/immunohorizons.2400059] [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: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024] Open
Abstract
The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied to tumors grown on the CAM. Four days post-CAR T cell treatment, HER2-expressing FaDu and SCC-47 tumors treated with CAR T showed reduced viable cancer cells as assessed by luciferase activity. This reduction in viable tumor cells was confirmed by histology, with lower Ki-67 staining observed in CAR T cell-treated tumors relative to T cell-treated controls. Persistence of CAR T in CAM and tumor tissue 4 days post-treatment was confirmed by CD3 staining. Altogether, our findings support further development of the chick CAM as an in vivo system for rapid, scalable screening of CAR T cell efficacy against human solid tumors.
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Affiliation(s)
- Allison J. Nipper
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Emilie A. K. Warren
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX
| | - Kershena S. Liao
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX
| | - Hsuan-Chen Liu
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX
| | - Chieko Michikawa
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Caroline E. Porter
- Department of Family and Community Medicine, Baylor College of Medicine, Houston, TX
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX
| | | | - Mariana Villanueva
- Department of Family and Community Medicine, Baylor College of Medicine, Houston, TX
| | | | - Ratna Veeramachaneni
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Hugo Villanueva
- Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX
- Advanced Technology Cores, Baylor College of Medicine, Houston, TX
| | - Masataka Suzuki
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX
- Texas Children’s Hospital, Houston, TX
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX
| | - Andrew G. Sikora
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX
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Li Y, Jin Y, Wang Y, Liu W, Jia W, Wang J. MR-based radiomics predictive modelling of EGFR mutation and HER2 overexpression in metastatic brain adenocarcinoma: a two-centre study. Cancer Imaging 2024; 24:65. [PMID: 38773634 PMCID: PMC11110398 DOI: 10.1186/s40644-024-00709-4] [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: 11/23/2023] [Accepted: 05/11/2024] [Indexed: 05/24/2024] Open
Abstract
OBJECTIVES Magnetic resonance (MR)-based radiomics features of brain metastases are utilised to predict epidermal growth factor receptor (EGFR) mutation and human epidermal growth factor receptor 2 (HER2) overexpression in adenocarcinoma, with the aim to identify the most predictive MR sequence. METHODS A retrospective inclusion of 268 individuals with brain metastases from adenocarcinoma across two institutions was conducted. Utilising T1-weighted imaging (T1 contrast-enhanced [T1-CE]) and T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, 1,409 radiomics features were extracted. These sequences were randomly divided into training and test sets at a 7:3 ratio. The selection of relevant features was done using the least absolute shrinkage selection operator, and the training cohort's support vector classifier model was employed to generate the predictive model. The performance of the radiomics features was evaluated using a separate test set. RESULTS For contrast-enhanced T1-CE cohorts, the radiomics features based on 19 selected characteristics exhibited excellent discrimination. No significant differences in age, sex, and time to metastasis were observed between the groups with EGFR mutations or HER2 + and those with wild-type EGFR or HER2 (p > 0.05). Radiomics feature analysis for T1-CE revealed an area under the curve (AUC) of 0.98, classification accuracy of 0.93, sensitivity of 0.92, and specificity of 0.93 in the training cohort. In the test set, the AUC was 0.82. The 19 radiomics features for the T2-FLAIR sequence showed AUCs of 0.86 in the training set and 0.70 in the test set. CONCLUSIONS This study developed a T1-CE signature that could serve as a non-invasive adjunctive tool to determine the presence of EGFR mutations and HER2 + status in adenocarcinoma, aiding in the direction of treatment plans. CLINICAL RELEVANCE STATEMENT We propose radiomics features based on T1-CE brain MR sequences that are both evidence-based and non-invasive. These can be employed to guide clinical treatment planning in patients with brain metastases from adenocarcinoma.
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Affiliation(s)
- Yanran Li
- Department of Radiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Yong Jin
- Department of Radiology, Changzhi People's Hospital, Changzhi, 046000, Shanxi Province, China
| | - Yunling Wang
- Department of Radiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Wenya Liu
- Department of Radiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Wenxiao Jia
- Department of Radiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China
| | - Jian Wang
- Department of Radiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China.
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Shaban N, Raevskiy M, Zakharova G, Shipunova V, Deyev S, Suntsova M, Sorokin M, Buzdin A, Kamashev D. Human Blood Serum Counteracts EGFR/HER2-Targeted Drug Lapatinib Impact on Squamous Carcinoma SK-BR-3 Cell Growth and Gene Expression. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:487-506. [PMID: 38648768 DOI: 10.1134/s000629792403009x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/17/2024] [Accepted: 02/20/2024] [Indexed: 04/25/2024]
Abstract
Lapatinib is a targeted therapeutic inhibiting HER2 and EGFR proteins. It is used for the therapy of HER2-positive breast cancer, although not all the patients respond to it. Using human blood serum samples from 14 female donors (separately taken or combined), we found that human blood serum dramatically abolishes the lapatinib-mediated inhibition of growth of the human breast squamous carcinoma SK-BR-3 cell line. This antagonism between lapatinib and human serum was associated with cancelation of the drug induced G1/S cell cycle transition arrest. RNA sequencing revealed 308 differentially expressed genes in the presence of lapatinib. Remarkably, when combined with lapatinib, human blood serum showed the capacity of restoring both the rate of cell growth, and the expression of 96.1% of the genes expression of which were altered by the lapatinib treatment alone. Co-administration of EGF with lapatinib also restores the cell growth and cancels alteration of expression of 95.8% of the genes specific to lapatinib treatment of SK-BR-3 cells. Differential gene expression analysis also showed that in the presence of human serum or EGF, lapatinib was unable to inhibit the Toll-Like Receptor signaling pathway and alter expression of genes linked to the Gene Ontology term of Focal adhesion.
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Affiliation(s)
- Nina Shaban
- Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia
- The National Medical Research Center for Endocrinology, Moscow, 117036, Russia
| | - Mikhail Raevskiy
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
| | - Galina Zakharova
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
| | - Victoria Shipunova
- Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia
| | - Sergey Deyev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
- "Biomarker" Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, 420008, Russia
| | - Maria Suntsova
- The National Medical Research Center for Endocrinology, Moscow, 117036, Russia.
- Sechenov First Moscow State Medical University, Moscow, 119991, Russia
| | - Maksim Sorokin
- Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia.
- Sechenov First Moscow State Medical University, Moscow, 119991, Russia
- PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), Brussels, 1200, Belgium
| | - Anton Buzdin
- Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia.
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia
- The National Medical Research Center for Endocrinology, Moscow, 117036, Russia
- World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, 119991, Russia
| | - Dmitri Kamashev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
- The National Medical Research Center for Endocrinology, Moscow, 117036, Russia
- Sechenov First Moscow State Medical University, Moscow, 119991, Russia
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11
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Nemtsova MV, Kuznetsova EB, Bure IV. Chromosomal Instability in Gastric Cancer: Role in Tumor Development, Progression, and Therapy. Int J Mol Sci 2023; 24:16961. [PMID: 38069284 PMCID: PMC10707305 DOI: 10.3390/ijms242316961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the TP53 gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.
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Affiliation(s)
- Marina V. Nemtsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Ekaterina B. Kuznetsova
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
| | - Irina V. Bure
- Laboratory of Medical Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; (M.V.N.); (E.B.K.)
- Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
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12
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Jayarajkumar S, Ramamoorthi R, Muniapillai S, Gopalakrishnan S, Jayaseelan VP. Assessment of salivary levels of ErbB2 in oral squamous cell carcinoma. J Oral Maxillofac Pathol 2023; 27:777. [PMID: 38304523 PMCID: PMC10829474 DOI: 10.4103/jomfp.jomfp_114_23] [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: 03/06/2023] [Revised: 05/19/2023] [Accepted: 05/19/2023] [Indexed: 02/03/2024] Open
Abstract
Introduction Oral cancer is the sixth-most common cancer globally. The survival rate of oral cancer is 5 years, depending on the stage it is diagnosed. To diagnose in the early stage, specialised tumour markers may assist and also help in improving the survival rate of oral cancer. ErbB2 is a transmembrane cell surface receptor required in signal transduction and an essential part of signalling pathways that take part in controlling the basic cellular processes like cell cycle, migration, metabolism and survival, besides cellular proliferation and differentiation. It is over-expressed in oral squamous cell carcinoma (OSCC) and is directly proportional to the poor prognosis, as it is expressed at a very low concentration in a healthy individual. Due to this, ErbB2 could be used as a diagnostic marker in OSCC. Nowadays, the search for tumour expression in the saliva with the use of salivary biomarkers could aid in the diagnosis of the OSSC. Aim and Objectives To assess the expression of ErbB2 in the saliva of patients with oral squamous cell carcinoma by correlating the ErbB2 level in the disease group with the healthy group. To determine the diagnostic significance of ErbB2 in OSCC. Materials and Methods The study comprises 20 salivary samples from OSCC patients and 20 salivary samples from healthy individuals. The salivary level of ErbB2 was estimated using Enzyme Linked Immunosorbent Assay. To analyse the data, SPSS (IBM SPSS Statistics for Windows, Version 26.0, Armonk, NY: IBM Corp. Released 2019) is used. The significance level is fixed at 5% (α = 0.05). P value <0.05 is considered to be statistically significant. To compare the mean values of mean and concentration, an unpaired/independent sample t-test was used. Results The mean age of OSCC and control were found to be 57 ± 8.13 and 26.6 ± 1.51, respectively. The mean age was compared between OSCC and control by the Chi-square test, and the P value was <0.01, which was found to be statistically significant. The salivary levels of ErbB2 in the OSCC and control groups were measured by an unpaired sample t-test. The mean salivary ErbB2 level in the OSCC group is 3.20 ng/ml ± 0.57, and in the control group, it is 2.43 ng/ml ± 0.13. When a pairwise comparison of ErbB2 concentration was performed between OSCC and control, it showed a statistically significant difference with a P value of 0.007, which is P < 0.05. Conclusion The present study has demonstrated an increased salivary expression of ErbB2 in OSCC patients when compared to healthy individuals. This suggests that ErbB2 could aid in the diagnosis of OSCC and could be used as a diagnostic marker in the early detection of oral cancer, a finding that has to be further established with a larger sample size.
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Affiliation(s)
- Sujithaa Jayarajkumar
- Department of Oral Pathology and Microbiology, Madha Dental College and Hospital, Kundrathur, Chennai, Tamil Nadu, India
| | - Raghini Ramamoorthi
- Department of Oral Pathology and Microbiology, Madha Dental College and Hospital, Kundrathur, Chennai, Tamil Nadu, India
| | - Sivakumar Muniapillai
- Department of Oral Pathology and Microbiology, Madha Dental College and Hospital, Kundrathur, Chennai, Tamil Nadu, India
| | - Sivakumar Gopalakrishnan
- Department of Oral Pathology and Microbiology, Madha Dental College, Research Scholar, Kundrathur, Chennai, Tamil Nadu, India
| | - Vijayashree Priyadharshini Jayaseelan
- Associate Professor/ Research Scientist, Clinical Genetics Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, India
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13
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Mckertish CM, Kayser V. A Novel Dual-Payload ADC for the Treatment of HER2+ Breast and Colon Cancer. Pharmaceutics 2023; 15:2020. [PMID: 37631234 PMCID: PMC10459570 DOI: 10.3390/pharmaceutics15082020] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/14/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Antibody-drug conjugates (ADCs) have demonstrated a great therapeutic potential against cancer due to their target specificity and cytotoxicity. To exert a maximum therapeutic effect on cancerous cells, we have conjugated two different payloads to different amino acids, cysteines (cys) and lysines (lys), on trastuzumab, which is a humanised anti-HER2 monoclonal antibody. First, trastuzumab was conjugated with monomethyl auristatin E (MMAE), an antimitotic agent, through a cleavable linker (Val-Cit) to prepare ADC (Tmab-VcMMAE). Then, the ADC (Tmab-VcMMAE) was conjugated with a second antimitotic agent, Mertansine (DM1), via a non-cleavable linker Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) to form a dual conjugate (Tmab-VcMMAE-SMCC-DM1). Our results indicated that the dual-payload conjugate, Tmab-VcMMAE-SMCC-DM1, had a synergistic and superior cytotoxic effect compared to trastuzumab alone. Ultimately employing a dual conjugation approach has the potential to overcome treatment-resistance and tumour recurrences and could pave the way to employ other payloads to construct dual (or multiple) payload complexes.
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Affiliation(s)
| | - Veysel Kayser
- Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
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14
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Yanagimoto Y, Imamura H, Adachi S, Odagiri K, Kawase T, Yamashita M, Takeyama H, Suzuki Y, Ikenaga M, Shimizu J, Tomita N, Dono K. The effect of specimen processing time on HER2 expression in gastric cancer and esophagogastric junction cancer: a single-center retrospective observational study. BMC Cancer 2023; 23:645. [PMID: 37434116 PMCID: PMC10334514 DOI: 10.1186/s12885-023-11148-y] [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: 03/29/2023] [Accepted: 07/04/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Recent developments in the field of companion diagnosis and molecular-targeting therapeutic agents have helped in developing treatments targeting human epidermal growth factor receptor 2 (HER2) in gastric cancer (GC) and esophagogastric junction cancer (EGJC), and the importance of accurate diagnosis of HER2 expression is increasing. However, the HER2-positivity rate significantly differs among reports in GC and EGJC, and factors that affect HER2-positivity require elucidation. METHODS The present study retrospectively examined factors related to HER2-positivity in a single institution, including age, sex, body mass index, the American Society of Anesthesiologists physical status, tumor information, and surgery information, including time to specimen processing. RESULTS Our study included 165 patients tested for HER2 using GC and EGJC surgery specimens among the 1,320 patients who underwent gastrectomy from January 2007 to June 2022. In total, 35 (21.2%) and 130 (78.8%) patients were HER2-positive and -negative, respectively. Multivariate analysis revealed that intestinal type (odds ratio [OR]: 3.41, 95% confidence interval [CI]: 1.44-8.09, p = 0.005), pM1 (OR: 3.99, 95% CI: 1.51-10.55, p = 0.005), and time to specimen processing of < 120 min (OR: 2.65, 95% CI: 1.01-6.98, p = 0.049) were independent factors that affected HER2-positivity. CONCLUSIONS The outcomes of the present study indicated that intestinal type, pM, and time to specimen processing are important factors affecting HER2-positive rates in GC and EGJC. Therefore, the risk of false-negative HER2 results may be reduced by decreasing the time required to process the resected specimen. Additionally, accurate diagnosis of HER2 expression may increase the opportunity to administer molecular-targeted drugs that can expect therapeutic effects to patients appropriately. TRAIL REGISTRATION Retrospectively registered.
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Affiliation(s)
- Yoshitomo Yanagimoto
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan.
| | - Hiroshi Imamura
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Shiro Adachi
- Department Diagnostic Pathology, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Kazuki Odagiri
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Tomono Kawase
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masafumi Yamashita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Hiroshi Takeyama
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Yozo Suzuki
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Masakazu Ikenaga
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Junzo Shimizu
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Naohiro Tomita
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
| | - Keizo Dono
- Department of Surgery, Toyonaka Municipal Hospital, 4-14-1 Shimahara-Cho, Toyonaka, Osaka, 560-8565, Japan
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15
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Cann CG, LaPelusa MB, Cimino SK, Eng C. Molecular and genetic targets within metastatic colorectal cancer and associated novel treatment advancements. Front Oncol 2023; 13:1176950. [PMID: 37409250 PMCID: PMC10319053 DOI: 10.3389/fonc.2023.1176950] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Colorectal cancer results in the deaths of hundreds of thousands of patients worldwide each year, with incidence expected to rise over the next two decades. In the metastatic setting, cytotoxic therapy options remain limited, which is reflected in the meager improvement of patient survival rates. Therefore, focus has turned to the identification of the mutational composition inherent to colorectal cancers and development of therapeutic targeted agents. Herein, we review the most up to date systemic treatment strategies for metastatic colorectal cancer based on the actionable molecular alterations and genetic profiles of colorectal malignancies.
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Affiliation(s)
- Christopher G. Cann
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Michael B. LaPelusa
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sarah K. Cimino
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cathy Eng
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
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16
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Reddy A, Nwankwo N, Sekar A, Kumar A. A Case of HER2 Mutated Colorectal Cancer Treated Successfully With Fam-Trastuzumab Deruxtecan. Cureus 2023; 15:e38582. [PMID: 37284365 PMCID: PMC10239608 DOI: 10.7759/cureus.38582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2023] [Indexed: 06/08/2023] Open
Abstract
Colorectal cancer is a malignant tumor arising from the inner lining of the colon or rectum and is the third most common cancer and the third leading cause of cancer-related deaths in the United States. Human epidermal growth factor receptor 2 (HER2) gene overexpressed or amplified colorectal cancer has shown treatment responses with HER2-directed therapies. We present a 78-year-old woman with metastatic colorectal cancer with a HER2 L726I mutation identified in tumor sequencing with amplification or overexpression of HER2. She had an excellent response to fam-trastuzumab deruxtecan. Our case is the first and most noteworthy case of a patient with metastatic colorectal cancer and a HER2 L726I mutation who achieved a remarkable clinical response to fam-trastuzumab deruxtecan.
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Affiliation(s)
- Aswanth Reddy
- Hematology and Oncology, Mercy Clinic, Fort Smith, USA
| | | | - Arjun Sekar
- Nephrology, Rochester Regional Health, Rochester, USA
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17
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Pham SH, Vuorinen SI, Arif KT, Griffiths LR, Okolicsanyi RK, Haupt LM. Syndecan-4 regulates the HER2-positive breast cancer cell proliferation cells via CK19/AKT signalling. Biochimie 2023; 207:49-61. [PMID: 36460206 DOI: 10.1016/j.biochi.2022.11.010] [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: 05/10/2022] [Revised: 10/27/2022] [Accepted: 11/18/2022] [Indexed: 12/02/2022]
Abstract
Despite the use of the highly specific anti-HER2 receptor (trastuzumab) therapy, HER2-positive breast cancers account for 20-30% of all breast cancer carcinomas, with HER2 status a challenge to treatment interventions. The heparan sulfate proteoglycans (HSPGs) are prominently expressed in the extracellular matrix (ECM), mediate breast cancer proliferation, development, and metastasis with most studies to date conducted in animal models. This study examined HSPGs in HER2-positive human breast cancer cell lines and their contribution to cancer cell proliferation. The study examined the cells following enhancement (via the addition of heparin) and knockdown (KD; using short interfering RNA, siRNA) of HSPG core proteins. The interaction of HSPG core proteins and AKT signalling molecules was examined to identify any influence of this signalling pathway on cancer cell proliferation. Our findings illustrated the HSPG syndecan-4 (SDC4) core protein significantly regulates cell proliferation with increased BC cell proliferation following heparin addition to cultures and decreased cell number following SDC4 KD. In addition, along with SDC4, significant changes in CK19/AKT signalling were identified as mediators of BC HER2-positive BC cell proliferation. This study provides evidence for a cell growth regulatory axis involving HSPGs/CK19 and AKT that represents a potential molecular target to prevent proliferation of HER2-positive breast cancer cells.
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Affiliation(s)
- Son H Pham
- Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, 60 Musk Ave., Kelvin Grove, Queensland, 4059, Australia
| | - Sofia I Vuorinen
- Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, 60 Musk Ave., Kelvin Grove, Queensland, 4059, Australia
| | - Km Taufiqul Arif
- Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, 60 Musk Ave., Kelvin Grove, Queensland, 4059, Australia
| | - Lyn R Griffiths
- Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, 60 Musk Ave., Kelvin Grove, Queensland, 4059, Australia
| | - Rachel K Okolicsanyi
- Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, 60 Musk Ave., Kelvin Grove, Queensland, 4059, Australia
| | - Larisa M Haupt
- Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, 60 Musk Ave., Kelvin Grove, Queensland, 4059, Australia; ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Australia.
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18
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Antibody-drug conjugates in lung cancer: dawn of a new era? NPJ Precis Oncol 2023; 7:5. [PMID: 36631624 PMCID: PMC9834242 DOI: 10.1038/s41698-022-00338-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 12/08/2022] [Indexed: 01/13/2023] Open
Abstract
Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work; we summarize the ADCs' recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.
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19
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Slezak AJ, Mansurov A, Raczy MM, Chang K, Alpar AT, Lauterbach AL, Wallace RP, Weathered RK, Medellin JE, Battistella C, Gray LT, Marchell TM, Gomes S, Swartz MA, Hubbell JA. Tumor Cell-Surface Binding of Immune Stimulating Polymeric Glyco-Adjuvant via Cysteine-Reactive Pyridyl Disulfide Promotes Antitumor Immunity. ACS CENTRAL SCIENCE 2022; 8:1435-1446. [PMID: 36313164 PMCID: PMC9615125 DOI: 10.1021/acscentsci.2c00704] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Indexed: 06/10/2023]
Abstract
Immune stimulating agents like Toll-like receptor 7 (TLR7) agonists induce potent antitumor immunity but are limited in their therapeutic window due to off-target immune activation. Here, we developed a polymeric delivery platform that binds excess unpaired cysteines on tumor cell surfaces and debris to adjuvant tumor neoantigens as an in situ vaccine. The metabolic and enzymatic dysregulation in the tumor microenvironment produces these exofacial free thiols, which can undergo efficient disulfide exchange with thiol-reactive pyridyl disulfide moieties upon intratumoral injection. These functional monomers are incorporated into a copolymer with pendant mannose groups and TLR7 agonists to target both antigen and adjuvant to antigen presenting cells. When tethered in the tumor, the polymeric glyco-adjuvant induces a robust antitumor response and prolongs survival of tumor-bearing mice, including in checkpoint-resistant B16F10 melanoma. The construct additionally reduces systemic toxicity associated with clinically relevant small molecule TLR7 agonists.
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Affiliation(s)
- Anna J. Slezak
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Aslan Mansurov
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Michal M. Raczy
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Kevin Chang
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Aaron T. Alpar
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Abigail L. Lauterbach
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Rachel P. Wallace
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Rachel K. Weathered
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Jorge E.G. Medellin
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Claudia Battistella
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Laura T. Gray
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Tiffany M. Marchell
- Committee
on Immunology, University of Chicago, Chicago, Illinois 60637, United States
| | - Suzana Gomes
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
| | - Melody A. Swartz
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
- Committee
on Immunology, University of Chicago, Chicago, Illinois 60637, United States
- Ben
May Department for Cancer Research, University
of Chicago, Chicago, Illinois 60637, United
States
- Committee
on Cancer Biology, University of Chicago, Chicago, Illinois 60637, United States
| | - Jeffrey A. Hubbell
- Pritzker
School of Molecular Engineering, University
of Chicago, Chicago, Illinois 60637, United States
- Committee
on Immunology, University of Chicago, Chicago, Illinois 60637, United States
- Committee
on Cancer Biology, University of Chicago, Chicago, Illinois 60637, United States
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20
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Wang M, Wang X, Li Y, Li Q, Cai S, Li X, Ma M. HER2 status is positively associated with vessel invasion of colorectal cancer: a retrospective large cohort study. Int J Colorectal Dis 2022; 37:2061-2067. [PMID: 36006442 PMCID: PMC9436852 DOI: 10.1007/s00384-022-04243-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/15/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE HER2-positive colorectal cancer was drawn increasing attention in recent years. Accumulating evidence showed HER2-positive metastatic colorectal cancer could benefit from HER2-targeted therapy. While HER2 expression and the relationship between HER2 status and clinicopathological characteristics of overall colorectal cancer remains largely unknown. The aim of this study was to evaluate HER2 expression in colorectal cancer and compare the clinicopathological features between HER2-positive and HER2-negative colorectal cancer. METHODS We retrospectively analyzed 3910 primary colorectal cancer patients treated in our institution from January 2016 to December 2019. Medical records and pathology reports after surgery were collected to provide information about HER2 status and other clinicopathological characteristics. RESULTS We identified 3347 HER2-negative and 79 HER2-positive colorectal cancer patients in our cohort. The chi-square test showed that vessel invasion was significantly more common in HER2-positive colorectal cancer patients. Crude analysis showed HER2 positive was associated with vessel invasion in colorectal cancer [OR and 95% CI 0.534 (0.341, 0.835), p = 0.006]. After adjusting for N stage, a significant association was still observed between HER2 status and vessel invasion in colorectal cancer [OR and 95% CI 0.550 (0.322, 0.941), p = 0.029]. Survival analysis showed that there was no significant difference in 3-year overall survival rate between HER2 positive and HER2 negative group (p = 0.603). CONCLUSION Our findings indicate that the rate of HER2 positivity in colorectal cancer was relatively low, and HER2 status was strongly associated with vessel invasion while having no significant influence on the 3-year overall survival rate in colorectal cancer patients.
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Affiliation(s)
- Mingdian Wang
- Department of Pathology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong Province, China
| | - Xiang Wang
- Department of General Surgery, the Second People’s Hospital of Hefei, Hefei Hospital Anhui Medical University, Hefei, Anhui Province, China
| | - Yiwei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Maoguang Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
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21
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Yang C, Fan S, Wang X, Liu W, Yang L, He B, Dai W, Zhang H, Wang X, Zhang Q. Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin. Asian J Pharm Sci 2022; 17:697-712. [PMID: 36382307 PMCID: PMC9640369 DOI: 10.1016/j.ajps.2022.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/12/2022] [Accepted: 06/25/2022] [Indexed: 11/02/2022] Open
Abstract
The combination regimen of trastuzumab (Tras) plus Nab-paclitaxel (Nab) is recommended to treat HER2-positive (HER2+) cancers. However, they exert effects in different mechanisms: Tras need to stay on cell membranes, while Nab need to be endocytosed, therefore the concurrent combination regimen may not be the best one in HER2+ tumors treatment. Caveolin-1 (Cav-1) is a key player in mediating their endocytosis and is associated with their efficacy, but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy. Herein, we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+ Cav-1High tumor treatment. In the regimen, lovastatin (Lova) was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression, increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+ Cav-1High cells but not in HER2+ Cav-1Low cells. Therefore, by exchanging the dosing sequence of Nab and Tras, and by adding Lova at appropriate time points, the precise three-drug-sequential regimen (PTDS, Nab(D1)-Lova(D2)-Lova & Tras(D2+12 h)) was established. Compared with the concurrent regimen, the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+ Cav-1High tumors, which might be a promising combination regimen for these patients in clinics.
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Affiliation(s)
- Canyu Yang
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing 100191, China
| | - Shumin Fan
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Xing Wang
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing 100191, China
| | - Wei Liu
- Department of Pharmacy, Peking University Third Hospital, Beijing, 100083, China
| | - Long Yang
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Bing He
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
| | - Wenbing Dai
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Hua Zhang
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Xueqing Wang
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing 100191, China
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Qiang Zhang
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing 100191, China
- Beijing Key Laboratory of Molecular Pharmaceutics, New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
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22
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Roviello G, Catalano M, Iannone LF, Marano L, Brugia M, Rossi G, Aprile G, Antonuzzo L. Current status and future perspectives in HER2 positive advanced gastric cancer. Clin Transl Oncol 2022; 24:981-996. [PMID: 35091998 DOI: 10.1007/s12094-021-02760-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 02/06/2023]
Abstract
Gastric cancer is one of the most common malignancy worldwide with a prognosis less than 1 year in unresectable or metastatic disease. HER2 expression is the main biomarker to lead the addition of trastuzumab to first line systemic chemotherapy improving the overall survival in advanced HER2-positivegastric adenocarcinoma. The inevitable development of resistance to trastuzumab remains a great problem inasmuch several treatment strategies that have proven effective in breast cancer failed to show clinical benefit in advanced gastric cancer. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance toHER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Further, we describe the prognostic value of new non-invasive screening techniques, the current development of novel agents such us HER2 antibody-drug conjugates and bispecific antibodies, and the strategies with antitumor activity on going.
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Affiliation(s)
- G Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
| | - M Catalano
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
| | - L F Iannone
- Department of Health Science, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - L Marano
- Department of Medical, Surgical and NeuroSciences, Section of Surgery, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
| | - M Brugia
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - G Rossi
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - G Aprile
- Department of Oncology, San Bortolo General Hospital, AULSS8 Berica, Vicenza, Italy
| | - L Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, 50134, Florence, Italy
- Medical Oncology Unit, Careggi University Hospital, 50134, Florence, Italy
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23
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Ahcene Djaballah S, Daniel F, Milani A, Ricagno G, Lonardi S. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am Soc Clin Oncol Educ Book 2022; 42:1-14. [PMID: 35580290 DOI: 10.1200/edbk_351354] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2) is a well-known oncogenic driver in different tumors and an approved therapeutic target in breast and gastroesophageal cancer. In metastatic colorectal cancer, only 3% to 5% of patients present with HER2 alterations: somatic mutations and amplifications. HER2 was first assessed as a biomarker of resistance to anti-EGFR therapy; however, in more recent years, its role as a potential actionable target has emerged. In this article, we discuss the predictive and prognostic value of HER2 in metastatic colorectal cancer, its emerging role as an actionable therapeutic target, and its possible future developments.
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Affiliation(s)
| | - Francesca Daniel
- Medical Oncology Unit 1, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Anna Milani
- Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy.,Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
| | - Gianmarco Ricagno
- Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy.,Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
| | - Sara Lonardi
- Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy
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24
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Park JH, Yeo JH, Kim YS, Park I, Ahn HK, Cho EK, Shin DB, Yang JY, Kim HS, Lee WK, Sym SJ. Efficacy and Safety of Trastuzumab Biosimilar (CT-P6) Compared With Reference Trastuzumab in Patients With HER2-positive Advanced Gastric Cancer: A Retrospective Analysis. Am J Clin Oncol 2022; 45:61-65. [PMID: 34991106 PMCID: PMC8781232 DOI: 10.1097/coc.0000000000000887] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Treatment with trastuzumab and chemotherapy significantly improves the outcome in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). CT-P6 (trastuzumab-pkrb; Herzuma) is a trastuzumab biosimilar approved for the treatment of HER2-positive gastric cancer. In this study, we aimed to compare the efficacy and safety of CT-P6 and reference trastuzumab as first-line treatment for HER2-positive AGC. MATERIALS AND METHODS The medical records of 102 patients with HER2-positive AGC treated with first-line trastuzumab-based chemotherapy were retrospectively reviewed. These patients were treated with either reference trastuzumab (n=72) or a biosimilar (n=30). Treatment outcomes, such as objective response rate, progression-free survival (PFS), and overall survival (OS), were compared between the reference and biosimilar groups. RESULTS The objective response rate of both groups (52.8% and 56.8% in the reference and biosimilar groups, respectively) were comparable (P=0.72). No statistically significant difference was observed with the reference versus biosimilar trastuzumab for PFS (median PFS, 6.9 vs. 5.4 mo; P=0.98) or OS (median OS, 12.3 mo vs. not reached; P=0.42). Safety profiles were similar between the 2 groups. CONCLUSIONS Biosimilar trastuzumab showed equivalent outcome to reference trastuzumab, with similar adverse events. Biosimilar trastuzumab can suitably and safely replace trastuzumab as a reference for the treatment of HER2-positive AGC.
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Affiliation(s)
- Joo-Hwan Park
- Division of Medical Oncology, Departments of Internal Medicine
| | - Ja Hyun Yeo
- Division of Medical Oncology, Departments of Internal Medicine
| | - Young Saing Kim
- Division of Medical Oncology, Departments of Internal Medicine
| | - Inkeun Park
- Division of Medical Oncology, Departments of Internal Medicine
| | - Hee Kyung Ahn
- Division of Medical Oncology, Departments of Internal Medicine
| | - Eun Kyung Cho
- Division of Medical Oncology, Departments of Internal Medicine
| | - Dong Bok Shin
- Division of Medical Oncology, Departments of Internal Medicine
| | | | - Hyung-Sik Kim
- Radiology, Gachon University Gil Medical Center, Incheon, Republic of Korea
| | | | - Sun Jin Sym
- Division of Medical Oncology, Departments of Internal Medicine
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25
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Siavoshinia L, Kheirollah A, Zeinali M, Barzegari E, Jamalan M. Combinatorial in silico and in vivo evaluation of immune response elicitation by the affibody Z HER2. Int Immunopharmacol 2021; 101:108368. [PMID: 34857479 DOI: 10.1016/j.intimp.2021.108368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/08/2021] [Accepted: 11/09/2021] [Indexed: 10/19/2022]
Abstract
Due to the high affinity for binding to target molecules and also other unique attributes, affibodies have a great potential to be used in immunotherapeutic and diagnostic approaches. However, the possibility of undesirable immune response is still a great concern. In the current study, we investigated the possible antigenicity, allergenicity and cytotoxicity of the HER2-targeting affibody ZHER2. The binding affinity of potential epitopes of the affibody to murine major histocompatibility complex (MHC) molecules was investigated by immunoinformatics tools and docking approaches. The possible interaction of ZHER2 with human leukocyte antigens HLA-DP, HLA-DM, HLA-DQ and HLA-DR was also studied by protein-protein docking. Additionally, the synthesized affibody gene was expressed and the protein was purified for boosted immunization of Balb/c mice. Induced secretion of IFN-γ, IL-2, IL-4 and IL-10, and total serum IgG were assessed in the immunized mice. Furthermore, MTT cell viability test was performed to evaluate the cytotoxicity of ZHER2 in splenocytes of the treated mice. In silico analyses showed the possible induction of the immune response by ZHER2. While the affibody could elicit the secretion of cellular immune cytokines, it could not induce a significant humoral response in the treated mice and did not show any cytotoxic effects on the exposed splenocytes. These findings explain the practicability of ZHER2 for therapeutic and in vivo diagnostic usages, though its ubiquitous application may need more studies.
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Affiliation(s)
- Leila Siavoshinia
- Department of Biochemistry, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Science, Medical School, Ahvaz, Iran
| | - Alireza Kheirollah
- Department of Biochemistry, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Science, Medical School, Ahvaz, Iran
| | - Majid Zeinali
- Biotechnology Research Center, Research Institute of Petroleum Industry (RIPI), Tehran, Iran
| | - Ebrahim Barzegari
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mostafa Jamalan
- Department of Biochemistry, Abadan University of Medical Sciences, Abadan, Iran.
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26
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Zhou J, Jin AQ, Zhou SC, Li JW, Zhi WX, Huang YX, Zhu Q, Qian L, Wu J, Chang C. Application of preoperative ultrasound features combined with clinical factors in predicting HER2-positive subtype (non-luminal) breast cancer. BMC Med Imaging 2021; 21:184. [PMID: 34856951 PMCID: PMC8641182 DOI: 10.1186/s12880-021-00714-0] [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: 10/21/2021] [Accepted: 11/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Human epidermal growth factor receptor2+ subtype breast cancer has a high degree of malignancy and a poor prognosis. The aim of this study is to develop a prediction model for the human epidermal growth factor receptor2+ subtype (non-luminal) of breast cancer based on the clinical and ultrasound features related with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor2. METHODS We collected clinical data and reviewed preoperative ultrasound images of enrolled breast cancers from September 2017 to August 2020. We divided the data into in three groups as follows. Group I: estrogen receptor ± , Group II: progesterone receptor ± and Group III: human epidermal growth factor receptor2 ± . Univariate and multivariate logistic regression analyses were used to analyze the clinical and ultrasound features related with biomarkers among these groups. A model to predict human epidermal growth factor receptor2+ subtype was then developed based on the results of multivariate regression analyses, and the efficacy was evaluated using the area under receiver operating characteristic curve, accuracy, sensitivity, specificity. RESULTS The human epidermal growth factor receptor2+ subtype accounted for 138 cases (11.8%) in the training set and 51 cases (10.1%) in the test set. In the multivariate regression analysis, age ≤ 50 years was an independent predictor of progesterone receptor + (p = 0.007), and posterior enhancement was a negative predictor of progesterone receptor + (p = 0.013) in Group II; palpable axillary lymph node, round, irregular shape and calcifications were independent predictors of the positivity for human epidermal growth factor receptor-2 in Group III (p = 0.001, p = 0.007, p = 0.010, p < 0.001, respectively). In Group I, shape was the only factor related to estrogen receptor status in the univariate analysis (p < 0.05). The area under receiver operating characteristic curve, accuracy, sensitivity, specificity of the model to predict human epidermal growth factor receptor2+ subtype breast cancer was 0.697, 60.14%, 72.46%, 58.49% and 0.725, 72.06%, 64.71%, 72.89% in the training and test sets, respectively. CONCLUSIONS Our study established a model to predict the human epidermal growth factor receptor2-positive subtype with moderate performance. And the results demonstrated that clinical and ultrasound features were significantly associated with biomarkers.
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Affiliation(s)
- Jin Zhou
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - An-Qi Jin
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shi-Chong Zhou
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Jia-Wei Li
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Xiang Zhi
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yun-Xia Huang
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qian Zhu
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lang Qian
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiong Wu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Cai Chang
- Department of Ultrasound, First Floor, Building 3, Fudan University Shanghai Cancer Center, No. 270 Dong'an Road, Xuhui District, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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27
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Pouya FD, Rasmi Y, Camci IY, Tutar Y, Nemati M. Performance of capecitabine in novel combination therapies in colorectal cancer. J Chemother 2021; 33:375-389. [PMID: 34019782 DOI: 10.1080/1120009x.2021.1920247] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 02/26/2021] [Accepted: 04/18/2021] [Indexed: 12/15/2022]
Abstract
Colorectal cancer is one of the most common cancers throughout the world, and no definitive cure has ever been found. Perhaps a new insight into the effectiveness of chemotherapy drugs could help better treat patients. Targeted therapies have significantly improved the median overall survival of colorectal cancer patients. One of the standard chemotherapy regimens used for colorectal cancer is capecitabine, which is important in monotherapy and combination therapies. Capecitabine, with other chemotherapeutic agents (irinotecan, oxaliplatin, perifosine, 17-allylamino-17-demethoxygeldanamycin, aspirin, celecoxib, statins, quinacrine, inositol hexaphosphate and inositol, cystine/theanine, curcumin, and isorhamnetin), and biological ones (antibodies) plays an important role in the inhibition of some signaling pathways, increasing survival, reducing tumor growth and side effects of capecitabine. However, some drugs, such as proton pump inhibitors, are negatively related to capecitabine; therefore, the purpose of this work is to review and discuss the performance of capecitabine combination therapies in colorectal cancer.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Irem Yalim Camci
- Department of Molecular Biology and Genetics, Faculty of Science, Gebze Technical University, Kocaeli, Turkey
| | - Yusuf Tutar
- Division of Biochemistry, Department of Basic Pharmaceutical Sciences, Hamidiye Faculty of Pharmacy, University of Health Sciences, Turkey Istanbul
| | - Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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28
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Abstract
This review article summarizes the clinical applications of established and emerging PET tracers in the evaluation of the 5 most common gynecologic malignancies: endometrial, ovarian, cervical, vaginal, and vulvar cancers. Emphasis is given to 2-deoxy-2-[18F]fluoro-d-glucose as the most widely used and studied tracer, with additional clinical tracers also explored. The common imaging protocols are discussed, including standard dose ranges and uptake times, established roles, as well as the challenges and future directions of these imaging techniques. The key points are emphasized with images from selected cases.
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Affiliation(s)
- Saul N Friedman
- Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA
| | - Malak Itani
- Section of Abdominal Imaging, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA
| | - Farrokh Dehdashti
- Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, 510 South Kingshighway Boulevard, St Louis, MO 63110, USA.
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29
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Roviello G, Aprile G, D'Angelo A, Iannone LF, Roviello F, Polom K, Mini E, Catalano M. Human epidermal growth factor receptor 2 (HER2) in advanced gastric cancer: where do we stand? Gastric Cancer 2021; 24:765-779. [PMID: 33742317 DOI: 10.1007/s10120-021-01182-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
Gastric cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and in generally less than a year. HER2 expression remains an important biomarker to lead the addition of trastuzumab to first-line systemic chemotherapy in unresectable or metastatic gastroesophageal adenocarcinoma. To date, a major issue is represented by resistance to trastuzumab developed during treatment, considering the not improved outcomes in this molecular subtype of gastroesophageal adenocarcinoma to other HER2 target strategies. In this review, we summarize the available data on the mechanisms underlying primary and secondary resistance to HER2-targeted therapy and current challenges in the treatment of HER2-positive advanced gastric cancer refractory to trastuzumab. Furthermore, we describe the prognostic value of new non-invasive screening methods, under development novel agents (e.g., HER2 antibody-drug conjugates and bispecific antibodies) and strategies with antitumor activity in early studies.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - Alberto D'Angelo
- Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK
| | | | - Franco Roviello
- Department of Medical, Surgical and Neuro Sciences, Section of Surgery, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
| | - Karol Polom
- Department of Medical, Surgical and Neuro Sciences, Section of Surgery, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Department of Surgical Oncology, Gdansk Medical University, Gdansk, Poland
| | - Enrico Mini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - Martina Catalano
- School of Human Health Sciences, University of Florence, Largo Brambilla 3, 50134, Florence, Italy
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30
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Guarini C, Grassi T, Pezzicoli G, Porta C. Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer. Int J Mol Sci 2021; 22:6813. [PMID: 34202896 PMCID: PMC8268006 DOI: 10.3390/ijms22136813] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2's role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.
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Affiliation(s)
- Chiara Guarini
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Teresa Grassi
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Gaetano Pezzicoli
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Camillo Porta
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
- Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, 70124 Bari, Italy
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31
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Espinosa ML, Abad C, Kurtzman Y, Abdulla FR. Dermatologic Toxicities of Targeted Therapy and Immunotherapy in Head and Neck Cancers. Front Oncol 2021; 11:605941. [PMID: 34123780 PMCID: PMC8190330 DOI: 10.3389/fonc.2021.605941] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 05/05/2021] [Indexed: 11/23/2022] Open
Abstract
Treatment of head and neck cancers requires multidisciplinary collaboration to reduce morbidity and mortality associated with the tumor burden, as well as to preserve function of organs and structures. With the use of various new targeted therapies come new adverse events including dermatologic toxicities, which may consist of xerosis, nail and hair changes, morbilliform or papulopustular rashes, to more severe eruptions such as Stevens–Johnson syndrome. We describe the dermatologic toxicities and corresponding grades of severity and associated pathophysiology resulting from seven therapeutics used to treat head and neck cancers: cetuximab, trastuzumab, pembrolizumab, nivolumab, lentatinib, larotrectinib, and entrectinib. Being familiar with these dermatologic toxicities allows clinicians to provide comprehensive counseling for patients, encourage preventative measures, and to know when it is appropriate to hold therapy or permanently stop treatment.
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Affiliation(s)
- Maria L Espinosa
- Department of Dermatology, University of Chicago Pritzker School of Medicine, Chicago, IL, United States
| | - Chelsea Abad
- Department of Dermatology, City of Hope Los Angeles, Duarte, CA, United States
| | - Yaira Kurtzman
- Department of Dermatology, City of Hope Los Angeles, Duarte, CA, United States
| | - Farah R Abdulla
- Department of Dermatology, City of Hope Los Angeles, Duarte, CA, United States
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Jafari E, Safinejad S, Dabiri S, Naghibzadeh-Tahami A. Study of the Relationship between MMP-2 and MMP-9 and Her2/neu Overexpression in Gastric Cancer: Clinico- Pathological Correlations. Asian Pac J Cancer Prev 2021; 22:811-817. [PMID: 33773545 PMCID: PMC8286688 DOI: 10.31557/apjcp.2021.22.3.811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Indexed: 12/09/2022] Open
Abstract
Background: The relationship between the expressions of matrix metalloproteinases with clinico-pathological data on gastric cancer has been investigated in many countries, but this relationship remains unexplored in Iranian patients. Also, the correlation of the MMPs and the HER-2/neu proto-oncogene with other clinic-pathological variables has been evaluated for several other malignancies, but little effort has been made to shed light on the relationship with gastric cancer. Methods: We investigated MMP-2 and MMP-9 expression and HERE-2/neu overexpression in 48 gastric cancer patients referred to Afzalipour Hospital, associated with Kerman Medical University. Immunohistochemistry staining with rabbit polyclonal antibodies was used. Data statistical analysis was done by SPSS software (Version 20.0). Results: The mean age was 59, most of the patients were male (79.2%), and the average tumor size was larger than 5 centimeters in its greatest diameter. The majority of tumors were of the intestinal subtype and were located in the pyloric and antrum regions (43.8%). Invasion to muscularis properia was seen in 87.5% of the tumors (T3). MMP-2 and MMP-9 were highly expressed in 58.3% and 50% of cases, respectively, and Her-2/neu positivity was 10.4%. MMP-2, MMP-9 and HER-2 were found to have no relation with any clinicopathological parameters. Conclusion: According to the results of this study, MMP-2 and MMP-9 were highly expressed in gastric cancer, but there was no significant association with other clinicopathological variables.
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Affiliation(s)
- Elham Jafari
- Pathology and Stem Cells Research Center, Department of Pathology, Kerman University of Medical Science, Kerman, Iran
| | - Somaye Safinejad
- Pathology and Stem Cells Research Center, Department of Pathology, Kerman University of Medical Science, Kerman, Iran
| | - Shahriar Dabiri
- Pathology and Stem Cells Research Center, Department of Pathology, Kerman University of Medical Science, Kerman, Iran
| | - Ahmad Naghibzadeh-Tahami
- Health Services Management Research Center, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran
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Ha GY, Yang SH, Kang HJ, Lee HL, Kim J, Kim YJ, Yu HJ, Lee JI, Jin SH. Comparison of survival outcomes according of patients with metastatic gastric cancer receiving trastuzumab with systemic chemotherapy. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2020; 16:63-70. [PMID: 36945715 PMCID: PMC9942733 DOI: 10.14216/kjco.20011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 11/07/2022]
Abstract
Purpose Currently, trastuzumab plus chemotherapy is the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric cancer (mGC) or esophagogastric junction cancer. However, it is not clear whether the prognosis of HER2-positive mGC treated with trastuzumab plus chemotherapy is better than that of HER2-negative mGC treated with chemotherapy as the first-line therapy. Methods We performed a retrospective study comparing the prognosis of mGC according to first-line treatment with trastuzumab plus chemotherapy or chemotherapy only, at the Korea Cancer Center Hospital from 2011 to 2018. The Kaplan-Meier method and Cox proportional hazards model were used for univariate and multivariate survival analyses. Results The median overall survival of trastuzumab group was 26.1 months and that of chemotherapy group was 14.8 months (P=0.047). Trastuzumab group had a longer median progression-free survival than chemotherapy group (23.4 vs. 9.2 months, P=0.026). By univariate analysis, sex, age, World Health Organization (WHO) histology, HER2 status, primary tumor site, extent of disease, number of lesions, number of metastatic, measurability of disease, prior gastrectomy, and chemotherapy group are statistically significant. Using multivariate analysis, number of lesions, number of metastatic, prior gastrectomy, and trastuzumab group (hazard ratio, 0.594; 95% confidence interval, 0.384-0.921; P=0.020) were found to be independent prognostic factors of overall survival. Conclusion The result suggests prognosis of HER2-positive mGC treated by trastuzumab plus chemotherapy could be better than that of HER2-negative mGC treated by chemotherapy only. Well-designed prospective cohort studies are needed to confirm the results of this study. HER2 testing should be performed routinely in all patients newly diagnosed with mGC.
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Affiliation(s)
- Gi-Young Ha
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sung-Hyun Yang
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hye-Jin Kang
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hyo-Lak Lee
- Hemato-Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Jin Kim
- Gastroenterology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Yun-Ju Kim
- Gastroenterology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Hang-Jong Yu
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Jong-Inn Lee
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Sung-Ho Jin
- Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
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34
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Luca SD, Verdoliva V, Saviano M. Peptide Ligands Specifically Targeting HER2 Receptor and the Role Played by a Synthetic Model System of the Receptor Extracellular Domain: Hypothesized Future Perspectives. J Med Chem 2020; 63:15333-15343. [PMID: 33226807 DOI: 10.1021/acs.jmedchem.0c01340] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A short (Fab)trastuzumab-derived peptide specific for HER2 receptor was identified. Its affinity for the model system HER2-DIVMP was found in a nanomolar range. The structural determinants responsible for the interaction between this ligand (A9) and HER2-DIVMP were investigated by both computational and NMR analysis. Next, the possibility of using A9 as HER2- specific probe for the nuclear medicine imaging was evaluated by conjugating A9 with the DTPA chelator and radiolabeling it with 111In. The developed probe retained a nanomolar affinity to HER2-overexpressing cancer cells, however, some unspecific binding also occurred. The peptide internalization into cells by receptor-mediated endocytosis was also studied. Future perspectives are aimed at using A9 as a probe for molecular imaging diagnostics as well as active targeting of anticancer drugs. Lead structure optimization is needed to minimize the percentage of A9 unspecific binding and to increase the binding affinity to the receptor.
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Affiliation(s)
- Stefania De Luca
- Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy
| | - Valentina Verdoliva
- Institute of Biostructures and Bioimaging, National Research Council, 80134 Naples, Italy
| | - Michele Saviano
- Institute of Crystallography, National Research Council, 70126 Bari, Italy
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35
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Dhakras P, Uboha N, Horner V, Reinig E, Matkowskyj KA. Gastrointestinal cancers: current biomarkers in esophageal and gastric adenocarcinoma. Transl Gastroenterol Hepatol 2020; 5:55. [PMID: 33073050 DOI: 10.21037/tgh.2020.01.08] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 01/15/2020] [Indexed: 12/29/2022] Open
Abstract
Esophageal and gastric adenocarcinomas are frequently diagnosed at an advanced stage and have a dismal prognosis. Even in patients with potentially curative cancer, nearly 50% will develop recurrent disease despite aggressive treatments. A number of biomarkers currently guide treatment decisions for patients with esophageal and gastric adenocarcinoma and include human epidermal growth factor receptor 2 (HER2) amplification, mismatch repair deficiency/microsatellite instability (dMMR/MSI-H) and program death-ligand 1 (PD-L1) expression. This review will focus on the function, testing and FDA-approved targeted therapies for HER2, dMMR/MSI-H and PD-L1. In addition, a number of novel targets in esophageal and gastric cancer are being studied in clinical trials. Neurotrophic-tropomyosin receptor kinase (NTRK), claudin-18 (CLDN18)/Rho GTPase activating protein 26 (ARHGAP26) gene fusion, fibroblast growth factor receptor (FGFR), lymphocyte-activation gene 3 (LAG3) and T cell immunoglobulin and mucin-domain containing-3 (TIM3) will be briefly reviewed. Despite several biomarkers used in the selection of treatment therapies, treatment outcomes remain poor. Future research efforts will focus on the identification of new biomarkers, moving existing biomarkers into earlier lines of therapy, and evaluating new combinations of existing biomarkers and therapies.
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Affiliation(s)
- Purabi Dhakras
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
| | - Nataliya Uboha
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin, Madison, WI, USA.,UW Carbone Cancer Center, Madison, WI, USA.,William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Vanessa Horner
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA.,Wisconsin State Lab of Hygiene, Madison, WI, USA
| | - Erica Reinig
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
| | - Kristina A Matkowskyj
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA.,UW Carbone Cancer Center, Madison, WI, USA.,William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
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36
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Kuroda M, Halfmann P, Kawaoka Y. HER2-mediated enhancement of Ebola virus entry. PLoS Pathog 2020; 16:e1008900. [PMID: 33052961 PMCID: PMC7556532 DOI: 10.1371/journal.ppat.1008900] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 08/17/2020] [Indexed: 11/29/2022] Open
Abstract
Multiple cell surface molecules including TAM receptors (TYRO3, AXL, and MERTK), a family of tyrosine kinase receptors, can serve as attachment receptors for Ebola virus (EBOV) entry into cells. The interaction of these receptors with EBOV particles is believed to trigger the initial internalization events that lead to macropinocytosis. However, the details of how these interactions lead to EBOV internalization have yet to be elucidated. Here, we screened receptor tyrosine kinase (RTK) inhibitors for anti-EBOV activity by using our previously established biologically contained Ebola virus that lacks the VP30 gene (EBOVΔVP30) and identified several RTKs, including human epidermal growth factor receptor 2 (HER2), as potential targets of anti-EBOV inhibitors and as novel host factors that have a role in EBOV infection. Of these identified RTKs, it was only HER2 whose knockdown by siRNAs impaired EBOVΔVP30-induced AKT1 phosphorylation, an event that is required for AKT1 activation and subsequent macropinocytosis. Stable expression of HER2 resulted in constitutive activation of AKT1, resulting in the enhancement of EBOVΔVP30 growth, EBOV GP-mediated entry, and macropinocytosis. Moreover, we found that HER2 interacts with the TAM receptors, and in particular forms a complex with TYRO3 and EBOVΔVP30 particles on the cell surface. Interestingly, HER2 was required for EBOVΔVP30-induced TYRO3 and AKT1 activation, but the other TAM receptors (TYRO3 and MERTK) were not essential for EBOVΔVP30-induced HER2 and AKT1 activation. Our findings demonstrate that HER2 plays an important role in EBOV entry and provide novel insights for the development of therapeutics against the virus.
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Affiliation(s)
- Makoto Kuroda
- Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Peter Halfmann
- Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
| | - Yoshihiro Kawaoka
- Department of Pathobiological Sciences, School of Veterinary Medicine, Influenza Research Institute, University of Wisconsin–Madison, Madison, Wisconsin, United States of America
- Department of Microbiology and Immunology, Division of Virology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Abd El-kader AM, Mahmoud BK, Hajjar D, Mohamed MFA, Hayallah AM, Abdelmohsen UR. Antiproliferative activity of new pentacyclic triterpene and a saponin from Gladiolus segetum Ker-Gawl corms supported by molecular docking study. RSC Adv 2020; 10:22730-22741. [PMID: 35514559 PMCID: PMC9054649 DOI: 10.1039/d0ra02775h] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/25/2020] [Indexed: 11/23/2022] Open
Abstract
A new triterpenoidal saponin identified as 3-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 4)-β-d-xylopyranosyl]-2β,3β,16α-trihydroxyolean-12-en-23,28-dioic acid-28-O-α-l-rhamnopyranosyl-(1 → 4)-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranosyl-(1 → 2)-α-l-arabinopyranoside 1 together with a new oleanane triterpene identified as 2β,3β,13α,22α-tetrahydroxy olean-23,28-dioic acid 2 and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms. The structural elucidation of the isolated compounds was confirmed using different chemical and spectroscopic methods, including 1D and 2D NMR experiments as well as HR-ESI-MS. Moreover, the in vitro cytotoxic activity of the fractions and that of the isolated compounds 1–8 were investigated against five human cancer cell lines (PC-3, A-549, HePG-2, MCF-7 and HCT-116) using doxorubicin as a reference drug. The results showed that the saponin fraction exhibited potent in vitro cytotoxic activity against the five human cancer cell lines, whereas the maximum activity was exhibited against the PC-3 and A-549 cell lines with the IC50 values of 1.13 and 1.98 μg mL−1, respectively. In addition, compound 1 exhibited potent activity against A-549 and PC-3 with the IC50 values of 2.41 μg mL−1 and 3.45 μg mL−1, respectively. Interestingly, compound 2 showed the maximum activity against PC-3 with an IC50 of 2.01 μg mL−1. These biological results were in harmony with that of the molecular modeling study, which showed that the cytotoxic activity of compound 2 might occur through the inhibition of the HER-2 enzyme. A new triterpenoidal saponin 1, a new oleanane triterpene 2, and 6 known compounds (3–8) have been isolated from Gladiolus segetum Ker-Gawl corms.![]()
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Affiliation(s)
| | | | - Dina Hajjar
- Department of Biochemistry
- Collage of Science
- University of Jeddah
- 80203 Jeddah
- Saudi Arabia
| | - Mamdouh F. A. Mohamed
- Department of Pharmaceutical Chemistry
- Faculty of Pharmacy
- Sohag University
- 82524 Sohag
- Egypt
| | - Alaa M. Hayallah
- Pharmaceutical Chemistry Department
- Faculty of Pharmacy
- Deraya University
- Minia
- Egypt
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Zhang Y, Wu S, Zhuang X, Weng G, Fan J, Yang X, Xu Y, Pan L, Hou T, Zhou Z, Chen S. Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab. Onco Targets Ther 2019; 12:11597-11608. [PMID: 31920346 PMCID: PMC6941612 DOI: 10.2147/ott.s232912] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/12/2019] [Indexed: 12/22/2022] Open
Abstract
Background The aberrant expression of HER2 is highly associated with tumour occurrence and metastasis, therefore HER2 is extensively targeted for tumour immunotherapy. For example, trastuzumab and pertuzumab are FDA-approved monoclonal antibodies that target HER2-positive tumour cells. Despite their advances in clinical applications, emerging resistance to these two HER2-targeting antibodies has hindered their further application. Somatic mutations in HER2 receptor have been identified as one of the major reasons for resistance to anti-HER2 antibodies. Methods We analysed the frequency of somatic mutations in various tumour types based on TCGA and COSMIC databases. Then, the effect of the most frequent mutation (S310F) on the interaction between pertuzumab and HER2 was analysed by molecular modelling analysis. The effect of the S310F mutation was further evaluated through multiple in vitro binding experiments and antitumour activity assays. Results We found through bioinformatics analysis that S310F, an activating mutation in the HER2 extracellular domain, was the most frequent mutation in HER2. The S310F mutation was shown to confer resistance of HER2-positive tumour cells to pertuzumab treatment. With molecular modelling analysis, we confirmed the possibility that the S310F mutation might disrupt the interaction between pertuzumab and HER2 as a result of a significant change in the critical residue S310. Further functional analyses revealed that the S310F mutation completely abolished pertuzumab binding to HER2 receptor and inhibited pertuzumab antitumour efficacy. Conclusion We demonstrated the loss-of-function mechanism underlying pertuzumab resistance in HER2-positive tumour cells bearing the S310F mutation.
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Affiliation(s)
- Ying Zhang
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Shanshan Wu
- Precision Medicine Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, People's Republic of China
| | - Xinlei Zhuang
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Gaoqi Weng
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Jiansheng Fan
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Xiaoyue Yang
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Yingchun Xu
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Liqiang Pan
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Tingjun Hou
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.,State Key Laboratory of Computer Aided Design and Computer Graphics (CAD&CG), Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Zhan Zhou
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
| | - Shuqing Chen
- Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China
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De Luca S, Verdoliva V, Saviano M, Fattorusso R, Diana D. SPR and NMR characterization of the molecular interaction between A9 peptide and a model system of HER2 receptor: A fragment approach for selecting peptide structures specific for their target. J Pept Sci 2019; 26:e3231. [PMID: 31749266 DOI: 10.1002/psc.3231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/30/2019] [Accepted: 10/22/2019] [Indexed: 01/01/2023]
Abstract
The binding process of A9 peptide toward HER2-DIVMP, a synthetic model of the receptor domain IV, was studied by using the surface plasmon resonance (SPR) technique, with the aim of validating it as a fast and reliable screening method for selecting peptide ligands specifically targeting a domain of their target. To investigate the structural basis of A9 binding to the model of HER2-DIVMP, multiple ligand-based nuclear magnetic resonance (NMR) methods were applied. The use of saturation transfer difference (STD) and WaterLOGSY NMR experiments identified key residues in the peptide for the receptor binding. Moreover, the bound conformation of the A9 peptide was obtained using transferred nuclear Overhauser effect spectroscopy (trNOESY) experiments. The NMR data revealed an extended binding surface that confirms an in silico model previously reported. These structural findings could provide good starting points for future lead structures optimization specific for the receptor target.
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Affiliation(s)
- Stefania De Luca
- Institute of Biostructures and Bioimaging, National Research Council, 80134, Naples, Italy
| | - Valentina Verdoliva
- Institute of Biostructures and Bioimaging, National Research Council, 80134, Naples, Italy
| | - Michele Saviano
- Institute of Crystallography, National Research Council, 70126, Bari, Italy
| | - Roberto Fattorusso
- Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania Luigi Vanvitelli, 81100, Caserta, Italy
| | - Donatella Diana
- Institute of Biostructures and Bioimaging, National Research Council, 80134, Naples, Italy
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40
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Namjoshi P, Showalter L, Czerniecki BJ, Koski GK. T-helper 1-type cytokines induce apoptosis and loss of HER-family oncodriver expression in murine and human breast cancer cells. Oncotarget 2019; 10:6006-6020. [PMID: 31666931 PMCID: PMC6800266 DOI: 10.18632/oncotarget.10298] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/12/2016] [Indexed: 12/31/2022] Open
Abstract
A recent neoadjuvant vaccine trial for early breast cancer induced strong Th1 immunity against the HER-2 oncodriver, complete pathologic responses in 18% of subjects, and for many individuals, dramatically reduced HER-2 expression on residual disease. To explain these observations, we investigated actions of Th1 cytokines (TNF-α and IFN-γ) on murine and human breast cancer cell lines that varied in the surface expression of HER-family receptor tyrosine kinases. Breast cancer lines were broadly sensitive to the combination of IFN-γ and TNF-α, as evidenced by lower metabolic activity, lower proliferation, and enhanced apoptosis, and in some cases a reversible inhibition of surface expression of HER proteins. Apoptosis was accompanied by caspase-3 activation. Furthermore, the pharmacologic caspase-3 activator PAC-1 mimicked both the killing effects and HER-2-suppressive activities of Th1 cytokines, while a caspase 3/7 inhibitor could prevent cytokine-induced HER-2 loss. These studies demonstrate that many in vivo effects of vaccination (apparent tumor cell death and loss of HER-2 expression) could be replicated in vitro using only the principle Th1 cytokines. These results are consistent with the notion that IFN-γ and TNF-α work in concert to mediate many biological effects of therapeutic vaccination through the induction of a caspase 3-associated cellular death mechanism.
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Affiliation(s)
- Prachi Namjoshi
- Department of Biological Sciences, Kent State University, Kent, Ohio, USA
| | - Lori Showalter
- Department of Biological Sciences, Kent State University, Kent, Ohio, USA
| | - Brian J Czerniecki
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Gary K Koski
- Department of Biological Sciences, Kent State University, Kent, Ohio, USA
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42
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Fernandes SRG, Fernandes R, Sarmento B, Pereira PMR, Tomé JPC. Photoimmunoconjugates: novel synthetic strategies to target and treat cancer by photodynamic therapy. Org Biomol Chem 2019; 17:2579-2593. [PMID: 30648722 DOI: 10.1039/c8ob02902d] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Photodynamic therapy (PDT) combines a photosensitizer (PS) with the physical energy of non-ionizing light to trigger cell death pathways. PDT has potential as a therapeutic modality to be used in alternative or in combination with other conventional cancer treatment protocols (e.g. surgery, chemotherapy and radiotherapy). Still, due to the lack of specificity of the current PSs to target the tumor cells, several studies have exploited their conjugation with targeting moieties. PSs conjugated with antibodies (Abs) or their fragments, able to bind antigens overexpressed in the tumors, have demonstrated potential in PDT of tumors. This review provides an overview of the most recent advances on photoimmunoconjugates (PICs) for cancer PDT, which involve the first and second-generation PSs conjugated to Abs. This is an update of our previous review "Antibodies armed with photosensitizers: from chemical synthesis to photobiological applications", published in 2015 in Org. Biomol. Chem.
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Affiliation(s)
- Sara R G Fernandes
- CQE, Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
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Doxorubicin loaded carboxymethyl Assam bora rice starch coated superparamagnetic iron oxide nanoparticles as potential antitumor cargo. Heliyon 2019; 5:e01955. [PMID: 31294107 PMCID: PMC6595192 DOI: 10.1016/j.heliyon.2019.e01955] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 04/30/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
In recent years, polysaccharide-decorated superparamagnetic iron oxide nanoparticles (SPIONs) have gained attention in the field of “nanotheranostics” with integrated diagnostic and therapeutic functions. Carboxymethyl Assam bora rice starch-stabilized SPIONs (CM-ABRS SPIONs), synthesized by co-precipitation method, has already shown exciting potential towards magnetic drug targeting potential. After establishing it as a promisable targeting carrier, the present study is focused on the next step i.e. to evaluate its In vitro anti-tumor potential by loading anticancer drug “Doxorubicin hydrochloride (DOX)” onto CM-ABRS SPIONs. DOX-loaded CM-ABRS SPIONs were physico-chemically characterized by DLS, zeta-potential, TEM, FT-IR, XRD, and VSM analysis. Spectroflourimetric analysis confirmed the maximum loading of DOX up to 6% (w/w) onto CM-ABRS SPIONs via electrostatic interactions. Further, molecular level drug performance was investigated by docking study against receptors (HER-2 and Folate receptor-α) over expressed in cancer cells and MTT assay (in MCF-7 and HeLa cell line), which conferred promisable results of DOX-CM-ABRS SPIONs as compared to standard DOX solution.
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Jeon HJ, Choi BBR, Park KH, Hwang DS, Kim UK, Kim GC. Induction of Melanoma Cell-Selective Apoptosis Using Anti-HER2 Antibody-Conjugated Gold Nanoparticles. Yonsei Med J 2019; 60:509-516. [PMID: 31124333 PMCID: PMC6536400 DOI: 10.3349/ymj.2019.60.6.509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/07/2019] [Accepted: 04/05/2019] [Indexed: 02/02/2023] Open
Abstract
PURPOSE This study was conducted to verify the induction and mechanism of selective apoptosis in G361 melanoma cells using anti-HER2 antibody-conjugated gold nanoparticles (GNP-HER2). MATERIALS AND METHODS Following GNP-HER2 treatment of G361 cells, cell cycle arrest and apoptosis were measured by WST-1 assay, Hemacolor staining, Hoechst staining, immunofluorescence staining, fluorescence-activated cell sorting analysis, and Western blotting. RESULTS G361 cells treated with GNP-HER2 showed condensation of nuclei, which is an apoptotic phenomenon, and translocation of apoptosis-inducing factor and cytochrome c from mitochondria into the nucleus and cytoplasm, respectively. Increases in BAX in cells undergoing apoptosis, activation of caspase-3 and -9, and fragmentation of poly (ADP-ribose) polymerase and DNA fragmentation factor 45 (inhibitor of caspase-activated DNase) were observed upon GNP-HER2 treatment. Following GNP-HER2 treatment, an increase of cells in sub-G1 phase, which is a signal of cell apoptosis, was observed. This resulted in the down-regulation of cyclin A, cyclin D1, cyclin E, cdk2, cdk4, and cdc2 and the up-regulation of p21. Thus, GNP-HER2 treatment was confirmed to induce the cessation of cell cycle progression. Also, decreases in phospho-focal adhesion kinase and phospho-human epidermal growth factor receptor, which activate cellular focal adhesion, and decreases in phospho-paxillin, which stimulates the disassembly of filamentous actin, were observed. Reduced cell adhesion and disassembly of the intracellular structure indicated cell deactivation. CONCLUSION GNP-HER2 can selectively kill G361 melanoma cells without affecting normal cells. The mechanism of G361 cell death upon treatment with GNP-HER2 was apoptosis accompanied by activation of caspases.
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Affiliation(s)
- Hyeon Jun Jeon
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Byul Bo Ra Choi
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Yangsan, Korea
- Feagle Co., Ltd., Yangsan, Korea
| | - Kwang Ha Park
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Dae Seok Hwang
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Uk Kyu Kim
- Department of Oral & Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea.
| | - Gyoo Cheon Kim
- Department of Oral Anatomy, School of Dentistry, Pusan National University, Yangsan, Korea.
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Su X, Xue Y, Wei J, Huo X, Gong Y, Zhang H, Han R, Chen Y, Chen H, Chen J. Establishment and Characterization of gc-006-03, a Novel Human Signet Ring Cell Gastric Cancer Cell Line Derived from Metastatic Ascites. J Cancer 2018; 9:3236-3246. [PMID: 30271482 PMCID: PMC6160672 DOI: 10.7150/jca.26051] [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: 03/14/2018] [Accepted: 07/17/2018] [Indexed: 12/15/2022] Open
Abstract
Signet ring cell gastric cancer (SRCGC) is a special type of gastric cancer with rapid progression and poor prognosis. However, few available SRCGC cell lines from Chinese patients can be used for research, the molecular mechanism of its growth and metastasis is still incompletely understood. In this study, we established and characterized a novel SRCGC cell line, gc-006-03.The cells showed a tendency to pile up without contact inhibition. G-band karyotypes of gc-006-03 were revealed hypotriploid with a modal chromosome number of 51. Immunohistochemistry analysis showed that the cells were positive for CEA, CK7, CDX2 and Ki-67(45%), and negative for CK20, TTF1and Li-cadherin. Flow cytometry analysis showed that gc-006-3 had 25% of CD44+ cells. The cells possessed strong clonality and high plating efficiency, and the doubling time was 36h. The cells grew vigorously for more than 100 passages in serial culture. Meanwhile, the cells showed a high rate of tumor formation. Tumors were observed in all of the nude mice (5/5) given injections of the cells. The metastatic capability of the cell line was found in zebrafish injected the cells. The results of whole genome sequencing revealed the unique genomic characteristics of gc-006-03. In summary, this new stable cell line may be useful in basic and clinical research on gastric signet ring cell carcinoma.
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Affiliation(s)
- Xinyu Su
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.,Department of Radiation Oncology, the Affiliated Huai'an Hospital of Xuzhou Medical College, Huai'an, China
| | - Yiqi Xue
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jingsun Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xinying Huo
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yang Gong
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Honghong Zhang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rongbo Han
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yuetong Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hong Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jinfei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Soltantoyeh T, Bahadori T, Hosseini-Ghatar R, Khoshnoodi J, Roohi A, Mobini M, Golsaz-Shirazi F, Jeddi-Tehrani M, Amiri MM, Shokri F. Differential Effects of Inhibitory and Stimulatory Anti-HER2 Monoclonal Antibodies on AKT/ERK Signaling Pathways. Asian Pac J Cancer Prev 2018; 19:2255-2262. [PMID: 30139234 PMCID: PMC6171393 DOI: 10.22034/apjcp.2018.19.8.2255] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Objective: Homo- and heterodimerization of the receptor tyrosine kinase HER2 hyperactivate several downstream signaling pathways, leading to uncontrolled growth and proliferation of tumor cells. Anti-HER2 monoclonal antibodies (mAbs) may induce different effects on HER2 dimerization and signaling. Methods: The effect of two inhibitory (2A8, 1T0) and one stimulatory (1H9) anti-HER2 mAbs either alone or in combination with trastuzumab was investigated on AKT and ERK signaling pathways and HER2 degradation in a human breast cancer cell line (BT-474) by Western blotting. Result: While 1H9 mAb had no significant effect on AKT and ERK signaling pathways, 1T0 and 2A8 mAbs inhibited phosphorylation of both pathways. Combination of 1T0 mAb with trastuzumab resulted in significant synergistic inhibition of both pathways and HER2 degradation, much more potently than the combination of trastuzumab and pertuzumab. Conclusion: Our data indicate that anti-HER2 mAbs may induce different signaling pathways depending on their effect on tumor cell growth and proliferation. The significant inhibition of ERK and AKT phosphorylation by 1T0 alone or particularly in combination with trastuzumab suggests its potential therapeutic application for targeted immunotherapy of HER2 overexpressing malignancies.
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Affiliation(s)
- Tahereh Soltantoyeh
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. and
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Feizy A, Karami A, Eghdamzamiri R, Moghimi M, Taheri H, Mousavinasab N. HER2 Expression Status and Prognostic, Diagnostic, and Demographic Properties of Patients with Gastric Cancer: a Single Center Cohort Study from Iran. Asian Pac J Cancer Prev 2018; 19:1721-1725. [PMID: 29938472 PMCID: PMC6103572 DOI: 10.22034/apjcp.2018.19.6.1721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Background: The fourth most prevalent cancer worldwide and a major cause of death in developing countries is
gastric cancer (GC). Human epidermal growth factor receptor 2 (HER2), is a proto-oncogene expressed in different
solid tumors. This study aimed to evaluate possible associations of HER2 expression status with survival rate, age,
sex, tumor grade, histopathological type, and primary tumor location in patients with GC. Methods: Subjects were
enrolled in this cohort study after consideration of inclusion and exclusion criteria. Biopsy specimens were stained using
immunohistochemistry. Samples with a score of 3+ were considered to exhibit HER2 overexpression. The mentioned
variables were extracted from patients’ files as well as by clinical evaluation. The Kaplan-Meier method was applied
for analyzing the survival rate and Chi square for possible factor associations. Results: A total of 210 patients (25.2%
female and 74.8% male) were enrolled. In a 5-year follow-up (adherence rate: 45.7%), the average survival was 9.4±10.9
months. HER2 overexpression was evident in 24%. There was no statistically significant association found between
HER2 expression and primary tumor location (p-value=0.63), histopathological type (p-value=0.72), or tumor grade
(p-value=0.051). Furthermore, no statistically significant links were apparent with tumor grade in either male or female
groups as well as patients aged ≥60 and ˂60 years (all p-values >0.05). Moreover, no statistically significant association
was detected between HER2 expression status (p-value=0.88), sex (p-value=0.31), and age (p-value=0.055) with patient
survival. Conclusions: No statistically meaningful association was found between all parameters examined and HER2
expression status. Divergence of the results from earlier studies might be due to genetic variation. Thus, performing a
meta-analysis on certain races might be helpful for clarification.
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Affiliation(s)
- Abdolamir Feizy
- Department of Pathology, Valiasr Hospital, Zanjan University of Medical Science, Zanjan, Iran.
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Torigoe H, Shien K, Takeda T, Yoshioka T, Namba K, Sato H, Suzawa K, Yamamoto H, Soh J, Sakaguchi M, Tomida S, Tsukuda K, Miyoshi S, Toyooka S. Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations. Cancer Sci 2018. [PMID: 29532558 PMCID: PMC5980184 DOI: 10.1111/cas.13571] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.
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Affiliation(s)
- Hidejiro Torigoe
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiko Shien
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Tatsuaki Takeda
- Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takahiro Yoshioka
- Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kei Namba
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroki Sato
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ken Suzawa
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiromasa Yamamoto
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Junichi Soh
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masakiyo Sakaguchi
- Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shuta Tomida
- Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazunori Tsukuda
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichiro Miyoshi
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinichi Toyooka
- Departments of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Jindal V, Arora E, Gupta S, Lal A, Masab M, Potdar R. Prospects of chimeric antigen receptor T cell therapy in ovarian cancer. Med Oncol 2018; 35:70. [PMID: 29651744 DOI: 10.1007/s12032-018-1131-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/08/2018] [Indexed: 01/12/2023]
Abstract
Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Immunotherapy provides a promising and novel treatment option for ovarian cancer. Recently, chimeric antigen receptor (CAR) T cell therapy has shown promising results in hematological tumors and current research is going on in various solid tumors like ovarian cancer. CAR T cells are genetically engineered T cells with major histocompatibility complex-independent, tumor-specific, immune-mediated cytolytic actions against cancer cells. Initial studies of CAR T cell therapy have shown promising results in ovarian cancer, but there are some obstacles like impaired T cell trafficking, lack of antigenic targets, cytokine release syndrome and most important immunosuppressive tumor microenvironment. Optimization of design, improving tumor microenvironment and combinations with other therapies may help us in improving CAR T cell efficacy. In this review article, we highlight the current knowledge regarding CAR T cell therapy in ovarian cancer. We have discussed basic functioning of CAR T cells, their rationale and clinical outcome in ovarian cancer with limitations.
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Affiliation(s)
- Vishal Jindal
- Department of Internal Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, 01608, USA.
| | - Ena Arora
- Department of Internal Medicine, Government Medical College and Hospital, Chandigarh, India
| | - Sorab Gupta
- Department of Hematology and Oncology, Einstein Healthcare Network, Philadelphia, USA
| | - Amos Lal
- Department of Internal Medicine, Saint Vincent Hospital, 123 Summer Street, Worcester, 01608, USA
| | - Muhammad Masab
- Department of Internal Medicine, Einstein Healthcare Network, Philadelphia, USA
| | - Rashmika Potdar
- Department of Hematology and Oncology, Einstein Healthcare Network, Philadelphia, USA
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Keller S, Zwingenberger G, Ebert K, Hasenauer J, Wasmuth J, Maier D, Haffner I, Schierle K, Weirich G, Luber B. Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines. Mol Oncol 2018; 12:441-462. [PMID: 29325228 PMCID: PMC5891041 DOI: 10.1002/1878-0261.12170] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 12/21/2017] [Accepted: 01/02/2018] [Indexed: 12/19/2022] Open
Abstract
The molecular mechanism of action of the HER2‐targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream‐acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI‐N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET‐amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
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Affiliation(s)
- Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Karolin Ebert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Jan Hasenauer
- Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Computational Biology, Neuherberg, Germany.,Department of Mathematical Modeling of Biological Systems, Center for Mathematics, Technische Universität München, Garching, Germany
| | - Jacqueline Wasmuth
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | | | | | - Katrin Schierle
- Institute of Pathology, Universitätsklinikum Leipzig, Germany
| | - Gregor Weirich
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
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