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Zhao Y, Cai Y, Pan Z, Tang F, Ma C, Wang Z, Li G, Chang H, Tian S, Li Z. Novel CHI3L1-Associated Angiogenic Phenotypes Define Glioma Microenvironments: Insights From Multi-Omics Integration. Cancer Sci 2025; 116:1433-1448. [PMID: 39989140 PMCID: PMC12044658 DOI: 10.1111/cas.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 02/05/2025] [Accepted: 02/14/2025] [Indexed: 02/25/2025] Open
Abstract
The CHI3L1 signaling pathway significantly influences glioma angiogenesis, but its role in the tumor microenvironment (TME) remains elusive. We propose a novel CHI3L1-associated vascular phenotype classification for glioma through integrative analyses of multiple datasets with bulk and single-cell transcriptome, genomics, digital pathology, and clinical data. We investigated the biological characteristics, genomic alterations, therapeutic vulnerabilities, and immune profiles within these phenotypes through a comprehensive multi-omics approach. We constructed the vascular-related risk (VR) score based on CHI3L1-associated vascular signatures (CAVS) identified by machine learning algorithms. Utilizing unsupervised consensus clustering, gliomas were stratified into three distinct vascular phenotypes: Cluster A, marked by high vascularization and stromal activation with a relatively low levels of tumor-infiltrating lymphocytes (TILs); Cluster B, characterized by moderate vascularization and stromal activity, coupled with a high density of TILs; and Cluster C, defined by low vascularization and sparse immune cell infiltration. We observed that the CAVS effectively indicated glioma-associated angiogenesis and immune suppression by single-cell RNA-seq analysis. Moreover, the high-VR-score group exhibited enhanced angiogenic activity, reduced immune response, resistance to immunotherapy, and poorer clinical outcomes. The VR score independently predicted glioma prognosis and, combined with a nomogram, provided a robust clinical decision-making tool. Potential drug prediction based on transcription factors for high-risk patients was also performed. Our study reveals that CHI3L1-associated vascular phenotypes shape distinct immune landscapes in gliomas, offering insights for optimizing therapeutic strategies to improve patient outcomes.
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Affiliation(s)
- Yu‐Hang Zhao
- Brain Glioma Center & Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Yu‐Xiang Cai
- Department of PathologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Zhi‐Yong Pan
- Brain Glioma Center & Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Feng Tang
- Brain Glioma Center & Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Chao Ma
- Brain Glioma Center & Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Ze‐Fen Wang
- Department of PhysiologyWuhan University School of Basic Medical SciencesWuhanChina
| | - Gang Li
- Department of Biological RepositoriesZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Hang Chang
- Berkeley Biomedical Data Science CenterLawrence Berkeley National LaboratoryBerkeleyCaliforniaUSA
| | - Su‐Fang Tian
- Department of PathologyZhongnan Hospital of Wuhan UniversityWuhanChina
| | - Zhi‐Qiang Li
- Brain Glioma Center & Department of NeurosurgeryZhongnan Hospital of Wuhan UniversityWuhanChina
- Hubei International Science and Technology Cooperation Base for Research and Clinical Techniques for Brain Glioma Diagnosis and TreatmentHubeiChina
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Ibrahim MAA, Mohamed DEM, Abdeljawaad KAA, Abdelrahman AHM, Sayed SRM, El-Tayeb MA, Sidhom PA, Paré PW. Structural and Energetic Insights into the Binding of L- and D-Arginine Analogs with Neuropilin-1 (NRP1): Molecular Docking, Molecular Dynamics and DFT Calculations. Cell Biochem Biophys 2025:10.1007/s12013-025-01754-x. [PMID: 40253666 DOI: 10.1007/s12013-025-01754-x] [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] [Accepted: 04/04/2025] [Indexed: 04/22/2025]
Abstract
Neuropilin-1 (NRP1) is a transmembrane glycoprotein that binds numerous ligands, including vascular endothelial growth factor A (VEGFA) that stimulates blood vessel formation. Preclinical trials propose that NRP1 inhibition blocks neoplasm cell proliferation and slows tumor growth by suppressing angiogenesis. As such, VEGFA/NRP1 signaling is a potential target for carcinoma inhibition. Since arginine (Arg) regulates nutrient-responsive rapamycin signaling, which in turn regulates cell growth and metabolism, Arg, as well as simple structural variations of L- and D-Arg, were selected to study in-silico structural and energetic influences of such ligands on NRP1 signaling. Initially, AutoDock Vina1.1.2 software performance was assessed to predict binding modes of Arg analogs with NRP1 based on the available experimental data. Molecular docking and molecular dynamics (MD) simulations over 100 ns were run to inspect the potency of Arg analogs to bind with NRP1. Analog-NRP1 complex binding affinities (ΔGbinding) were evaluated using the MM/GBSA approach. Results indicated that L-/D-Agd- and L-/D-Agn-NRP1 complexes exhibited binding affinities greater than the co-crystallized L-homoarginine ligand (calc.-31.2 kcal.mol-1) with ΔGbinding values of -40.5/-40.6 and -40.0/-36.2 kcal.mol-1, respectively. Structural and energetic analyses were performed to examine further L-/D-Agd and L-/D-Agn. Quantum mechanical calculations were performed to confirm the outcomes obtained from docking computations and MD simulations.
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Affiliation(s)
- Mahmoud A A Ibrahim
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt.
- Department of Engineering, College of Engineering and Technology, University of Technology and Applied Sciences, Nizwa, Sultanate of Oman.
- School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, South Africa.
| | - Dina E M Mohamed
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
| | - Khlood A A Abdeljawaad
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
| | - Alaa H M Abdelrahman
- Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt
| | - Shaban R M Sayed
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh, Saudi Arabia
| | - Mohamed A El-Tayeb
- Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh, Saudi Arabia
| | - Peter A Sidhom
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Paul W Paré
- Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, TX, USA.
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Nahm WJ, Falanga V. The Adverse Impact of Tyrosine Kinase Inhibitors on Wound Healing and Repair. Int Wound J 2025; 22:e70513. [PMID: 40251464 PMCID: PMC12008022 DOI: 10.1111/iwj.70513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/20/2025] [Accepted: 04/02/2025] [Indexed: 04/20/2025] Open
Abstract
Tyrosine kinase inhibitors (TKIs) can treat various cancers, primarily through their antiangiogenic effects. However, as angiogenesis is crucial for successful wound healing, TKIs may adversely impact wound repair. This review analysed all 63 FDA-approved TKIs and identified evidence for wound healing and repair implications in 24 agents. The primary mechanism contributing to impaired wound healing appears to be the inhibition of vascular endothelial growth factor receptors, with secondary targets, such as epidermal growth factor receptors and platelet-derived growth factor receptors, potentially playing a role. Information from safety package inserts, preclinical studies, case reports and clinical trials suggests that these TKIs can cause delayed or impaired wound healing. The safety information generally recommends discontinuing treatment for at least one to 2 weeks before elective surgery and resuming treatment only after adequate wound healing has occurred. Neoadjuvant therapy with TKIs may be feasible if sufficient time is allowed between the cessation of the TKI and the onset of surgery. As the use of TKIs continues to increase, healthcare professionals should be aware of their potential impact on wound healing and take appropriate precautions to minimise the risk of wound-related complications.
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Affiliation(s)
- William J. Nahm
- New York University Grossman School of MedicineNew YorkNew YorkUSA
| | - Vincent Falanga
- Department of DermatologyBoston University Chobanian and Avedisian School of MedicineBostonMassachusettsUSA
- Department of Biochemistry & Cell BiologyBoston University Chobanian and Avedisian School of MedicineBostonMassachusettsUSA
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Zeng M, Lin A, Jiang A, Qiu Z, Zhang H, Chen S, Xu M, Liu Z, Cheng Q, Zhang J, Luo P. Decoding the mechanisms behind second primary cancers. J Transl Med 2025; 23:115. [PMID: 39856672 PMCID: PMC11762917 DOI: 10.1186/s12967-025-06151-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 01/19/2025] [Indexed: 01/27/2025] Open
Abstract
Second Primary Cancers (SPCs) are defined as cancers that develop either simultaneously or metachronously in the same individual who has been diagnosed with and survived one primary cancer. SPCs exhibit a high incidence rate and represent the primary cause of mortality among survivors of first primary cancers. There is growing concern about the dangers of SPCs. This review summarizes recent studies on the mechanisms of SPCs, including the roles of genomic changes after first primary cancer (FPC) treatments, stromal cell phenotypic and metabolic changes, hormone levels and receptor expression, immunosuppression, aberrant gene methylation, EGFR signaling, and cell-free DNA in SPC development. This comprehensive analysis contributes to elucidating current research trends in SPC mechanisms and enhances our understanding of the underlying pathophysiology. Furthermore, potential applications of intratumoral microbes, single-cell multi-omics, and metabolomics in investigating SPC mechanisms are also discussed, providing new ideas for follow-up studies.
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Affiliation(s)
- Meiyuan Zeng
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Zhengang Qiu
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Hongman Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China
| | - Shifu Chen
- HaploX Biotechnology, Shenzhen, China
- Faculty of Data Science, City University of Macau, Macau, China
| | | | - Zaoqu Liu
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China.
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China.
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, 510282, Guangdong, China.
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Tanaka I, Hori K, Koyama J, Gen S, Morise M, Kodama Y, Matsui A, Miyazawa A, Hase T, Hibino Y, Yokoyama T, Kimura T, Yoshida N, Sato M, Ishii M. Femoral bone metastasis is a poor prognostic factor in EGFR-TKIs-treated patients with EGFR-mutated non-small-cell lung cancer: a retrospective, multicenter cohort study. Ther Adv Med Oncol 2024; 16:17588359241303090. [PMID: 39712073 PMCID: PMC11662391 DOI: 10.1177/17588359241303090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 11/11/2024] [Indexed: 12/24/2024] Open
Abstract
Background Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers (NSCLCs) have higher frequencies of bone metastases than those of wild type; however, the metastatic pattern and influence on clinical outcome remain unclear. Objectives To analyze the association between bone metastatic sites and the clinical efficacy of the first-, second-, and third-generation EGFR-tyrosine kinase inhibitors (TKI), in these patients. Design Retrospective multicenter cohort study. Methods The clinical data of patients with advanced-NSCLC harboring EGFR mutation, who were treated by EGFR-TKIs as first-line treatment at five medical institutions (N = 411), were retrospectively assessed for bone metastatic sites, overall survival (OS), and progression-free survival (PFS). Results Bone metastases were found in 41.1% of the patients at diagnosis, including 13.1%, 8.0%, and 20.0 for single, double, and multiple lesions (⩾3), respectively. The vertebra (76.3%) and pelvis (60.9%) were the most frequent metastatic sites. Femoral-, sternum-, and scapula-metastases were remarkably increased in the patients with multiple-bone metastases. In the EGFR-mutant NSCLC patient treated with osimertinib, both the OS and the PFS of the patients with femoral bone metastasis were significantly shorter than those of the patients without femoral bone metastasis (OS: not reached vs 12.1 months, p < 0.0001; and PFS: 17.2 vs 9.3 months, p < 0.0018). Furthermore, a multivariable Cox regression analysis, including several poor prognostic factors, such as L858R mutation and liver metastasis, demonstrated that femoral bone metastasis was a statistically independent predictor of OS. Conclusion Femoral bone metastasis is associated with poor survival of EGFR-mutant NSCLC patients who were treated with EGFR-TKIs, including osimertinib, and is an independent prognostic factor of OS.
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Affiliation(s)
- Ichidai Tanaka
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Kazumi Hori
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Junji Koyama
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Soei Gen
- Department of Respiratory Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | - Masahiro Morise
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuta Kodama
- Department of Respiratory Medicine, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Akira Matsui
- Department of Respiratory Medicine, Kariya Toyota General Hospital, Kariya, Japan
| | - Ayako Miyazawa
- Department of Respiratory Medicine, Konan Kosei Hospital, Konan, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshitaka Hibino
- Department of Respiratory Medicine, Konan Kosei Hospital, Konan, Japan
| | - Toshihiko Yokoyama
- Department of Respiratory Medicine, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Tomoki Kimura
- Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan
| | - Norio Yoshida
- Department of Respiratory Medicine, Kariya Toyota General Hospital, Kariya, Japan
| | - Mitsuo Sato
- Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Makoto Ishii
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Liu M, Wang Y, Wang C, Li P, Qiu J, Yang N, Sun M, Han L. A Microfluidic 3D-Tumor-Spheroid Model for the Evaluation of Targeted Therapies from Angiogenesis-Related Cytokines at the Single Spheroid Level. Adv Healthc Mater 2024; 13:e2402321. [PMID: 39126126 DOI: 10.1002/adhm.202402321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Indexed: 08/12/2024]
Abstract
Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level.
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Affiliation(s)
- Mengqi Liu
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Yihe Wang
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Chao Wang
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Ping Li
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Jiaoyan Qiu
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Ningkai Yang
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Mingyuan Sun
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Lin Han
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
- Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, 250100, P. R. China
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7
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Wang Y, Liu C, Fang C, Peng Q, Qin W, Yan X, Zhang K. Engineered Cancer Nanovaccines: A New Frontier in Cancer Therapy. NANO-MICRO LETTERS 2024; 17:30. [PMID: 39347944 PMCID: PMC11442722 DOI: 10.1007/s40820-024-01533-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/08/2024] [Indexed: 10/01/2024]
Abstract
Vaccinations are essential for preventing and treating disease, especially cancer nanovaccines, which have gained considerable interest recently for their strong anti-tumor immune capabilities. Vaccines can prompt the immune system to generate antibodies and activate various immune cells, leading to a response against tumor tissues and reducing the negative effects and recurrence risks of traditional chemotherapy and surgery. To enhance the flexibility and targeting of vaccines, nanovaccines utilize nanotechnology to encapsulate or carry antigens at the nanoscale level, enabling more controlled and precise drug delivery to enhance immune responses. Cancer nanovaccines function by encapsulating tumor-specific antigens or tumor-associated antigens within nanomaterials. The small size of these nanomaterials allows for precise targeting of T cells, dendritic cells, or cancer cells, thereby eliciting a more potent anti-tumor response. In this paper, we focus on the classification of carriers for cancer nanovaccines, the roles of different target cells, and clinically tested cancer nanovaccines, discussing strategies for effectively inducing cytotoxic T lymphocytes responses and optimizing antigen presentation, while also looking ahead to the translational challenges of moving from animal experiments to clinical trials.
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Affiliation(s)
- Yijie Wang
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, People's Republic of China
| | - Congrui Liu
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, People's Republic of China
| | - Chao Fang
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, People's Republic of China
| | - Qiuxia Peng
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, People's Republic of China
- Department of Stomatology and Central Laboratory, School of Medicine, Shanghai Tenth People's Hospital, Tongji University, NO. 301 Yan-Chang-Zhong Road, Shanghai, 200072, People's Republic of China
| | - Wen Qin
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, People's Republic of China
| | - Xuebing Yan
- Jiangsu Provincial Innovation and Practice Base for Postdoctors, Suining People's Hospital, Affiliated Hospital of Xuzhou Medical University, No.2, Bayi West Road, Suining, Xu Zhou, 221000, Jiangsu Province, People's Republic of China.
| | - Kun Zhang
- Central Laboratory and Department of Medical Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, People's Republic of China.
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Xie P, Yin Q, Wang S, Song D. Prognostic Protein Biomarker Screening for Thyroid Carcinoma Based on Cancer Proteomics Profiles. Biomedicines 2024; 12:2066. [PMID: 39335579 PMCID: PMC11428938 DOI: 10.3390/biomedicines12092066] [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: 07/25/2024] [Revised: 08/28/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Thyroid carcinoma (THCA) ranks among the most prevalent cancers globally. Integrating advanced genomic and proteomic analyses to construct a protein-based prognostic model promises to identify effective biomarkers and explore new therapeutic avenues. In this study, proteomic data from The Cancer Proteomics Atlas (TCPA) and clinical data from The Cancer Genome Atlas (TCGA) were utilized. Using Kaplan-Meier, Cox regression, and LASSO penalized Cox analyses, we developed a prognostic risk model comprising 13 proteins (S100A4, PAI1, IGFBP2, RICTOR, B7-H3, COLLAGENVI, PAR, SNAIL, FAK, Connexin-43, Rheb, EVI1, and P90RSK_pT359S363). The protein prognostic model was validated as an independent predictor of survival time in THCA patients, based on risk curves, survival analysis, receiver operating characteristic curves and independent prognostic analysis. Additionally, we explored the immune cell infiltration and tumor mutational burden (TMB) related to these features. Notably, our study proved a novel approach for predicting treatment responses in THCA patients, including those undergoing chemotherapy and targeted therapy.
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Affiliation(s)
- Pu Xie
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qinglei Yin
- Guangdong Geriatric Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China;
| | - Shu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Dalong Song
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China
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Abstract
Over the past decade, circular RNA (circRNA) research has evolved into a bona fide research field shedding light on the functional consequence of this unique family of RNA molecules in cancer. Although the method of formation and the abundance of circRNAs can differ from their cognate linear mRNA, the spectrum of interacting partners and their resultant cellular functions in oncogenesis are analogous. However, with 10 times more diversity in circRNA variants compared with linear RNA variants, combined with their hyperstability in the cell, circRNAs are equipped to influence every stage of oncogenesis. This is an opportune time to address the breadth of circRNA in cancer focused on their spatiotemporal expression, mutations in biogenesis factors and contemporary functions through each stage of cancer. In this Review, we highlight examples of functional circRNAs in specific cancers, which satisfy critical criteria, including their physical co-association with the target and circRNA abundance at stoichiometrically valid quantities. These considerations are essential to develop strategies for the therapeutic exploitation of circRNAs as biomarkers and targeted anticancer agents.
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Affiliation(s)
- Vanessa M Conn
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Arul M Chinnaiyan
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Urology, University of Michigan, Ann Arbor, MI, USA
| | - Simon J Conn
- Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, South Australia, Australia.
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10
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Zhang Z, Chen W, Sun M, Aalders T, Verhaegh GW, Kouwer PHJ. TempEasy 3D Hydrogel Coculture System Provides Mechanistic Insights into Prostate Cancer Bone Metastasis. ACS APPLIED MATERIALS & INTERFACES 2024; 16:25773-25787. [PMID: 38739686 PMCID: PMC11129143 DOI: 10.1021/acsami.4c03453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/16/2024]
Abstract
Patients diagnosed with advanced prostate cancer (PCa) often experience incurable bone metastases; however, a lack of relevant experimental models has hampered the study of disease mechanisms and the development of therapeutic strategies. In this study, we employed the recently established Temperature-based Easy-separable (TempEasy) 3D cell coculture system to investigate PCa bone metastasis. Through coculturing PCa and bone cells for 7 days, our results showed a reduction in PCa cell proliferation, an increase in neovascularization, and an enhanced metastasis potential when cocultured with bone cells. Additionally, we observed increased cell proliferation, higher stemness, and decreased bone matrix protein expression in bone cells when cocultured with PCa cells. Furthermore, we demonstrated that the stiffness of the extracellular matrix had a negligible impact on molecular responses in both primary (PCa cells) and distant malignant (bone cells) sites. The TempEasy 3D hydrogel coculture system is an easy-to-use and versatile coculture system that provides valuable insights into the mechanisms of cell-cell communication and interaction in cancer metastasis.
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Affiliation(s)
- Zhaobao Zhang
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
| | - Wen Chen
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
| | - Mingchen Sun
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
| | - Tilly Aalders
- Department
of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Geert Grooteplein Zuid 28, Nijmegen 6525 GA, The Netherlands
| | - Gerald W. Verhaegh
- Department
of Urology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, Geert Grooteplein Zuid 28, Nijmegen 6525 GA, The Netherlands
| | - Paul H. J. Kouwer
- Institute
for Molecules and Materials, Radboud University, Heyendaalseweg 135, Nijmegen 6525 AJ, The Netherlands
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Hu X, Yuan X, Zhang G, Song H, Ji P, Guo Y, Liu Z, Tian Y, Shen R, Wang D. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis. Life Sci 2024; 344:122452. [PMID: 38462226 DOI: 10.1016/j.lfs.2024.122452] [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] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 03/12/2024]
Abstract
The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
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Affiliation(s)
- Xiaohui Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Guokun Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Haoyun Song
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Zihua Liu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu Province 73000, China
| | - Yixiao Tian
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province 730000, China.
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Manzanares-Guzmán A, Lugo-Fabres PH, Camacho-Villegas TA. vNARs as Neutralizing Intracellular Therapeutic Agents: Glioblastoma as a Target. Antibodies (Basel) 2024; 13:25. [PMID: 38534215 DOI: 10.3390/antib13010025] [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: 11/27/2023] [Revised: 03/03/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
Glioblastoma is the most prevalent and fatal form of primary brain tumors. New targeted therapeutic strategies for this type of tumor are imperative given the dire prognosis for glioblastoma patients and the poor results of current multimodal therapy. Previously reported drawbacks of antibody-based therapeutics include the inability to translocate across the blood-brain barrier and reach intracellular targets due to their molecular weight. These disadvantages translate into poor target neutralization and cancer maintenance. Unlike conventional antibodies, vNARs can permeate tissues and recognize conformational or cryptic epitopes due to their stability, CDR3 amino acid sequence, and smaller molecular weight. Thus, vNARs represent a potential antibody format to use as intrabodies or soluble immunocarriers. This review comprehensively summarizes key intracellular pathways in glioblastoma cells that induce proliferation, progression, and cancer survival to determine a new potential targeted glioblastoma therapy based on previously reported vNARs. The results seek to support the next application of vNARs as single-domain antibody drug-conjugated therapies, which could overcome the disadvantages of conventional monoclonal antibodies and provide an innovative approach for glioblastoma treatment.
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Affiliation(s)
- Alejandro Manzanares-Guzmán
- Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico
| | - Pavel H Lugo-Fabres
- Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT)-Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico
| | - Tanya A Camacho-Villegas
- Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT)-Unidad de Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ), Guadalajara 44270, Mexico
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13
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Abrahams B, Gerber A, Hiss DC. Combination Treatment with EGFR Inhibitor and Doxorubicin Synergistically Inhibits Proliferation of MCF-7 Cells and MDA-MB-231 Triple-Negative Breast Cancer Cells In Vitro. Int J Mol Sci 2024; 25:3066. [PMID: 38474312 DOI: 10.3390/ijms25053066] [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: 02/19/2024] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
The role of the epidermal growth factor receptor (EGFR) in tumor progression and survival is often underplayed. Its expression and/or dysregulation is associated with disease advancement and poor patient outcome as well as drug resistance in breast cancer. EGFR is often overexpressed in breast cancer and particularly triple-negative breast cancer (TNBC), which currently lacks molecular targets. We examined the synergistic potential of an EGFR inhibitor (EGFRi) in combination with doxorubicin (Dox) in estrogen-positive (ER+) MCF-7 and MDA-MB-231 TNBC cell lines. The exposure of MDA-MB-231 and MCF-7 to EGFRi produced an IC50s of 6.03 µM and 3.96 µM, respectively. Dox induced MDA-MB-231 (IC50 9.67 µM) and MCF-7 (IC50 1.4 µM) cytotoxicity. Combinations of EGFRi-Dox significantly reduced the IC50 in MCF-7 (0.46 µM) and MBA-MB 231 (0.01 µM). Synergistic drug interactions in both cell lines were confirmed using the Bliss independence model. Pro-apoptotic Caspase-3/7 activation occurred in MCF-7 at 0.1-10 µM of EGFRi and Dox single treatments, whilst 1 μM Dox yielded a more potent effect on MDA-MB-231. EGFRi and Dox individually and in combination downregulated the EGFR gene expression in MCF-7 and MDA-MB-231 (p < 0.001). This study demonstrates EGFRi's potential for eliciting synergistic interactions with Dox, causing enhanced growth inhibition, apoptosis induction, and downregulation of EGFR in both cell lines.
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Affiliation(s)
- Beynon Abrahams
- Department of Basic Medical Sciences, Faculty of Health Sciences, University of the Free State, Bloemfontein 9301, South Africa
| | - Anthonie Gerber
- Department of Basic Medical Sciences, Faculty of Health Sciences, University of the Free State, Bloemfontein 9301, South Africa
| | - Donavon Charles Hiss
- Department of Medical Biosciences, Faculty of Natural Sciences, University of the Western Cape, Bellville 7535, South Africa
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Liu J, Han X, Hu X, He Y, Shao Y, Yang Y, Wang K, Zhao Y. An epidermal growth factor receptor-mutated lung adenocarcinoma patient with brain lesions resisted to osimertinib monotherapy but achieved more than 4 years of survival in osimertinib plus bevacizumab metronomic treatment. Heliyon 2024; 10:e24378. [PMID: 38298673 PMCID: PMC10827756 DOI: 10.1016/j.heliyon.2024.e24378] [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: 08/07/2023] [Revised: 12/18/2023] [Accepted: 01/08/2024] [Indexed: 02/02/2024] Open
Abstract
Background Epidermal growth factor receptor (EGFR) mutations have been identified as promising therapeutic targets for non-small cell lung cancer. Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor-targeting drug, has good anti-tumor ability and excellent intracranial effects. However, management of osimertinib resistance is a clinical challenge. The clinical benefit of osimertinib combined with the antiangiogenic drug, bevacizumab, remains to be determined. Case presentation A 40-year-old female with right lung adenocarcinoma (cT2aN3M1c, IVb) was confirmed positive for EGFR exon 19 deletion mutation (c.2235_2249del, 1.3%). After receiving 5 months of osimertinib (80 mg, qd) therapy, the patient's disease progressed and she subsequently accepted treatment with osimertinib (80 mg, qd) plus bevacizumab (15 mg/kg, q21d) and achieved notable clinical remission for 23 months until renal impairment occurred, after which bevacizumab was discontinued. The patient had 6 months of remission before progression, after which bevacizumab was added again. To date, the disease has been under control. The brain lesion showed partial response again, and the side effects of bevacizumab were tolerable. The overall survival time exceeded 4 years. Conclusion This case report describes a treatment strategy for osimertinib-resistant patients with EGFR exon 19 deletion mutations. Metronomic treatment with osimertinib plus bevacizumab was achieved for more than 4 years.
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Affiliation(s)
- Jie Liu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xiao Han
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Xiufeng Hu
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Yuange He
- Geneplus-Beijing, Beijing ,102206, China
| | - Yijia Shao
- Geneplus-Beijing, Beijing ,102206, China
| | | | - Kai Wang
- Geneplus-Beijing, Beijing ,102206, China
| | - Yanqiu Zhao
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
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15
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Sun D, Qian H, Li J, Xing P. Targeting MDM2 in malignancies is a promising strategy for overcoming resistance to anticancer immunotherapy. J Biomed Sci 2024; 31:17. [PMID: 38281981 PMCID: PMC10823613 DOI: 10.1186/s12929-024-01004-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 01/08/2024] [Indexed: 01/30/2024] Open
Abstract
MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.
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Affiliation(s)
- Dantong Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Haili Qian
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Puyuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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16
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Al-Qadhi MA, Allam HA, Fahim SH, Yahya TAA, Ragab FAF. Design and synthesis of certain 7-Aryl-2-Methyl-3-Substituted Pyrazolo{1,5-a}Pyrimidines as multikinase inhibitors. Eur J Med Chem 2023; 262:115918. [PMID: 37922829 DOI: 10.1016/j.ejmech.2023.115918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/07/2023]
Abstract
Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC50 0.087and 0.105 μM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC50 0.82 and 4.13 μM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC50 3.36, 1.40 and 3.49 μM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes.
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Affiliation(s)
- Mustafa A Al-Qadhi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Sana'a University, P.O. Box, 18084, Sana'a, Yemen
| | - Heba Abdelrasheed Allam
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt.
| | - Samar H Fahim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt
| | - Tawfeek A A Yahya
- Department of Medicinal Chemistry, Faculty of Pharmacy, Sana'a University, P.O. Box, 18084, Sana'a, Yemen
| | - Fatma A F Ragab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box, 11562, Egypt
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17
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Huang S, Ye J, Gao X, Huang X, Huang J, Lu L, Lu C, Li Y, Luo M, Xie M, Lin Y, Liang R. Progress of research on molecular targeted therapies for colorectal cancer. Front Pharmacol 2023; 14:1160949. [PMID: 37614311 PMCID: PMC10443711 DOI: 10.3389/fphar.2023.1160949] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 07/26/2023] [Indexed: 08/25/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.
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Affiliation(s)
- Shilin Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xing Gao
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xi Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Julu Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu Lu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Cheng Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yan Lin
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Rong Liang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
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18
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Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023; 8:198. [PMID: 37169756 PMCID: PMC10175505 DOI: 10.1038/s41392-023-01460-1] [Citation(s) in RCA: 437] [Impact Index Per Article: 218.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/20/2023] [Accepted: 04/20/2023] [Indexed: 05/13/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
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Affiliation(s)
- Zhen-Ling Liu
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Huan-Huan Chen
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Li Zheng
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
| | - Lei Shi
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
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Song X, Zang Q, Li C, Zhou T, Zare RN. Immuno-Desorption Electrospray Ionization Mass Spectrometry Imaging Identifies Functional Macromolecules by Using Microdroplet-Cleavable Mass Tags. Angew Chem Int Ed Engl 2023; 62:e202216969. [PMID: 36622964 DOI: 10.1002/anie.202216969] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/02/2023] [Accepted: 01/09/2023] [Indexed: 01/11/2023]
Abstract
We present immunoassay-based desorption electrospray ionization mass spectrometry imaging (immuno-DESI-MSI) to visualize functional macromolecules such as drug targets and cascade signaling factors. A set of boronic acid mass tags (BMTs) were synthesized to label antibodies as MSI probes. The boronic ester bond is employed to cross-link the BMT with the galactosamine-modified antibody. The BMT can be released from its tethered antibody by ultrafast cleavage of the boronic ester bond caused by the acidic condition of sprayed DESI microdroplets containing water. The fluorescent moiety enables the BMT to work in both optical and MS imaging modes. The positively charged quaternary ammonium group enhances the ionization efficiency. The introduction of the boron element also makes mass tags readily identified because of its unique isotope pattern. Immuno-DESI-MSI provides an appealing strategy to spatially map macromolecules beyond what can be observed by conventional DESI-MSI, provided antibodies are available to the targeted molecules of interest.
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Affiliation(s)
- Xiaowei Song
- Department of Chemistry, Stanford University, Stanford, CA-94305, USA.,Department of Chemistry, Fudan University, Shanghai, 200016, China
| | - Qingce Zang
- Institution of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Chao Li
- Department of Medicine, Stanford University School of Medicine, Palo Alto, CA-94304, USA
| | - Tianhao Zhou
- National Clinical Research Center of Cancer, Tianjin Medical University, Tianjin, 300060, China
| | - Richard N Zare
- Department of Chemistry, Stanford University, Stanford, CA-94305, USA
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A Mechanism Exploration for the Yi-Fei-San-Jie Formula against Non-Small-Cell Lung Cancer Based on UPLC-MS/MS, Network Pharmacology, and In Silico Verification. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2023; 2023:3436814. [PMID: 36654811 PMCID: PMC9842415 DOI: 10.1155/2023/3436814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 10/07/2022] [Accepted: 10/10/2022] [Indexed: 01/11/2023]
Abstract
Non-small-cell lung cancer (NSCLC) is one of the most prevalent cancers worldwide. A Yi-Fei-San-Jie formula (YFSJF), widely used in NSCLC treatment in south China, has been validated in clinical studies. However, the pharmacological mechanism behind it remains unclear. In this study, 73 compounds were identified using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), with 58 enrolled in network pharmacology. The protein-protein interaction network, functional enrichment analysis, and compound-target-pathway network were constructed using 74 overlapping targets from 58 drugs and NSCLC. YFSJF has many targets and pathways in the fight against NSCLC. PIK3R1, PIK3CA, and AKT1 were identified as key targets, and the PI3K/AKT pathway was identified as the key pathway. According to the Human Protein Atlas (THPA) database and the Kaplan-Meier Online website, the three key targets had varying expression levels in normal and abnormal tissues and were linked to prognosis. Molecular docking and dynamics simulations verified that hub compounds have a strong affinity with three critical targets. This study revealed multiple compounds, targets, and pathways for YFSJF against NSCLC and suggested that YFSJF might inhibit PIK3R1, PIK3CA, and AKT1 to suppress the PI3K/AKT pathway and play its pharmacological role.
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21
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Development of a bridging ELISA for detection of antibodies against ZV0203 in cynomolgus monkey serum. J Pharmacol Toxicol Methods 2023; 119:107210. [PMID: 36028046 DOI: 10.1016/j.vascn.2022.107210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 01/03/2023]
Abstract
Immunogenicity has been a major concern in the safety evaluation of therapeutic proteins. The assessment of the unwanted immunogenicity of the therapeutic proteins performed in animals prior to clinical trials has been a regulatory requirement. In preclinical studies of therapeutic proteins, cynomolgus monkeys are usually the most relevant animal species. ZV0203, a recombinant humanized anti-human epidermal growth factor receptor 2 monoclonal antibody covalently bound to a cytotoxic drug (Duo-5), possesses a novel format of antibody drug conjugates. In this study, we reported the development, validation, and application of a bridging enzyme-linked immunosorbent assay for the detection of antibodies against ZV0203 in cynomolgus monkey serum. Drug interference at low positive control (18.0 ng/mL) and high positive control (130 ng/mL) of anti-ZV0203 antibodies was not observed when ZV0203 concentration is below 1.74 μg/mL and 1.49 μg/mL, respectively. In addition, no interference was found from mouse IgG1, but interference was observed with human IgG1. No effect of hemolysis was found on the analysis results of the testing samples present in 100% pooled rabbit serum containing 2% (V/V) erythrocyte hemolysates. Besides, spiked anti-ZV0203 antibody in rabbit serum was stable after 5 freeze/thaw cycles. The results showed that the method is suitable for the detection of anti-ZV0203 antibodies in cynomolgus monkey serum. The assay was also successfully applied in the repeated dose study of ZV0203.
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22
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Amelia T, Setiawan AN, Kartasasmita RE, Ohwada T, Tjahjono DH. Computational Prediction of Resistance Induced Alanine-Mutation in ATP Site of Epidermal Growth Factor Receptor. Int J Mol Sci 2022; 23:ijms232415828. [PMID: 36555475 PMCID: PMC9784575 DOI: 10.3390/ijms232415828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/03/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) resistance to tyrosine kinase inhibitors can cause low survival rates in mutation-positive non-small cell lung cancer patients. It is necessary to predict new mutations in the development of more potent EGFR inhibitors since classical and rare mutations observed were known to affect the effectiveness of the therapy. Therefore, this research aimed to perform alanine mutagenesis scanning on ATP binding site residues without COSMIC data, followed by molecular dynamic simulations to determine their molecular interactions with ATP and erlotinib compared to wild-type complexes. Based on the result, eight mutations were found to cause changes in the binding energy of the ATP analogue to become more negative. These included G779A, Q791A, L792A, R841A, N842A, V843A, I853A, and D855A, which were predicted to enhance the affinity of ATP and reduce the binding ability of inhibitors with the same interaction site. Erlotinib showed more positive energy among G779A, Q791A, I853A, and D855A, due to their weaker binding energy than ATP. These four mutations could be anticipated in the development of the next inhibitor to overcome the incidence of resistance in lung cancer patients.
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Affiliation(s)
- Tasia Amelia
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia
| | - Aderian Novito Setiawan
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia
| | | | - Tomohiko Ohwada
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
| | - Daryono Hadi Tjahjono
- School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40132, Indonesia
- Correspondence: ; Tel.: +62-22-250-4852
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Zhou S, Li C, Yuan Y, Jiang L, Chen W, Jiang X. Dendritic lipopeptide liposomes decorated with dual-targeted proteins. Biomater Sci 2022; 10:7032-7041. [PMID: 36318065 DOI: 10.1039/d2bm00952h] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Due to their homing effects, cell and cell membrane-derived nanocarriers have been widely used to enhance drug target delivery. Inspired by the protein-anchored cell membrane architecture, we here report a tumor-targeted liposome, dtDLP, which was constructed through the electrostatic interaction between dendritic lipopeptide liposomes and a dual-targeted recombinant protein, achieving superior tumor homing, cellular endocytotic and penetration abilities. The dual-targeted recombinant protein consists of an anti-epidermal growth factor receptor single domain antibody and a peptide ligand for the integrin αvβ3. dtDLPs substantially reduced macrophage phagocytosis and increased drug internalization in both 4T1 cells and HeLa cells by providing more endocytic pathways. In addition, the dtDLPs showed great penetration ability in both multicellular spheroids and tumor tissues. Due to the improved cancer cellular uptake and tumor penetration, the dtDLPs exhibited a superior anticancer effect in both HeLa and 4T1 tumor-bearing mice. This work will be helpful for the design of cell-specific liposomes with admirable tumor targeting, endocytotic and penetration abilities.
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Affiliation(s)
- Sensen Zhou
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P.R. China.
| | - Cheng Li
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P.R. China.
| | - Yang Yuan
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P.R. China.
| | - Lei Jiang
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P.R. China. .,State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
| | - Weizhi Chen
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P.R. China.
| | - Xiqun Jiang
- Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory for Nanotechnology, Nanjing University, Nanjing, 210093, P.R. China.
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AlShatnawi MN, Shawashreh RA, Sunoqrot MA, Yaghi AR. A systematic review of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure and its management. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2022. [DOI: 10.1186/s43162-022-00176-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Abstract
Background
Multiple case reports and case series have been published on heart failure due to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), yet the management and outcome of the said disease have been scarcely discussed in sufficient details. This review is aimed at characterizing the signs, symptoms, laboratory parameters, and outcomes of this entity by analyzing recent published case reports and case series reporting new-onset heart failure in non-small cell lung cancer tumor (NSCLC) patients who are being treated with EGFR TKIs.
Methods
This is a systematic review of case reports and case series for cases of EGFR TKI-induced heart failure. A systematic search was conducted across a number of databases starting with PubMed databases utilizing its MeSH database; after that, a complementary search through Google Scholar was conducted.
Results
In total, 23 cases of epidermal growth factor receptor tyrosine kinase inhibitor-induced heart failure were included. The majority of the reported case were females (20 females and three males) with a male-to-female ratio of 1:6.6. Ages ranged from 47 to 91 years of age with a mean age of 70.73 and a median of 71 years of age. Symptom improvement and being symptom-free from a heart failure perspective after treatment from the acute event were observed in 18 cases (78.26%) while heart failure progressively worsened and led to the death of the patient in only one case (4.3%).
Conclusion
The utilization of EGFR TKIs in NSCLCs has been associated with a better outcome and fewer side effects when compared to classical chemotherapeutic agents. However, cardiotoxic effects, such as heart failure, could be significant for a small proportion of patients. Recent papers have reported heart failure in younger and cardiac risk-free patients. Still, it is only advised to monitor for heart failure in the high-risk group. Treatment should be individualized and based on a case-by-case basis.
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25
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Zhang Y, Zhang M, Cheng W, Fang S. Case report: Almonertinib in combination with bevacizumab for leptomeningeal metastases from epidermal growth factor receptor-mutation non-small cell lung cancer: Case series. Front Oncol 2022; 12:1040450. [DOI: 10.3389/fonc.2022.1040450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/20/2022] [Indexed: 11/11/2022] Open
Abstract
Leptomeningeal metastasis (LM) is a lethal complication of advanced non-small cell lung cancer (NSCLC) with rapid deterioration and poor prognosis. It has no standard treatment for epidermal growth factor receptor mutation (EGFRm) NSCLC, and improving the clinical outcomes for patients with LM has become an urgent problem in clinical treatment. Both almonertinib and bevacizumab are capable of crossing the blood–brain barrier with comparable central nervous system effectiveness. To date, the almonertinib treatment in combination with bevacizumab in EGFRm NSCLC with LM has not been studied. We herein present five cases to further evaluate the effectiveness and tolerability of almonertinib in combination with bevacizumab for patients with EGFRm NSCLC and LM. For the first time, we report that almonertinib plus bevacizumab can not only effectively improve the neurological symptoms caused by LM but also prolong the survival time of patients with limited and controllable side effects, which provided a novel therapeutic approach for LM from EGFRm NSCLC.
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Zhang Y, Zhang W, Zheng L, Guo Q. The roles and targeting options of TRIM family proteins in tumor. Front Pharmacol 2022; 13:999380. [PMID: 36249749 PMCID: PMC9561884 DOI: 10.3389/fphar.2022.999380] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Tripartite motif (TRIM) containing proteins are a class of E3 ubiquitin ligases, which are critically implicated in the occurrence and development of tumors. They can function through regulating various aspects of tumors, such as tumor proliferation, metastasis, apoptosis and the development of drug resistance during tumor therapy. Some members of TRIM family proteins can mediate protein ubiquitination and chromosome translocation via modulating several signaling pathways, like p53, NF-κB, AKT, MAPK, Wnt/β-catenin and other molecular regulatory mechanisms. The multi-domain nature/multi-functional biological role of TRIMs implies that blocking just one function or one domain might not be sufficient to obtain the desired therapeutic outcome, therefore, a detailed and systematic understanding of the biological functions of the individual domains of TRIMs is required. This review mainly described their roles and underlying mechanisms in tumorigenesis and progression, and it might shade light on a potential targeting strategy for TRIMs in tumor treatment, especially using PROTACs.
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Affiliation(s)
- Yuxin Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
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27
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Design Strategies and Precautions for Using Vaccinia Virus in Tumor Virotherapy. Vaccines (Basel) 2022; 10:vaccines10091552. [PMID: 36146629 PMCID: PMC9504998 DOI: 10.3390/vaccines10091552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/27/2022] [Accepted: 09/10/2022] [Indexed: 11/17/2022] Open
Abstract
Oncolytic virotherapy has emerged as a novel form of cancer immunotherapy. Oncolytic viruses (OVs) can directly infect and lyse the tumor cells, and modulate the beneficial immune microenvironment. Vaccinia virus (VACV) is a promising oncolytic vector because of its high safety, easy gene editing, and tumor intrinsic selectivity. To further improve the safety, tumor-targeting ability, and OV-induced cancer-specific immune activation, various approaches have been used to modify OVs. The recombinant oncolytic VACVs with deleting viral virulence factors and/or arming various therapeutic genes have displayed better therapeutic effects in multiple tumor models. Moreover, the combination of OVs with other cancer immunotherapeutic approaches, such as immune checkpoint inhibitors and CAR-T cells, has the potential to improve the outcome in cancer patients. This will open up new possibilities for the application of OVs in cancer treatment, especially for personalized cancer therapies.
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GC S, Bellis SL, Hjelmeland AB. ST6Gal1: Oncogenic signaling pathways and targets. Front Mol Biosci 2022; 9:962908. [PMID: 36106023 PMCID: PMC9465715 DOI: 10.3389/fmolb.2022.962908] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
The Golgi-sialyltransferase ST6Gal1 (βgalactosidase α2,6 sialyltransferase 1), adds the negatively charged sugar, sialic acid, to the terminal galactose of N-glycosylated proteins. Upregulation of ST6Gal1 is observed in many malignancies, and a large body of research has determined that ST6Gal1-mediated α2,6 sialylation impacts cancer hallmarks. ST6Gal1 affects oncogenic behaviors including sustained proliferation, enhanced self-renewal, epithelial-to-mesenchymal transition, invasion, and chemoresistance. However, there are relatively few ST6GaL1 related signaling pathways that are well-established to mediate these biologies: greater delineation of specific targets and signaling mechanisms that are orchestrated by ST6Gal1 is needed. The aim of this review is to provide a summary of our current understanding of select oncogenic signaling pathways and targets affected by ST6Gal1.
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Affiliation(s)
| | | | - Anita B. Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
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29
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Yuan JJ, Ding JW, Li JW, Hu RH, Gong D, Hu JL, Zhu KB, Liu Y, Ding YH, Wei JW, Zeng JL, Lu ZB, Yin WH, Ai SF, Zha GH, Zhang ZL, Zou R, Zeng L. Nimotuzumab plus induction chemotherapy followed by radiotherapy/concurrent chemoradiotherapy plus nimotuzumab for locally advanced nasopharyngeal carcinoma: protocol of a multicentre, open-label, single-arm, prospective phase II trial. BMJ Open 2022; 12:e051594. [PMID: 36008072 PMCID: PMC9422822 DOI: 10.1136/bmjopen-2021-051594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022] Open
Abstract
UNLABELLED Epidermal growth factor receptor (EGFR) is a therapeutic target in nasopharyngeal carcinoma (NPC). The optimal combined modality of optimal combined modality of anti--EGFR monoclonal antibodies, induction chemotherapy (ICT), concurrent chemotherapy and radiotherapy for NPC remains poorly defined. None of previous studies have developed subsequent treatment strategies on the basis of stratification according to the efficacy following ICT plus anti-EGFR mAbs. This study aims to increase treatment intensity for patients with poor efficacy of ICT and reduce treatment toxicity for patients with favourable efficacy of ICT by assessing whether the efficacy of this treatment regimen is non-inferior to ICT plus concurrent chemoradiotherapy (historic controls). INTRODUCTION METHODS AND ANALYSIS: Pathology-confirmed WHO type II/III NPC patients at clinical stage III-IVA (eighth American Joint Committee on Cancer/Union for International Cancer Control staging system) will be included in the study. They will receive ICT plus nimotuzumab (NTZ), followed by radiotherapy plus NTZ or concurrent chemoradiotherapy plus NTZ (stratified based on the efficacy of ICT plus NTZ). The primary endpoint is 3-year failure-free survival rate; while the secondary endpoints are 3-year overall survival rate, distant metastasis-free survival rate and locoregional recurrence-free survival rate, and short-term remission rate of tumour and treatment toxicity. ETHICS AND DISSEMINATION The study protocol has been approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Our findings will be disseminated in a peer-reviewed journal. Implementation strategies are in place to ensure privacy and confidentiality of participants. TRIAL REGISTRATION NUMBER ChiCTR2000041139.
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Affiliation(s)
- Jing-Jing Yuan
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- The First Clinical Medical College, Nanchang University, Nanchang, China
| | - Jian-Wu Ding
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
| | - Jin-Wei Li
- Department of Radiotherapy, Ganzhou Cancer Hospital, Ganzhou, China
| | - Rong-Huan Hu
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
| | - Dan Gong
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
| | - Jia-Li Hu
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
| | - Kai-Bin Zhu
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
| | - Yan Liu
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
| | - Yu-Hai Ding
- Department of Oncology, Ganzhou People's Hospital, Ganzhou, Jiangxi, China
| | - Jia-Wang Wei
- Department of Oncology, Ganzhou People's Hospital, Ganzhou, Jiangxi, China
| | - Jian-Lun Zeng
- Department of Oncology, Pingxiang People's Hospital, Pingxiang, China
| | - Zhi-Bing Lu
- Department of Oncology, Pingxiang People's Hospital, Pingxiang, China
| | - Wei-Hua Yin
- Department of Oncology, Yichun People's Hospital, Yichun, China
| | - Su-Fen Ai
- Department of Oncology, Yichun People's Hospital, Yichun, China
| | - Guo-Hua Zha
- Department of Oncology, Fuzhou First People's Hospital, Fuzhou, China
| | - Zhi-Lin Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, Nanchang University Second Affiliated Hospital, Nanchang, China
| | - Rui Zou
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- The First Clinical Medical College, Nanchang University, Nanchang, China
| | - Lei Zeng
- Department Of Oncology, Nanchang University Second Affiliated Hospital, Nanchang, China
- Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, China
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30
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[Research Progress of Angiogenesis Inhibitors Plus EGFR-TKI in EGFR-mutated
Advanced Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:583-592. [PMID: 36002195 PMCID: PMC9411955 DOI: 10.3779/j.issn.1009-3419.2022.101.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Lung cancer is one of the leading causes of cancer-related morbidity and mortality. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) have become the standard treatment for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Unfortunately, drug resistance is inevitable in most cases. EGFR-TKI combined with angiogenesis inhibitors is a treatment scheme being explored to delay the therapeutic resistance, which is called "A+T treatment". Several clinical trials have demonstrated that the A+T treatment can improve the progression free survival (PFS) of the NSCLC patients. However, compared to EGFR-TKI monotherapy, the benefits of the A+T treatment based on different EGFR-TKIs, as well as its safety and exploration prospects are still unclear. Therefore, we reviewed the literature related to all three generations EGFR-TKIs combined with angiogenesis inhibitors, and summarized the mechanism, benefit, safety, optimal target population of A+T treatment.
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31
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The Role of Connexin in Ophthalmic Neovascularization and the Interaction between Connexin and Proangiogenic Factors. J Ophthalmol 2022; 2022:8105229. [PMID: 35783340 PMCID: PMC9242797 DOI: 10.1155/2022/8105229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 06/11/2022] [Indexed: 12/02/2022] Open
Abstract
The formation of new blood vessels is an important physiological process that occurs during development. When the body is injured, new blood vessel formation helps the body recuperate by supplying more oxygen and nutrients. However, this mechanism can have a negative effect. In ophthalmologic diseases, such as corneal new blood vessels, neonatal vascular glaucoma, and diabetes retinopathy, the formation of new blood vessels has become a critical component in patient survival. Connexin is a protein that regulates the cellular and molecular material carried by cells. It has been demonstrated that it is widely expressed in vascular endothelial cells, where it forms a slit connection between adjacent cells to promote cell-cell communication via hemichannels, as well as substance exchange into intracellular environments. Numerous studies have demonstrated that connexin in vascular endothelial cells plays an important role in angiogenesis and vascular leakage. The purpose of this study was to investigate the effect between the angiogenesis-associated factor and the connexin. It also reveals the effect of connexin on ophthalmic neovascularization.
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Xu Z, Teng F, Hao X, Li J, Xing P. Bevacizumab Combined with Continuation of EGFR-TKIs in NSCLC Beyond Gradual Progression. Cancer Manag Res 2022; 14:1891-1902. [PMID: 35693116 PMCID: PMC9176636 DOI: 10.2147/cmar.s363446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/28/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Ziyi Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Fei Teng
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Xuezhi Hao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
- Correspondence: Junling Li; Puyuan Xing, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China, Email ;
| | - Puyuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
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Wu K, Fu Y, Gao Z, Jiang J. Salvage therapy of osimertinib plus anlotinib in advanced lung adenocarcinoma with leptomeningeal metastasis: A case report. Respir Med Case Rep 2022; 38:101682. [PMID: 35707406 PMCID: PMC9189884 DOI: 10.1016/j.rmcr.2022.101682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 05/04/2022] [Accepted: 06/01/2022] [Indexed: 11/25/2022] Open
Abstract
Leptomeningeal metastasis (LM) is one of the most serious complications of advanced non-small cell lung cancer (NSCLC) and lacks standard treatment. Patients with LM often have a poor prognosis. Here, we report a 51-year-old man diagnosed as advanced lung adenocarcinoma and gene sequencing indicated no sensitive driver gene mutation. Pemetrexed and cisplatin plus bevacizumab was administered as first-line therapy. He received pembrolizumab plus nab-paclitaxel as second-line therapy and developed neurological symptoms soon. Later, he was diagnosed LM by cerebrospinal fluid (CSF) cytology and gene sequencing of lung tissue rebiopsy demonstrated epidermal growth factor receptor (EGFR) sensitive mutation. The patient received high-dose (160mg) osimertinib therapy but still could not tolerate severe neurological symptoms and developed cardiac adverse event. After that, standard-dose (80mg) osimertinib plus anlotinib was administered and this treatment regimen resulted in the alleviation of neurological symptoms. As the recent follow up, the curative effect was evaluated stable disease (SD) and the patient gained a progression-free survival (PFS) of more than 15 months. We report this successful salvage therapy of osimertinib plus anlotinib in an advanced lung adenocarcinoma patient who developed LM after failure on previous treatment until EGFR mutation was confirmed through rebiopsy.
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Monocentric evaluation of Ki-67 labeling index in combination with a modified RPA score as a prognostic factor for survival in IDH-wildtype glioblastoma patients treated with radiochemotherapy. Strahlenther Onkol 2022; 198:892-906. [PMID: 35612598 PMCID: PMC9515058 DOI: 10.1007/s00066-022-01959-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 04/24/2022] [Indexed: 11/05/2022]
Abstract
Purpose The prognosis for glioblastoma patients remains dismal despite intensive research on better treatment options. Molecular and immunohistochemical markers are increasingly being investigated as understanding of their role in disease progression grows. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been shown to have prognostic and therapeutic relevance for glioblastoma patients. Other markers implicated in tumor formation and/or malignancy are p53, Alpha thalassemia/mental retardation syndrome X-linked (ATRX), Epidermal Growth Factor Receptor splice variant III (EGFRvIII), and Ki-67, with loss of nuclear ATRX expression and lower Ki-67 index being associated with prolonged survival. For p53 and EGFRvIII the data are contradictory. Our aim was to investigate the markers mentioned above regarding progression-free (PFS) and overall survival (OS) to evaluate their viability as independent prognostic markers for our patient collective. Methods In this retrospective study, we collected data on patients undergoing radiotherapy due to isocitrate dehydrogenase (IDH) wildtype glioblastoma at a single university hospital between 2014 and 2020. Results Our findings confirm Ki-67 labeling index ≤ 20% as an independent prognostic factor for prolonged PFS as well as MGMT promoter methylation for both prolonged PFS and OS, in consideration of age and Eastern Cooperative Oncology Group (ECOG) status, chemotherapy treatment, and total radiation dose for PFS as well as additionally sex, resection status, and receipt of treatment for progression or recurrence for OS. Additionally, Ki-67 labeling index ≤ 20% showed a significant correlation with prolonged OS in univariate analysis. Modification of the recursive partitioning analysis (RPA) score to include Ki-67 labeling index resulted in a classification with the possible ability to distinguish long-term-survivors from patients with unfavorable prognosis. Conclusion MGMT promoter methylation and Ki-67 labeling index were independent predictors of survival in our collective. We see further studies pooling patient collectives to reach larger patient numbers concerning Ki-67 labeling index as being warranted. Supplementary Information The online version of this article (10.1007/s00066-022-01959-6) contains supplementary material, which is available to authorized users.
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Kitadai R, Okuma Y. Treatment Strategies for Non-Small Cell Lung Cancer Harboring Common and Uncommon EGFR Mutations: Drug Sensitivity Based on Exon Classification, and Structure-Function Analysis. Cancers (Basel) 2022; 14:2519. [PMID: 35626123 PMCID: PMC9139782 DOI: 10.3390/cancers14102519] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/02/2022] [Accepted: 05/13/2022] [Indexed: 02/04/2023] Open
Abstract
The identification of epidermal growth factor receptor (EGFR) mutations and development of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved the prognosis of advanced EGFR-mutated non-small cell lung cancer (NSCLC), setting a landmark in precision oncology. Exon 19 deletions and exon 21 L858R substitutions, which comprise the majority of common EGFR mutations, are predictors of good sensitivity to EGFR-TKIs. However, not all cancers harboring EGFR mutations are sensitive to EGFR-TKIs. Most patients harboring uncommon EGFR mutations demonstrate a poorer clinical response than those harboring common EGFR mutations. For example, cancers harboring exon 20 insertions, which represent approximately 4-12% of EGFR mutations, are generally insensitive to first- and second-generation EGFR-TKIs. Although understanding the biology of uncommon EGFR mutations is essential for developing treatment strategies, there is little clinical data because of their rarity. Moreover, clarifying the acquired resistance of EGFR-mutated NSCLC may lead to more precise treatments. Sequencing and structure-based analyses of EGFRmutated NSCLC have revealed resistance mechanisms and drug sensitivity. In this review, we discuss the strategies in development for treating NSCLC harboring common and uncommon EGFR mutations. We will also focus on EGFR-TKI sensitivity in patients harboring EGFR mutations based on the structural features.
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Affiliation(s)
- Rui Kitadai
- Department of Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan;
| | - Yusuke Okuma
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
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Choi SH, Yoo SS, Lee SY, Park JY. Anti-angiogenesis revisited: reshaping the treatment landscape of advanced non-small cell lung cancer. Arch Pharm Res 2022; 45:263-279. [PMID: 35449345 DOI: 10.1007/s12272-022-01382-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 04/17/2022] [Indexed: 11/29/2022]
Abstract
Although anti-angiogenic agents have been of limited use in the treatment of non-small cell lung cancer (NSCLC) until recently, further roles for the use of angiogenesis inhibition have emerged in the era of targeted therapy and immune checkpoint blockade. Given the shared common downstream signals of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) with their complementary roles in tumorigenesis and tumor angiogenesis, the dual inhibition of EGFR and VEGF pathways represents a rational strategy to maximize clinical efficacy and overcome resistance in the treatment of EGFR-mutant NSCLC. VEGF-driven angiogenesis is a potent driver of immunosuppressive tumor microenvironment (TME), with the recruited immunosuppressive cells driving angiogenesis, highlighting the interplay between the tumor vasculature and the anticancer immunity. Anti-angiogenic therapy can normalize the tumor vasculature and reprogram the TME from immunosuppressive into immunosupportive. Intensive research is under way to utilize the anti-angiogenic combination therapy to its full potential in diverse clinical settings in urgent unmet needs for the treatment of NSCLC. In this review, we present an overview of tumor angiogenesis and summarize the scientific background and preclinical and clinical evidence of anti-angiogenic therapy in combination with target therapy and immunotherapy for the treatment of NSCLC.
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Affiliation(s)
- Sun Ha Choi
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Korea.,Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, 41404, Korea
| | - Seung Soo Yoo
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Korea.,Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, 41404, Korea
| | - Shin Yup Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Korea. .,Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, 41404, Korea. .,Vessel-Organ Interaction Research Center, Kyungpook National University, Daegu, 41566, Korea.
| | - Jae Yong Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Korea.,Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, 41404, Korea
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The EGFR Signaling Modulates in Mesenchymal Stem Cells the Expression of miRNAs Involved in the Interaction with Breast Cancer Cells. Cancers (Basel) 2022; 14:cancers14071851. [PMID: 35406622 PMCID: PMC8997927 DOI: 10.3390/cancers14071851] [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: 03/08/2022] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
We previously demonstrated that the epidermal growth factor receptor (EGFR) modulates in mesenchymal stem cells (MSCs) the expression of a number of genes coding for secreted proteins that promote breast cancer progression. However, the role of the EGFR in modulating in MSCs the expression of miRNAs potentially involved in the progression of breast cancer remains largely unexplored. Following small RNA-sequencing, we identified 36 miRNAs differentially expressed between MSCs untreated or treated with the EGFR ligand transforming growth factor α (TGFα), with a fold change (FC) < 0.56 or FC ≥ 1.90 (CI, 95%). KEGG analysis revealed a significant enrichment in signaling pathways involved in cancer development and progression. EGFR activation in MSCs downregulated the expression of different miRNAs, including miR-23c. EGFR signaling also reduced the secretion of miR-23c in conditioned medium from MSCs. Functional assays demonstrated that miR-23c acts as tumor suppressor in basal/claudin-low MDA-MB-231 and MDA-MB-468 cells, through the repression of IL-6R. MiR-23c downregulation promoted cell proliferation, migration and invasion of these breast cancer cell lines. Collectively, our data suggested that the EGFR signaling regulates in MSCs the expression of miRNAs that might be involved in breast cancer progression, providing novel information on the mechanisms that regulate the MSC-tumor cell cross-talk.
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Shoari A, Tahmasebi M, Khodabakhsh F, Cohan RA, Oghalaie A, Behdani M. Angiogenic biomolecules specific nanobodies application in cancer imaging and therapy; review and updates. Int Immunopharmacol 2022; 105:108585. [DOI: 10.1016/j.intimp.2022.108585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/18/2022] [Accepted: 01/25/2022] [Indexed: 11/05/2022]
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Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors. Molecules 2022; 27:molecules27030819. [PMID: 35164092 PMCID: PMC8838133 DOI: 10.3390/molecules27030819] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug’s ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
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Kim M, Hwang SU, Yoon JD, Lee J, Kim E, Cai L, Kim G, Choi H, Oh D, Hyun SH. Beneficial Effects of Neurotrophin-4 Supplementation During in vitro Maturation of Porcine Cumulus-Oocyte Complexes and Subsequent Embryonic Development After Parthenogenetic Activation. Front Vet Sci 2021; 8:779298. [PMID: 34869748 PMCID: PMC8632945 DOI: 10.3389/fvets.2021.779298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Neurotrophin-4 (NT-4) is a neurotrophic factor that plays an important role in follicular development and oocyte maturation. However, it is not yet known whether NT-4 is related to oocyte maturation and follicular development in pigs. This study aims to investigate the effects of NT-4 supplementation during in vitro maturation (IVM) of porcine oocytes and subsequent embryonic development after parthenogenetic activation (PA). First, NT-4 and its receptors (TrkB and p75NTR) were identified through fluorescent immunohistochemistry in porcine ovaries. NT-4 was mainly expressed in theca and granulosa cells; phospho-TrkB and total TrkB were expressed in theca cells, granulosa cells, and oocytes; p75NTR was expressed in all follicular cells. During IVM, the defined maturation medium was supplemented with various concentrations of NT-4 (0, 1, 10, and 100 ng/mL). After IVM, the nuclear maturation rate was significantly higher in the 10 and 100 ng/mL NT-4 treated groups than in the control. There was no significant difference in the intracellular reactive oxygen species levels in any group after IVM, but the 1 and 10 ng/mL NT-4 treatment groups showed a significant increase in the intracellular glutathione levels compared to the control. In matured cumulus cells, the 10 ng/mL NT-4 treatment group showed significantly increased cumulus expansion-related genes and epidermal growth factor (EGF) signaling pathway-related genes. In matured oocytes, the 10 ng/mL treatment group showed significantly increased expression of cell proliferation-related genes, antioxidant-related genes, and EGF signaling pathway-related genes. We also investigated the subsequent embryonic developmental competence of PA embryos. After PA, the cleavage rates significantly increased in the 10 and 100 ng/mL NT-4 treatment groups. Although there was no significant difference in the total cell number of blastocysts, only the 10 ng/mL NT-4 treatment group showed a higher blastocyst formation rate than the control group. Our findings suggest that supplementation with the 10 ng/mL NT-4 can enhance porcine oocyte maturation by interacting with the EGF receptor signaling pathway. In addition, we demonstrated for the first time that NT-4 is not only required for porcine follicular development, but also has beneficial effects on oocyte maturation and developmental competence of PA embryos.
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Affiliation(s)
- Mirae Kim
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Seon-Ung Hwang
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Junchul David Yoon
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Joohyeong Lee
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Eunhye Kim
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Graduate School of Veterinary Biosecurity and Protection, Chungbuk National University, Cheongju, South Korea
| | - Lian Cai
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Graduate School of Veterinary Biosecurity and Protection, Chungbuk National University, Cheongju, South Korea
| | - Gahye Kim
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Hyerin Choi
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Dongjin Oh
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea
| | - Sang-Hwan Hyun
- Laboratory of Veterinary Embryology and Biotechnology (VETEMBIO), Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, South Korea.,Institute of Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju, South Korea.,Graduate School of Veterinary Biosecurity and Protection, Chungbuk National University, Cheongju, South Korea
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Pathak N, Chitikela S, Malik PS. Recent advances in lung cancer genomics: Application in targeted therapy. ADVANCES IN GENETICS 2021; 108:201-275. [PMID: 34844713 DOI: 10.1016/bs.adgen.2021.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Genomic characterization of lung cancer has not only improved our understanding of disease biology and carcinogenesis but also revealed several therapeutic opportunities. Targeting tumor dependencies on specific genomic alterations (oncogene addiction) has accelerated the therapeutic developments and significantly improved the outcomes even in advanced stage of disease. Identification of genomic alterations predicting response to specific targeted treatment is the key to success for this "personalized treatment" approach. Availability of multiple choices of therapeutic options for specific genomic alterations highlight the importance of optimum sequencing of drugs. Multiplex gene testing has become mandatory in view of constantly increasing number of therapeutic targets and effective treatment options. Influence of genomic characteristics on response to immunotherapy further makes comprehensive genomic profiling necessary before therapeutic decision making. A comprehensive elucidation of resistance mechanisms and directed treatments have made the continuum of care possible and transformed this deadly disease into a chronic condition. Liquid biopsy-based approach has made the dynamic monitoring of disease possible and enabled treatment optimizations accordingly. Current lung cancer management is the perfect example of "precision-medicine" in clinical oncology.
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Affiliation(s)
- Neha Pathak
- Department of Medical Oncology, Dr. B.R.A.I.R.C.H., All India Institute of Medical Sciences, New Delhi, India
| | - Sindhura Chitikela
- Department of Medical Oncology, Dr. B.R.A.I.R.C.H., All India Institute of Medical Sciences, New Delhi, India
| | - Prabhat Singh Malik
- Department of Medical Oncology, Dr. B.R.A.I.R.C.H., All India Institute of Medical Sciences, New Delhi, India.
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Saviana M, Romano G, Le P, Acunzo M, Nana-Sinkam P. Extracellular Vesicles in Lung Cancer Metastasis and Their Clinical Applications. Cancers (Basel) 2021; 13:5633. [PMID: 34830787 PMCID: PMC8616161 DOI: 10.3390/cancers13225633] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/04/2021] [Accepted: 11/09/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) are heterogenous membrane-encapsulated vesicles secreted by every cell into the extracellular environment. EVs carry bioactive molecules, including proteins, lipids, DNA, and different RNA forms, which can be internalized by recipient cells, thus altering their biological characteristics. Given that EVs are commonly found in most body fluids, they have been widely described as mediators of communication in several physiological and pathological processes, including cancer. Moreover, their easy detection in biofluids makes them potentially useful candidates as tumor biomarkers. In this manuscript, we review the current knowledge regarding EVs and non-coding RNAs and their role as drivers of the metastatic process in lung cancer. Furthermore, we present the most recent applications for EVs and non-coding RNAs as cancer therapeutics and their relevance as clinical biomarkers.
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Affiliation(s)
- Michela Saviana
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
- Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy
| | - Giulia Romano
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
| | - Patricia Le
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
| | - Mario Acunzo
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
| | - Patrick Nana-Sinkam
- Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; (M.S.); (G.R.); (P.L.); (M.A.)
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43
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Wang C, Zhao N, Sato F, Tanimoto K, Okada H, Liu Y, Bhawal UK. The roles of Y-box-binding protein (YB)-1 and C-X-C motif chemokine ligand 14 (CXCL14) in the progression of prostate cancer via extracellular-signal-regulated kinase (ERK) signaling. Bioengineered 2021; 12:9128-9139. [PMID: 34696665 PMCID: PMC8809965 DOI: 10.1080/21655979.2021.1993537] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The cold-shock protein Y-box-binding protein (YB)-1 regulates the expression of various chemokines and their receptors at the transcriptional level. Expression of the orphan chemokine CXCL14 is repressed by EGF induced signaling. The possible links between EGF-mediated YB-1 and CXCL14 as well as the functions of critical kinase pathways in the progression of prostate cancer have remained unexplored. Here we examined the correlation between YB-1 and CXCL14, and the ERK/AKT/mTOR pathways in prostate cancer. Knockdown of YB-1 decreased cyclinD1 expression with an upregulation of cleaved-PARP in human prostate cancer cells. EGF treatment upregulated phospho-YB-1 expression in a time-dependent manner, while treatment with an ERK inhibitor completely silenced its expression in prostate cancer cells. EGF treatment stimulates CyclinD1 and YB-1 phosphorylation in an ERK-dependent pathway. Positive and negative regulation of YB-1 and CXCL14 was observed after EGF treatment in prostate cancer cells, respectively. EGF rescues cell cycle and apoptosis via the AKT and ERK pathways. Furthermore, YB-1 silencing induces G1 arrest and apoptosis, while knockdown of CXCL14 facilitates cell growth and inhibits apoptosis in prostate cancer cells. YB-1 and CXCL14 were inversely correlated in prostate cancer cells and tissues. A significant association between poor overall survival and High YB-1 expression was observed in human prostate cancer patients. In conclusion, our data reveal the functional relationship between YB-1 and CXCL14 in EGF mediated ERK signaling, and YB-1 expression is a significant prognostic marker to predict prostate cancer.
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Affiliation(s)
- Chen Wang
- Department of Histology, Nihon University School of Dentistry at Matsudo, Chiba, Japan
| | - Na Zhao
- Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Fuyuki Sato
- Pathology Division, Shizuoka Cancer Center, Shizuoka, Japan
| | - Keiji Tanimoto
- Department of Translational Cancer Research, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Okada
- Department of Histology, Nihon University School of Dentistry at Matsudo, Chiba, Japan
| | - Yang Liu
- Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ujjal K Bhawal
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, India.,Department of Biochemistry and Molecular Biology, Nihon University School of Dentistry at Matsudo, Chiba, Japan
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44
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Sharma B, Singh VJ, Chawla PA. Epidermal growth factor receptor inhibitors as potential anticancer agents: An update of recent progress. Bioorg Chem 2021; 116:105393. [PMID: 34628226 DOI: 10.1016/j.bioorg.2021.105393] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/16/2021] [Accepted: 09/28/2021] [Indexed: 12/20/2022]
Abstract
Epidermal growth factor receptor (EGFR) is a vital intermediate in cell signaling pathway including cell proliferation, angiogenesis, apoptosis, and metastatic spread and also having four divergent members with similar structural features, such as EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Despite this, clinically exploited inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific thus provoking unenviable adverse effects. Some of the paramount obstacles to generate and develop new lead molecules of EGFR inhibitors are drug resistance, mutation, and also selectivity which inspire medicinal chemists to generate novel chemotypes. The discovery of therapeutic agents that inhibit the precise stage in tumorous cells such as EGFR is one of the chief successful targets in many cancer therapies, including lung and breast cancers. This review aims to compile the various recent progressions (2016-2021) in the discovery and development of diverse epidermal growth factor receptor (EGFR) inhibitors belonging to distinct structural classes like pyrazoline, pyrazole, imidazole, pyrimidine, coumarin, benzothiazole, etc. We have summarized preclinical and clinical data, structure-activity relationships (SAR) containing mechanistic and in silico studies to provide proposals for the design and invention of new EGFR inhibitors with therapeutic significance. The detailed progress of the work in the field will provide inexorable scope for the development of novel drug candidates with greater selectivity and efficacy.
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Affiliation(s)
- Bharti Sharma
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Vikram Jeet Singh
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India
| | - Pooja A Chawla
- Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India.
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Lawal B, Wang YC, Wu ATH, Huang HS. Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives. Front Pharmacol 2021; 12:691234. [PMID: 34512327 PMCID: PMC8429938 DOI: 10.3389/fphar.2021.691234] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 08/16/2021] [Indexed: 12/11/2022] Open
Abstract
Genetic and environmental factors play important roles in cancer progression, metastasis, and drug resistance. Herein, we used a multiomics data analysis to evaluate the predictive and prognostic roles of genetic and epigenetic modulation of c-MET (hepatocyte growth factor receptor)/epidermal growth factor receptor (EGFR) in colorectal cancer (CRC). First, we found that overexpressions of c-MET/EGFR were associated with the infiltration of tumor immune cells and cancer-associated fibroblasts, and were of prognostic relevance in CRC cohorts. We also observed that genetic alterations of c-MET/EGFR in CRC co-occurred with other gene alterations and were associated with overexpression of messenger (m)RNA of some cancer hallmark proteins. More specifically, DNA-methylation and somatic copy number alterations of c-MET/EGFR were associated with immune infiltration, dysfunctional T-cell phenotypes, and poor prognoses of the cohorts. Moreover, we describe two novel gefitinib-inspired small molecules derivatives of 3-phenyl-2H-benzo[e] [1,3]-oxazine-2,4(3H)-dione, NSC777205 and NSC777207, which exhibited wide-spectrum antiproliferative activities and selective cytotoxic preference for drug-sensitive and multidrug-resistant melanoma, renal, central nervous system, colon, and non-small cell lung cancer cell lines. We further provided in silico mechanistic evidence implicating c-MET/EGFR/phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibition in anticancer activities of those compounds. Our overall structure-activity relationship study revealed that the addition of an –OCH3 group to salicylic core of NSC777207 was not favorable, as the added moiety led to overall less-favorable drug properties as well as weaker anticancer activities compared to the properties and activities demonstrated by NSC777205 that has no –OCH3 substituent group. Further in vitro and in vivo analyses in tumor-bearing mice are ongoing in our lab to support this claim and to unravel the full therapeutic efficacies of NSC777205 and NSC777207 in CRC.
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Affiliation(s)
- Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.,Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yu-Chi Wang
- Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Alexander T H Wu
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.,The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei, Taiwan.,Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Hsu-Shan Huang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.,Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.,PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
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Mashayekhi V, Mocellin O, Fens MH, Krijger GC, Brosens LA, Oliveira S. Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma. Theranostics 2021; 11:9022-9037. [PMID: 34522225 PMCID: PMC8419040 DOI: 10.7150/thno.60350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail.
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Affiliation(s)
- Vida Mashayekhi
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Orsola Mocellin
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Marcel H.A.M. Fens
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Gerard C. Krijger
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A.A. Brosens
- Department of Pathology, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Sabrina Oliveira
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
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The role of anlotinib-mediated EGFR blockade in a positive feedback loop of CXCL11-EGF-EGFR signalling in anaplastic thyroid cancer angiogenesis. Br J Cancer 2021; 125:390-401. [PMID: 34088989 PMCID: PMC8328993 DOI: 10.1038/s41416-021-01340-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/05/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hypoxia-induced angiogenesis functions importantly in anaplastic thyroid cancer (ATC) progression. However, the therapeutic potential of broad-spectrum anti-angiogenic agent remains undefined. Anlotinib conventionally targets VEGFR, FGFR and PDGFR. Here, a novel role of anlotinib on ATC angiogenesis was illustrated. METHODS Molecular expressions were established via tissue microarray. Multiple assays (tubule formation, 3D sprouting and chicken chorioallantoic membrane model) were used for angiogenic evaluation. Panels of molecular screening were achieved by antibody and PCR arrays. The loop binding motif of EGFR for homology modelling was prepared using Maestro. RESULTS Anlotinib could dose- and time-dependently inhibit cell viability under normoxia and hypoxia and could repress hypoxia-activated angiogenesis more efficiently in vitro and in vivo. CXCL11 and phospho-EGFR were hypoxia-upregulated with a positive correlation. The cancer-endothelium crosstalk could be mediated by the positive CXCL11-EGF-EGFR feedback loop, which could be blocked by anlotinib directly targeting EGFR via a dual mechanism by simultaneous inhibitory effects on cancer and endothelial cells. The AKT-mTOR pathway was involved in this regulatory network. CONCLUSIONS The newly identified CXCL11-EGF-EGFR signalling provided mechanistic insight into the interaction between cancer and endothelial cells under hypoxia, and EGFR was a novel target. Anlotinib may be the encouraging therapeutic candidate in ATC.
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48
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Conventional Molecular and Novel Structural Mechanistic Insights into Orderly Organelle Interactions. Chem Res Chin Univ 2021. [DOI: 10.1007/s40242-021-1191-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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49
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TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib. Transl Oncol 2021; 14:101163. [PMID: 34192651 PMCID: PMC8254117 DOI: 10.1016/j.tranon.2021.101163] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 12/25/2022] Open
Abstract
We evaluated 180 patients' EGFR and TP53 co-mutation types, who received gefitinib targeted therapy, through sequencing their ctDNA in plasma. Patients with TP53 mutation is predictive of poor survival. Patients with EGFR exon 19 and TP53 co-mutations had better prognosis value than those with EGFR L585R and TP53 co-mutations. 4.Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types. Tumor protein p53 (TP53) is a tumor suppressor gene and TP53 mutations are associated with poor prognosis in non-small cell lung cancer. However, the in-depth classification of TP53 and its relationship with treatment response and prognosis in epidermal growth factor receptor (EGFR)-mutant tumors treated with EGFR tyrosine kinase inhibitors are unclear. Circulating tumor DNA was prospectively collected at baseline in advanced treatment-naïve EGFR-mutant lung adenocarcinoma patients treated with gefitinib in an open-label, single-arm, prospective, multicenter, phase 2 clinical trial (BENEFIT trial) and analyzed using next-generation sequencing. Survival was estimated using the Kaplan–Meier method. Of the 180 enrolled patients, 115 (63.9%) harbored TP53 mutations. The median progression-free survival (PFS) and overall survival (OS) of patients with TP53-wild type tumors were significantly longer than those of patients with TP53-mutant tumors. Mutations in exons 5–8 accounted for 80.9% of TP53 mutations. Mutations in TP53 exons 6 and 7 were significantly associated with inferior PFS and OS compared to wild-type TP53. TP53 mutation also influenced the prognosis of patients with different EGFR mutations. Patients with TP53 and EGFR exon 19 mutations had significantly longer PFS and OS than patients with TP53 and EGFR L858R mutations, and both groups had worse survival than patients with only EGFR mutations. Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. Moreover, TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types.
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Krasulova K, Illes P. Intestinal interplay of quorum sensing molecules and human receptors. Biochimie 2021; 189:108-119. [PMID: 34186126 DOI: 10.1016/j.biochi.2021.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/03/2021] [Accepted: 06/22/2021] [Indexed: 12/20/2022]
Abstract
Human gut is in permanent contact with microorganisms that play an important role in many physiological processes including metabolism and immunologic activity. These microorganisms communicate and manage themself by the quorum sensing system (QS) that helps to coordinate optimal growth and subsistence by activating signaling pathways that regulate bacterial gene expression. Diverse QS molecules produced by pathogenic as well as resident microbiota have been found throughout the human gut. However, even a host can by affected by these molecules. Intestinal and immune cells possess a range of molecular targets for QS. Our present knowledge on bacteria-cell communication encompasses G-protein-coupled receptors, nuclear receptors and receptors for bacterial cell-wall components. The QS of commensal bacteria has been approved as a protective factor with favourable effects on intestinal homeostasis and immunity. Signaling molecules of QS interacting with above-mentioned receptors thus parcipitate on maintaining of barrier functions, control of inflammation processes and increase of resistance to pathogen colonization in host organisms. Pathogens QS molecules can have a dual function. Host cells are able to detect the ongoing infection by monitoring the presence and changes in concentrations of QS molecules. Such information can help to set the most effective immune defence to prevent or overcome the infection. Contrary, pathogens QS signals can target the host receptors to deceive the immune system to get the best conditions for growth. However, our knowledge about communication mediated by QS is still limited and detailed understanding of molecular mechanisms of QS signaling is desired.
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Affiliation(s)
- Kristyna Krasulova
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
| | - Peter Illes
- Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71, Olomouc, Czech Republic
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