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Riaz R, Parveen S, Shafiq N, Ali A, Rashid M. Virtual screening, ADME prediction, drug-likeness, and molecular docking analysis of Fagonia indica chemical constituents against antidiabetic targets. Mol Divers 2025; 29:1139-1160. [PMID: 39012565 DOI: 10.1007/s11030-024-10897-7] [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: 03/27/2024] [Accepted: 05/13/2024] [Indexed: 07/17/2024]
Abstract
Fagonia indica from Zygophyllaceae family is a medicinal specie with significant antidiabetic potential. The present study aimed to investigate the in vitro antidiabetic activity of Fagonia indica crude extract followed by an in silico screening of its phytoconstituents. For this purpose, crude extract of Fagonia indica was prepared and divided in three different parts, i.e., n-hexane, ethyl acetate, and methanolic fraction. Based on in vitro outcomes, the phytochemical substances of Fagonia indica were virtually screened through a literature survey and a screening library of compounds (1-13) was prepared. The clinical potential of these novel drug candidates was assessed by applying an ADME screening profile. Findings of SwissADME indicators (Absorption, Distribution, Metabolism, and Excretion) for the compounds (1-13) presented relatively optimal physicochemical characteristics, drug-likeness, and medicinal chemistry. The antidiabetic action of these leading drug candidates was optimized through molecular docking analysis against 3 different human pancreatic α-amylase macromolecular targets with (PDB ID 1B2Y), (PDB ID 3BAJ), and (PDB ID: 3OLI) by applying Virtual Docker (Molegro MVD). Metformin was taken as a reference standard for the sake of comparison. In vitro antidiabetic evaluation gave good results with promising α-amylase inhibitory action in the form of IC50 values, as for n-hexane extract = 206.3 µM, ethyl acetate = 41.64 µM, and methanolic extract = 9.61 µM. According to in silico outcomes, all 13 phytoconstituents possess the best binding affinity with successful MolDock scores ranging from - 97.2003 to - 65.6877 kcal/mol and show a great number of binding interactions than native drug metformin. Therefore, the current work concluded that the diabetic inhibition prospective of extract and the compounds of Fagonia indica may contribute to being investigated as a new class of antidiabetic drug or drug-like candidate for further studies.
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Affiliation(s)
- Rabia Riaz
- Synthetic & Natural Product Discovery Lab, Department of Chemistry, Government College Women University, Faisalabad, 38000, Pakistan
| | - Shagufta Parveen
- Synthetic & Natural Product Discovery Lab, Department of Chemistry, Government College Women University, Faisalabad, 38000, Pakistan
| | - Nusrat Shafiq
- Synthetic & Natural Product Discovery Lab, Department of Chemistry, Government College Women University, Faisalabad, 38000, Pakistan.
| | - Awais Ali
- Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan, 2300, Pakistan
| | - Maryam Rashid
- Synthetic & Natural Product Discovery Lab, Department of Chemistry, Government College Women University, Faisalabad, 38000, Pakistan
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Rama NJG, Sousa I. Bridging the gap: The role of technological advances in shaping gastrointestinal oncological outcomes. World J Gastrointest Oncol 2025; 17:101752. [PMID: 40092923 PMCID: PMC11866242 DOI: 10.4251/wjgo.v17.i3.101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/13/2024] [Accepted: 12/16/2024] [Indexed: 02/14/2025] Open
Abstract
Gastrointestinal (GI) cancers are highly prevalent and considered a major global health challenge. Their approach has undergone a remarkable transformation over the past years due to the development of new technologies that enabled better outcomes regarding their diagnosis and management. These include artificial intelligence, robotics, next-generation sequencing and personalized medicine. Nonetheless, the integration of these advances into everyday clinical practice remains complex and challenging as we are still trying to figure out if these innovations tangibly improve oncological outcomes or if the current state of art should remain as the gold standard for the treatment of these patients. Additionally, there are also some issues regarding ethical subjects, data privacy, finances and governance. Precision surgery concept has evolved considerably over the past decades, especially for oncological patients. It aims to customize medical treatments and to operate on those patients who most likely will benefit from a specific surgical procedure. In the future, to improve GI oncological outcomes, a delicate balance between technological advances adoption and evidence-based care should be chased. As we move forward, the question will be to harness the power of innovation while keeping up the highest standards of patient care.
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Affiliation(s)
- Nuno J G Rama
- Division of Colorectal Surgical, Leiria Hospital Centre, Leiria 2410-021, Portugal
| | - Inês Sousa
- Department of Surgical, Leiria Hospital Centre, Leiria 2410-021, Portugal
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Guo H, Miao L, Yu C. The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with colorectal cancer: A network meta-analysis. Eur J Pharmacol 2025; 988:177219. [PMID: 39716565 DOI: 10.1016/j.ejphar.2024.177219] [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: 08/22/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer. METHODS A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS). RESULTS A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET. CONCLUSIONS In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.
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Affiliation(s)
- Haoyan Guo
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China
| | - Longjie Miao
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, 518104, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chengdong Yu
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Wang W, Lian B, Xu C, Wang Q, Li Z, Zheng N, Liu A, Yu J, Zhong W, Wang Z, Zhang Y, Liu J, Zhang S, Cai X, Liu A, Li W, Mao L, Zhan P, Liu H, Lv T, Miao L, Min L, Chen Y, Yuan J, Wang F, Jiang Z, Lin G, Huang L, Pu X, Lin R, Liu W, Rao C, Lv D, Yu Z, Li X, Tang C, Zhou C, Zhang J, Xue J, Guo H, Chu Q, Meng R, Liu X, Wu J, Zhang R, Zhou J, Zhu Z, Li Y, Qiu H, Xia F, Lu Y, Chen X, Feng J, Ge R, Dai E, Han Y, Pan W, Pang F, Huang X, Hu M, Hao Q, Wang K, Wu F, Song B, Xu B, Wang L, Zhu Y, Lin L, Xie Y, Lin X, Cai J, Xu L, Li J, Jiao X, Li K, Wei J, Feng H, Wang L, Du Y, Yao W, Shi X, Niu X, Yuan D, Yao Y, Huang J, Feng Y, Zhang Y, Sun P, Wang H, Ye M, Wang D, Wang Z, Hao Y, Wang Z, Wan B, Lv D, Yang S, Kang J, Zhang J, Zhang C, et alWang W, Lian B, Xu C, Wang Q, Li Z, Zheng N, Liu A, Yu J, Zhong W, Wang Z, Zhang Y, Liu J, Zhang S, Cai X, Liu A, Li W, Mao L, Zhan P, Liu H, Lv T, Miao L, Min L, Chen Y, Yuan J, Wang F, Jiang Z, Lin G, Huang L, Pu X, Lin R, Liu W, Rao C, Lv D, Yu Z, Li X, Tang C, Zhou C, Zhang J, Xue J, Guo H, Chu Q, Meng R, Liu X, Wu J, Zhang R, Zhou J, Zhu Z, Li Y, Qiu H, Xia F, Lu Y, Chen X, Feng J, Ge R, Dai E, Han Y, Pan W, Pang F, Huang X, Hu M, Hao Q, Wang K, Wu F, Song B, Xu B, Wang L, Zhu Y, Lin L, Xie Y, Lin X, Cai J, Xu L, Li J, Jiao X, Li K, Wei J, Feng H, Wang L, Du Y, Yao W, Shi X, Niu X, Yuan D, Yao Y, Huang J, Feng Y, Zhang Y, Sun P, Wang H, Ye M, Wang D, Wang Z, Hao Y, Wang Z, Wan B, Lv D, Yang S, Kang J, Zhang J, Zhang C, Li W, Fu J, Wu L, Lan S, Ou J, Shi L, Zhai Z, Wang Y, Li B, Zhang Z, Wang K, Ma X, Li Z, Liu Z, Yang N, Wu L, Wang H, Jin G, Wang G, Wang J, Shi H, Fang M, Fang Y, Li Y, Wang X, Chen J, Zhang Y, Zhu X, Shen Y, Ma S, Wang B, Song Y, Song Z, Fang W, Lu Y, Si L. Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations. Innovation (N Y) 2024; 5:100661. [PMID: 39529955 PMCID: PMC11551471 DOI: 10.1016/j.xinn.2024.100661] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/19/2024] [Indexed: 11/16/2024] Open
Abstract
The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth, differentiation, and survival. When the BRAF gene mutates, it can lead to abnormal activation of the signaling pathway, which promotes cell proliferation, inhibits cell apoptosis, and ultimately contributes to the occurrence and development of cancer. BRAF mutations are widely present in various cancers, including malignant melanoma, thyroid cancer, colorectal cancer, non-small cell lung cancer, and hairy cell leukemia, among others. BRAF is an important target for the treatment of various solid tumors, and targeted combination therapies, represented by BRAF inhibitors, have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors. Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This is also the first time a BRAF/MEK inhibitor combination has been approved for use in pediatric patients. As research into the diagnosis and treatment of BRAF mutations advances, standardizing the detection of BRAF mutations and the clinical application of BRAF inhibitors becomes increasingly important. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations.
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Affiliation(s)
- Wenxian Wang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Bin Lian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Chunwei Xu
- Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, P.R. China
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Qian Wang
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Ziming Li
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Nan Zheng
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing 200030, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 200030, China
| | - Aijun Liu
- Senior Department of Pathology, the 7 Medical Center of PLA General Hospital, Beijing 100700, P.R. China
| | - Jinpu Yu
- Department of Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Wenzhao Zhong
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, 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, P.R. China
| | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingjing Liu
- Department of Thoracic Cancer, Jilin Cancer Hospital, Jilin, Changchun 130012, P.R. China
| | - Shirong Zhang
- Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, West Lake University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiuyu Cai
- Department of VIP Inpatient, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. ChinaP.R. China
| | - Anwen Liu
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wen Li
- Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Lili Mao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Ping Zhan
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Hongbing Liu
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Tangfeng Lv
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Liyun Miao
- Department of Respiratory Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Lingfeng Min
- Department of Respiratory Medicine, Clinical Medical School of Yangzhou University, Subei People’s Hospital of Jiangsu Province, Yangzhou, Jiangsu 225001, P.R. China
| | - Yu Chen
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Jingping Yuan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Feng Wang
- Department of Internal Medicine, Cancer Center of PLA, Qinhuai Medical Area, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhansheng Jiang
- Derpartment of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
| | - Gen Lin
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Long Huang
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xingxiang Pu
- Department of Medical Oncology, Lung Cancer and Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Rongbo Lin
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Weifeng Liu
- Department of Orthopaedic Oncology Surgery, Beijing Ji Shui Tan Hospital, Peking University, Beijing 100035, P.R. China
| | - Chuangzhou Rao
- Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, P.R. China
| | - Dongqing Lv
- Department of Pulmonary Medicine, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Zongyang Yu
- Department of Respiratory Medicine, the 900 Hospital of the Joint Logistics Team (the Former Fuzhou General Hospital), Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Xiaoyan Li
- Department of Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100700, P.R. China
| | - Chuanhao Tang
- Department of Medical Oncology, Peking University International Hospital, Beijing 102206, P.R. China
| | - Chengzhi Zhou
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510300, P.R. China
| | - Junping Zhang
- Department of Thoracic Oncology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Junli Xue
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200123, P.R. China
| | - Hui Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, P.R. China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Rui Meng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Xuewen Liu
- Department of Oncology, the Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingxun Wu
- Department of Medical Oncology, the First Affiliated Hospital of Medicine, Xiamen University, Xiamen, Fujian 361003, P.R. China
| | - Rui Zhang
- Department of Medical Oncology, Cancer Hospital of China Medical University, Shenyang, Liaoning 110042, P.R. China
| | - Jin Zhou
- Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology, Chengdu, Sichuan 610041, P.R. China
| | - Zhengfei Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Yongheng Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Hong Qiu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Fan Xia
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi 710032, P.R. China
| | - Xiaofeng Chen
- Department of Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Jian Feng
- Department of Respiratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Rui Ge
- Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
| | - Enyong Dai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 13003, P.R. China
| | - Yu Han
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 1550081, P.R. China
| | - Weiwei Pan
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001, P.R. China
| | - Fei Pang
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Xin Huang
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Meizhen Hu
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Qing Hao
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Kai Wang
- Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai 201114, P.R. China
| | - Fan Wu
- Department of Medical, Menarini Silicon Biosystems Spa, Shanghai 400000, P.R. China
| | - Binbin Song
- Department of Medical Oncology, The Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Bingwei Xu
- Department of Biotherapy, Cancer Institute, First Affiliated Hospital of China Medical University, Shenyang 110001, P.R. China
| | - Liping Wang
- Department of Oncology, Baotou Cancer Hospital, Baotou, Inner Mongolia 014000, P.R. China
| | - Youcai Zhu
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, The Third Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Li Lin
- Department of Medical Oncology, Peking University International Hospital, Beijing 102206, P.R. China
| | - Yanru Xie
- Department of Oncology, Lishui Municipal Central Hospital, Lishui, Zhejiang 323000, P.R. China
| | - Xinqing Lin
- Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315010, P.R. China
| | - Jing Cai
- Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ling Xu
- Department of Interventional Pulmonary Diseases, Anhui Chest Hospital, Hefei, Anhui 230011, P.R. China
| | - Jisheng Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinnan, Shangdong 250012, P.R. China
| | - Xiaodong Jiao
- Department of Medical Oncology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200070, P.R. China
| | - Kainan Li
- Department of Oncology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, P.R. China
| | - Jia Wei
- Department of the Comprehensive Cancer Center, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
| | - Huijing Feng
- Department of Thoracic Oncology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Lin Wang
- Department of Pathology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan, Shanxi 030032, P.R. China
| | - Yingying Du
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Wang Yao
- Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Xuefei Shi
- Department of Respiratory Medicine, Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, P.R. China
| | - Xiaomin Niu
- Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China
| | - Dongmei Yuan
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yanwen Yao
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianhui Huang
- Department of Oncology, Lishui Municipal Central Hospital, Lishui, Zhejiang 323000, P.R. China
| | - Yue Feng
- Department of Gynecologic Radiation Oncology, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Yinbin Zhang
- Department of Oncology, the Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi 710004, P.R. China
| | - Pingli Sun
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Hong Wang
- Senior Department of Oncology, The 5 Medical Center of PLA General Hospital, Beijing 100071, P.R. China
| | - Mingxiang Ye
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Dong Wang
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhaofeng Wang
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yue Hao
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Zhen Wang
- Department of Radiation Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Bin Wan
- Department of Respiratory Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu 210002, P.R. China
| | - Donglai Lv
- Department of Clinical Oncology, The 901 Hospital of Joint Logistics Support Force of People Liberation Army, Hefei, Anhui 230031, P.R. China
| | - Shengjie Yang
- Department of Thoracic Surgery, Chuxiong Yi Autonomous Prefecture People’s Hospital, Chuxiong, Yunnan 675000, P.R. China
| | - Jin Kang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Jiatao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Chao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou, Guangdong 510080, P.R. China
| | - Wenfeng Li
- Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, China
| | - Jianfei Fu
- Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, P.R. China
| | - Lizhi Wu
- Department of Microsurgery, Taizhou Hospital Affiliated to Wenzhou Medical University, Taizhou, Zhejiang 317000, China
| | - Shijie Lan
- Department of Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Juanjuan Ou
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, P.R. China
| | - Lin Shi
- Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhanqiang Zhai
- Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, The Third Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P.R. China
| | - Yina Wang
- Department of Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310000, P.R. China
| | - Bihui Li
- Department of Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541199, P.R. China
| | - Zhang Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Ke Wang
- National Health Commission (NHC) Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China
- Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 210000, People's Republic of China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhongwu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
| | - Zhefeng Liu
- Senior Department of Oncology, The 5 Medical Center of PLA General Hospital, Beijing 100071, P.R. China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lin Wu
- Department of Medical Oncology, Lung Cancer and Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Huijuan Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450000, P.R. China
| | - Gu Jin
- Department of Bone and Soft-tissue Surgery, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Guansong Wang
- Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China
| | - Jiandong Wang
- Department of Pathology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Hubing Shi
- Frontier Science Center for Disease Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Meiyu Fang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Yong Fang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China
| | - Yuan Li
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
| | - Xiaojia Wang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Jing Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yiping Zhang
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Xixu Zhu
- Department of Radiation Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Yi Shen
- Department of Thoracic Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Shenglin Ma
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Biyun Wang
- Department of Breast Cancer and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Yong Song
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Zhengbo Song
- Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, P.R. China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
| | - Yuanzhi Lu
- Department of Clinical Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Lu Si
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing 100142, P.R. China
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5
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Seif SE, Wardakhan WW, Hassan RA, Abdou AM, Mahmoud Z. New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway. Drug Dev Res 2024; 85:e70007. [PMID: 39425261 DOI: 10.1002/ddr.70007] [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: 07/23/2024] [Revised: 09/25/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024]
Abstract
Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound 9c displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.
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Affiliation(s)
- Safaa E Seif
- National Organization for Drug Control and Research, Cairo, Egypt
| | | | - Rasha A Hassan
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Amr M Abdou
- Department of Microbiology and Immunology, National Research Centre, Dokki, Giza, 12622, Egypt
| | - Zeinab Mahmoud
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
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6
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Mosaferi Z, Pirestani M, Arefian E, Gojani G, Kavousinasab N, Karimi P, Deilami A, Abrehdari-Tafreshi Z. Exploring the Relationship Between KRAS, NRAS, and BRAF Mutations and Clinical Characteristics in Iranian Colorectal Cancer Patients. J Gastrointest Cancer 2024; 55:1134-1143. [PMID: 38709419 DOI: 10.1007/s12029-024-01064-0] [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] [Accepted: 04/27/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND Patients with colorectal cancer can benefit from anti-EGFR (epidermal growth factor receptor) therapy. However, this therapy is not effective for treating colorectal cancers with constitutive activating mutations in the KRAS, NRAS, and BRAF genes. Molecular analysis of tumor tissue frequently informs treatment decisions for colorectal cancer. This study aims to identify KRAS, NRAS, and BRAF mutations in Iranian patients diagnosed with colorectal cancer and to assess the prevalence of these mutations relative to the tumor differentiation stage within these populations. METHODS From April 2018 to December 2022, 2000 specimens from patients with colorectal cancer were collected. Data on sex, age, and tumor differentiation stage were recorded for all samples. For mutation detection, the KRAS and NRAS exons (2, 3, and 4) were amplified using the Diatech kit, and a specific primer was used to amplify BRAF exon 15. Pyrosequencing was then performed. RESULTS Analysis of samples revealed that 1105 specimens (55.3%) contained mutations in at least one of the screened genes. Among the genes studied, the highest occurrence was the KRAS mutation at 47.4%, followed by NRAS at 5.3% and BRAF at 2.7%. Most KRAS mutations were found in exon 2 (89.7%), with the G12D mutation being the most prevalent at 32% of cases. There was a significant difference in the rate of KRAS mutations in women (52.5%) compared to men (43.5%) (P = 0.02). For NRAS, the majority mutations were observed in exon 3 (76.2%), with the Q61H mutation being the most prevalent at 28.5% of cases. There were no significant associations between the clinicopathological parameters and mutations. CONCLUSION The study's findings indicate a rising frequency of mutations in these genes in Iran, highlighting the need to screening mutations in the main exons of all three genes for effective colorectal cancer treatment strategies.
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Affiliation(s)
- Zahra Mosaferi
- Department of Cell and Molecular Biology, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Majid Pirestani
- Parasitology & Entomology Dept, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Sciences, University of Tehran, Tehran, Iran
- Pediatric Cell and Gene Therapy Research Center, & Tissue Research Institute, Tehran University of Medical Sciences, GeneTehran, Cell, Iran
| | - Goli Gojani
- National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Nastaran Kavousinasab
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Parto Karimi
- Department of Chemistry, Faculty of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Azam Deilami
- Department of Cell and Molecular Biology, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Abrehdari-Tafreshi
- Department of Cell and Molecular Biology, School of Biology, College of Sciences, University of Tehran, P. O. Box, Tehran, 14155-6455, Iran.
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7
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Gholizadeh N, Rokni GR, Zaresharifi S, Gheisari M, Tabari MAK, Zoghi G. Revolutionizing non-melanoma skin cancer treatment: Receptor tyrosine kinase inhibitors take the stage. J Cosmet Dermatol 2024; 23:2793-2806. [PMID: 38812406 DOI: 10.1111/jocd.16355] [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: 02/13/2024] [Revised: 03/29/2024] [Accepted: 04/22/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Innovative treatments for non-melanoma skin cancers (NMSCs) are required to enhance patient outcomes. AIMS This review examines the effectiveness and safety of receptor tyrosine kinase inhibitors (RTKIs). METHODS A comprehensive review was conducted on the treatment potential of several RTKIs, namely cetuximab, erlotinib, gefitinib, panitumumab, and lapatinib. RESULTS The findings indicate that these targeted therapies hold great promise for the treatment of NMSCs. However, it is crucial to consider relapse rates and possible adverse effects. Further research is needed to improve treatment strategies, identify patient groups that would benefit the most, and assess the long-term efficacy and safety, despite the favorable results reported in previous studies. Furthermore, it is crucial to investigate the potential benefits of integrating RTKIs with immunotherapy and other treatment modalities to enhance the overall efficacy of therapy for individuals with NMSC. CONCLUSIONS Targeted therapies for NMSCs may be possible with the use of RTKIs. The majority of studies focused on utilizing epidermal growth factor receptor inhibitors as the primary class of RTKIs for the treatment of NMSC. Other RTKIs were only employed in experimental investigations. Research indicates that RTKIs could potentially serve as a suitable alternative for elderly patients who are unable to undergo chemotherapy and radiotherapy.
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Affiliation(s)
- Nasim Gholizadeh
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ghasem Rahmatpour Rokni
- Department of Dermatology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shirin Zaresharifi
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Gheisari
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Ghazal Zoghi
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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8
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Riaz R, Parveen S, Shafiq N, Ali A, Rashid M. Virtual screening, ADME prediction, drug-likeness, and molecular docking analysis of Fagonia indica chemical constituents against antidiabetic targets. Mol Divers 2024. [DOI: https:/doi.org/10.1007/s11030-024-10897-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 05/13/2024] [Indexed: 01/06/2025]
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9
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Yang Q, Qu R, Lu S, Zhang Y, Zhang Z, Fu W. Biological and Clinical Characteristics of Proximal Colon Cancer: Far from Its Anatomical Subsite. Int J Med Sci 2024; 21:1824-1839. [PMID: 39113889 PMCID: PMC11302569 DOI: 10.7150/ijms.97574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
Colorectal cancer is a heterogeneous disease which can be divided into proximal colon cancer, distal colon cancer and rectal cancer according to the anatomical location of the tumor. Each anatomical location of colorectal cancer exhibits distinct characteristics in terms of incidence, clinical manifestations, molecular phenotypes, treatment, and prognosis. Notably, proximal colon cancer differs significantly from cancers of other anatomical subsites. An increasing number of studies have highlighted the presence of unique tumor biological characteristics in proximal colon cancer. Gaining a deeper understanding of these characteristics will facilitate accurate diagnosis and treatment approaches.
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Affiliation(s)
- Qing Yang
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Ruize Qu
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Siyi Lu
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Yi Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Zhipeng Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
| | - Wei Fu
- Department of General Surgery, Peking University Third Hospital, Beijing China
- Cancer Center, Peking University Third Hospital, Beijing China
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10
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Yang J, Wang QL, Wang GN, Ye JC, Li ZQ, Wang JY, Liang ZH, Li SX, Sun C, Liao WT, Gao YJ, Wang J, Mao Y, Yu C, Feng GK, Zeng MS. A pan-KRAS degrader for the treatment of KRAS-mutant cancers. Cell Discov 2024; 10:70. [PMID: 38937452 PMCID: PMC11211324 DOI: 10.1038/s41421-024-00699-4] [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: 09/07/2023] [Accepted: 06/02/2024] [Indexed: 06/29/2024] Open
Abstract
KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.
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Affiliation(s)
- Jie Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qiao-Li Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Guan-Nan Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jia-Cong Ye
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zi-Qian Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jing-Yun Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Zhao-Hui Liang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Shu-Xin Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Cong Sun
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Wen-Ting Liao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yi-Jun Gao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Jing Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Chunjing Yu
- Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Guo-Kai Feng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
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11
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Savel H, Meyer-Losic F, Proust-Lima C, Richert L. Statistical classification of treatment responses in mouse clinical trials for stratified medicine in oncology drug discovery. Sci Rep 2024; 14:934. [PMID: 38195626 PMCID: PMC10776864 DOI: 10.1038/s41598-023-51055-7] [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: 08/08/2023] [Accepted: 12/29/2023] [Indexed: 01/11/2024] Open
Abstract
Translational oncology research strives to explore a new aspect: identifying subgroups that exhibit treatment response even during pre-clinical phases. In this study, we focus on PDX models and their implementation in mouse clinical trials (MCT). Our primary objective was to identify subgroups with different treatment responses using Latent Class Mixed Model (LCMM).We used a public dataset and focused on one treatment, encorafenib, and two indications, melanoma and colorectal cancer, for which efficacy depends on a specific mutation BRAF V600E. One LCMM per indication was implemented to classify treatment responses at the PDX level, analyzing the growth kinetics of treated tumors and matched controls within the PDX models. A simulation study was carried out to explore the performance of LCMM in this context. For both applications, LCMM identified classes for which the higher the proportion of mutated BRAF V600E PDX models the greater the treatment effect, which is aligned with encorafenib use recommendations. The simulation study showed that LCMM could identify classes with large differences in treatment effects. LCMM is a suitable tool for MCT to explore treatment response subgroups of PDX. Once these subgroups are defined, characterization of their phenotypes/genotypes could be performed to explore treatment response predictors.
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Affiliation(s)
- Hélène Savel
- U1219, Inserm Bordeaux Population Health Research Centre, Department of Public Health, Université de Bordeaux, 33000, Bordeaux, France
- Ipsen Innovation, 5 Avenue du Canada, 91940, Les Ulis, France
- Inria, SISTM, 33400, Talence, France
| | | | - Cécile Proust-Lima
- U1219, Inserm Bordeaux Population Health Research Centre, Department of Public Health, Université de Bordeaux, 33000, Bordeaux, France
- Institut Bergonié, CHU de Bordeaux, INSERM, Université de Bordeaux, CIC-EC 1401, 33000, Bordeaux, France
| | - Laura Richert
- U1219, Inserm Bordeaux Population Health Research Centre, Department of Public Health, Université de Bordeaux, 33000, Bordeaux, France.
- Institut Bergonié, CHU de Bordeaux, INSERM, Université de Bordeaux, CIC-EC 1401, 33000, Bordeaux, France.
- Inria, SISTM, 33400, Talence, France.
- Université de Bordeaux, 146 Rue Léo Saignat, 33076, Bordeaux Cedex, France.
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12
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Matsuoka T, Yashiro M. Current status and perspectives of genetic testing in gastrointestinal cancer (Review). Oncol Lett 2024; 27:21. [PMID: 38058469 PMCID: PMC10696628 DOI: 10.3892/ol.2023.14155] [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: 06/22/2023] [Accepted: 10/30/2023] [Indexed: 12/08/2023] Open
Abstract
Genetic testing has become widespread in daily medical care for gastrointestinal (GI) cancers. However, unlike breast cancer and non-small cell lung cancer, in which personalized medicine targeting various driver genes is standardized, the incidence of targeted gene abnormalities in GI cancers is low. Nevertheless, such abnormalities may be linked to therapeutic agents and the further development of therapeutic agents for personalized medicine for GI cancers is desired. A liquid biopsy is of great benefit in offering clinical decision support, in applications such as GI cancer screening, surgical interventions, monitoring disease status and enhancing patient survival outcomes, all of which would contribute to personalized medicine. Germline genetic testing is required for several types of GI cancer, which shows clinical indications of hereditary predisposition. The increasing use of multigene panel testing has redefined gene-cancer associations, and consequently the estimate of cancer risk that vary from low to high penetrance. Comprehensive genetic testing can enable the detection of novel treatment targets and the discovery of undefined multiple diagnostic/predictive markers, which may enhance the molecular-level understanding of GI cancers. Genetic testing can also aid the design of more appropriate and adequate genomic-driven therapies for patients who may benefit from other standardized therapeutic methods.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, Osaka 5458585, Japan
- Institute of Medical Genetics, Osaka Metropolitan University, Osaka 5458585, Japan
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13
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Hamdani S, Allali H, Bouchentouf S. Exploring the Therapeutic Potential of Ginkgo biloba Polyphenols in Targeting Biomarkers of Colorectal Cancer: An In-silico Evaluation. Curr Drug Discov Technol 2024; 21:e020224226651. [PMID: 38318835 DOI: 10.2174/0115701638282497240124102345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 02/07/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is a major contributor to cancer-related deaths worldwide, driving the need for effective anticancer therapies with fewer side effects. The exploration of Ginkgo biloba, a natural source, offers a hopeful avenue for novel treatments targeting key colorectal biomarkers involved in CRC treatment. OBJECTIVE The aim of this study was to explore the binding affinity of natural molecules derived from G. biloba to essential biomarkers associated with CRC, including Kirsten rat sarcoma virus, neuroblastoma RAS mutations, serine/threonine-protein kinase B-Raf, phosphatidylinositol 3'-kinase, and deleted colorectal cancer, using molecular docking. The focus of this research was to evaluate how effectively these molecules bind to specified targets in order to identify potential inhibitors for the treatment of CRC. METHODS A total of 152 polyphenolic compounds from G. biloba were selected and subjected to molecular docking simulations to evaluate their interactions with CRC-related biomarkers. The docking results were analysed to identify ligands exhibiting strong affinities towards the targeted genes, suggesting potential inhibitory effects. RESULTS Docking simulations unveiled the strong binding affinities between selected polyphenolic compounds derived from G. biloba and genes associated with CRC. The complex glycoside structures that are found in flavonols are of significant importance. These compounds, including derivatives with distinctive arrangements, exhibited promising docking scores, signifying substantial interactions with the targeted biomarkers. CONCLUSION The study demonstrates the potential of G. biloba-derived molecules as effective anticancer agents for colorectal cancer. The identified ligands exhibit strong interactions with crucial CRC-related biomarkers, suggesting potential inhibition ability. Further in vitro and in vivo investigations are needed to validate and build upon these promising findings, advancing the development of novel and efficient CRC therapies.
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Affiliation(s)
- Sarra Hamdani
- Department of Chemistry, Faculty of Sciences, Abou Bekr Belkaïd University, P.O. Box 119, Tlemcen 13000, Algeria
- Laboratory of Natural and Bioactive Substances (LASNABIO), Department of Chemistry, Faculty of Sciences, Abou Bekr Belkaïd University, P.O. Box 119, Tlemcen 13000, Algeria
| | - Hocine Allali
- Department of Chemistry, Faculty of Sciences, Abou Bekr Belkaïd University, P.O. Box 119, Tlemcen 13000, Algeria
- Laboratory of Natural and Bioactive Substances (LASNABIO), Department of Chemistry, Faculty of Sciences, Abou Bekr Belkaïd University, P.O. Box 119, Tlemcen 13000, Algeria
| | - Salim Bouchentouf
- Laboratory of Natural and Bioactive Substances (LASNABIO), Department of Chemistry, Faculty of Sciences, Abou Bekr Belkaïd University, P.O. Box 119, Tlemcen 13000, Algeria
- Department of Process Engineering, Faculty of Technology, Doctor Tahar Moulay University of Saida, BP 138 cité EN-NASR, Saïda 20000, Algeria
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14
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Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H, Salehian-Dehkordi H, Abdolvand M, Salmanizadeh S, Rashidi M, Niazmand A, Ahmadi S, Feizbakhshan S, Kabiri S, Vatandoost N, Ranjbarnejad T. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer 2023; 22:189. [PMID: 38017433 PMCID: PMC10683363 DOI: 10.1186/s12943-023-01873-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/27/2023] [Indexed: 11/30/2023] Open
Abstract
The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
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Affiliation(s)
- Matin Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fereshteh Behdarvand Dehkordi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Mohammad Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran.
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Hamidreza Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | | | - Mohammad Abdolvand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Sharareh Salmanizadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar-Jereeb Street, Isfahan, 81746-73441, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saba Ahmadi
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
| | - Sara Feizbakhshan
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saber Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Nasimeh Vatandoost
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tayebeh Ranjbarnejad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
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15
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Kollipara S, Ahmed T, Praveen S. Physiologically based pharmacokinetic modelling to predict drug-drug interactions for encorafenib. Part I. Model building, validation, and prospective predictions with enzyme inhibitors, inducers, and transporter inhibitors. Xenobiotica 2023; 53:366-381. [PMID: 37609899 DOI: 10.1080/00498254.2023.2250856] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 08/24/2023]
Abstract
Encorafenib, a potent BRAF kinase inhibitor undergoes significant metabolism by CYP3A4 (83%) and CYP2C19 (16%) and also a substrate of P-glycoprotein (P-gp). Because of this, encorafenib possesses potential for enzyme-transporter related interactions. Clinically, its drug-drug interactions (DDIs) with CYP3A4 inhibitors (posaconazole, diltiazem) were reported and hence there is a necessity to study DDIs with multiple enzyme inhibitors, inducers, and P-gp inhibitors.USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors, CYP3A4 inducers were selected and prospective DDIs were simulated using physiologically based pharmacokinetic modelling (PBPK). Impact of dose (50 mg vs. 300 mg) and staggering of administrations (0-10 h) on the DDIs were predicted.PBPK models for encorafenib, perpetrators simulated PK parameters within twofold prediction error. Clinically reported DDIs with posaconazole and diltiazem were successfully predicted.CYP2C19 inhibitors did not result in significant DDI whereas strong CYP3A4 inhibitors resulted in DDI ratio up to 4.5. Combining CYP3A4, CYP2C19 inhibitors yielded DDI equivalent CYP3A4 alone. Strong CYP3A4 inducers yielded DDI ratio up to 0.3 and no impact of P-gp inhibitors on DDIs was observed. The DDIs were not impacted by dose and staggering of administration. Overall, this work indicated significance of PBPK modelling for evaluating clinical DDIs with enzymes, transporters and interplay.
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Affiliation(s)
- Sivacharan Kollipara
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India
| | - Tausif Ahmed
- Biopharmaceutics Group, Global Clinical Management, Dr. Reddy's Laboratories Ltd., Integrated Product Development Organization (IPDO), Hyderabad, Telangana, India
| | - Sivadasu Praveen
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, Guntur, Andhra Pradesh, India
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16
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Fowler M, Tobback H, Karuri A, Fernández-Ortega P. Nursing care and management of adverse events for patients with BRAF V600E-mutant metastatic colorectal cancer receiving encorafenib in combination with cetuximab: a review. Support Care Cancer 2023; 31:204. [PMID: 36881161 PMCID: PMC9989561 DOI: 10.1007/s00520-023-07579-9] [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: 07/08/2022] [Accepted: 01/05/2023] [Indexed: 03/08/2023]
Abstract
Encorafenib is a B-Raf proto-oncogene serine/threonine-protein kinase (BRAF) inhibitor, approved in the EU and USA, in combination with the epidermal growth factor receptor (EGFR) inhibitor cetuximab, for the treatment of patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC). In the pivotal BEACON CRC trial, patients achieved longer survival with encorafenib in combination with cetuximab vs. conventional chemotherapy. This targeted therapy regimen is also generally better tolerated than cytotoxic treatments. However, patients may present with adverse events unique to the regimen and characteristic of BRAF and EGFR inhibitors, which produce their own set of challenges. Nurses play an essential role in navigating the care of patients with BRAFV600E-mutant mCRC and managing adverse events that patients may experience. This includes early and efficient identification of treatment-related adverse events, subsequent management of adverse events and education of patients and their caregivers around key adverse events. This manuscript aims to provide support to nurses managing patients with BRAFV600E-mutant mCRC receiving encorafenib in combination with cetuximab, by summarising potential adverse events and providing guidance on how to manage them. Special attention will be paid to the presentation of key adverse events, dose modifications that may be required, practical recommendations and supportive care measures.
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Affiliation(s)
- Matthew Fowler
- University Hospitals of Derby and Burton NHSFT, Uttoxeter Road, DE22 3NE, Derby, UK.
| | | | | | - Paz Fernández-Ortega
- Institut Català d'Oncologia, Granvia de l'Hospitalet, L'Hospitalet de Llobregat, Barcelona, Spain
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17
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Krstulović L, Leventić M, Rastija V, Starčević K, Jirouš M, Janić I, Karnaš M, Lasić K, Bajić M, Glavaš-Obrovac L. Novel 7-Chloro-4-aminoquinoline-benzimidazole Hybrids as Inhibitors of Cancer Cells Growth: Synthesis, Antiproliferative Activity, in Silico ADME Predictions, and Docking. Molecules 2023; 28:540. [PMID: 36677600 PMCID: PMC9866588 DOI: 10.3390/molecules28020540] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/29/2022] [Accepted: 01/02/2023] [Indexed: 01/08/2023] Open
Abstract
In this study, new 7-chloro-4-aminoquinoline-benzimidazole compounds were synthesized and characterized by NMR, MS, and elemental analysis. These novel hybrids differ in the type of linker and in the substituent on the benzimidazole moiety. Their antiproliferative activities were evaluated on one non-tumor (MDCK1) and seven selected tumor (CaCo-2, MCF-7, CCRF-CEM, Hut78, THP-1, and Raji) cell lines by MTT test and flow cytometry analysis. The compounds with different types of linkers and an unsubstituted benzimidazole ring, 5d, 8d, and 12d, showed strong cytotoxic activity (the GI50 ranged from 0.4 to 8 µM) and effectively suppressed the cell cycle progression in the leukemia and lymphoma cells. After 24 h of treatment, compounds 5d and 12d induced the disruption of the mitochondrial membrane potential as well as apoptosis in HuT78 cells. The drug-like properties and bioavailability of the compounds were calculated using the Swiss ADME web tool, and a molecular docking study was performed on tyrosine-protein kinase c-Src (PDB: 3G6H). Compound 12d showed good solubility and permeability and bound to c-Src with an energy of -119.99 kcal/mol, forming hydrogen bonds with Glu310 and Asp404 in the active site and other residues with van der Waals interactions. The results suggest that compound 12d could be a leading compound in the further design of effective antitumor drugs.
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Affiliation(s)
- Luka Krstulović
- Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
| | - Marijana Leventić
- Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
| | - Vesna Rastija
- Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
| | - Kristina Starčević
- Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
| | - Maja Jirouš
- Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
| | - Ivana Janić
- Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
| | - Maja Karnaš
- Department of Agroecology and Environmental Protection, Faculty of Agrobiotechnical Sciences Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
| | - Kornelija Lasić
- R&D, Pliva Croatia Ltd., TEVA Group Member, HR-10000 Zagreb, Croatia
| | - Miroslav Bajić
- Department of Chemistry and Biochemistry, Faculty of Veterinary Medicine, University of Zagreb, HR-10000 Zagreb, Croatia
| | - Ljubica Glavaš-Obrovac
- Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, HR-31000 Osijek, Croatia
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18
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Pang K, Wang W, Qin J, Shi Z, Hao L, Ma Y, Xu H, Wu Z, Pan D, Chen Z, Han C. Role of protein phosphorylation in cell signaling, disease, and the intervention therapy. MedComm (Beijing) 2022; 3:e175. [PMID: 36349142 PMCID: PMC9632491 DOI: 10.1002/mco2.175] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/06/2022] Open
Abstract
Protein phosphorylation is an important post-transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small-molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin-dependent protein kinase (CaMK) group, CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group, sterile (STE)-MAPKs group, tyrosine kinases (TK) group, tyrosine kinase-like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.
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Affiliation(s)
- Kun Pang
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Wei Wang
- Department of Medical CollegeSoutheast UniversityNanjingJiangsuChina
| | - Jia‐Xin Qin
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Zhen‐Duo Shi
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Lin Hao
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Yu‐Yang Ma
- Graduate SchoolBengbu Medical CollegeBengbuAnhuiChina
| | - Hao Xu
- Graduate SchoolBengbu Medical CollegeBengbuAnhuiChina
| | - Zhuo‐Xun Wu
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's University, QueensNew YorkNew YorkUSA
| | - Deng Pan
- Graduate SchoolBengbu Medical CollegeBengbuAnhuiChina
| | - Zhe‐Sheng Chen
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's University, QueensNew YorkNew YorkUSA
| | - Cong‐Hui Han
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
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19
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Dain Md Opo FA, Alsaiari AA, Rahman Molla MH, Ahmed Sumon MA, Yaghmour KA, Ahammad F, Mohammad F, Simal-Gandara J. Identification of novel natural drug candidates against BRAF mutated carcinoma; An integrative in-silico structure-based pharmacophore modeling and virtual screening process. Front Chem 2022; 10:986376. [PMID: 36267655 PMCID: PMC9577413 DOI: 10.3389/fchem.2022.986376] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/07/2022] [Indexed: 12/30/2022] Open
Abstract
The BRAF gene is responsible for transferring signals from outside of the cell to inside of the nucleus by converting a protein namely B-Raf through the RAS/MAPK pathway. This pathway contribute to cell division, proliferation, migration, and apoptotic cell death of human and animal. Mutation in this gene may cause the development of several cancers, including lung, skin, colon, and neuroblastoma. Currently, a few available drugs are being used that has developed by targeting the BRAF mutated protein, and due to the toxic side effects, patients suffer a lot during their treatment. Therefore this study aimed to identify potentially lead compounds that can target and block the expression of BRAF and subsequently inhibit the cancer. The hits were generated through the pharmacophore model-based virtual screening, molecular docking, pharmacohore model validation, ADME (absorption, distribution, metabolism, and excretion) analysis molecular dynamics (MD) simulation to find more suitable candidate against the overexpress BRAF gene. The pharmacophore based screening initially identified 14 k possible hits from online database which were further screened by ligand scout advance software to get hit compound. Based on molecular docking score of ZINC70454679 (-10.6 kcal/mol), ZINC253500968 (-9.4 kcal/mol), ZINC106887736 (-8.6 kcal/mol), and ZINC107434492 (-8.1 kcal/mol), pharmacophore feature and toxicity evaluation, we selected four possible lead compounds. The dynamic simulation with Schrodinger Maestro software was used to determine the stability of the potential lead candidates with target protein (PDB ID: 5VAM). The results showed that the newly obtained four compounds were more stable than the control ligand (Pub Chem ID: 90408826). The current results showed that the ZINC70454679, ZINC253500968, ZINC106887736, and ZINC107434492 compounds may be able to work against several cancers through targeting the BRAF overexpressed gene. To develop a novel drug candidate, however the evaluation of the web lab based experimental work are necessary to evaluate the efficiency of the each compound against the BRAF target gene.
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Affiliation(s)
- F. A. Dain Md Opo
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University (KAU), Jeddah, Saudi Arabia
- Embryonic Stem Cell Research Unit, King Fahd Medical Research Center (KFMRC), KAU, Jeddah, Saudi Arabia
| | - Ahad Amer Alsaiari
- Clinical Laboratories, Science Department, College of Applied Medical Science, Taif University, Taif, Saudi Arabia
| | | | - Md Afsar Ahmed Sumon
- Department of Marine Biology, Faculty of Marine Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Khaled A. Yaghmour
- Family Medicine Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Foysal Ahammad
- Department of Biological Science, Faculty of Sciences, King Abdulaziz University (KAU), Jeddah, Saudi Arabia
- Division of Biological and Biomedical Sciences (BBS), College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar
- *Correspondence: Foysal Ahammad, ; Farhan Mohammad, ; Jesus Simal-Gandara,
| | - Farhan Mohammad
- Division of Biological and Biomedical Sciences (BBS), College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar
- *Correspondence: Foysal Ahammad, ; Farhan Mohammad, ; Jesus Simal-Gandara,
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo, Ourense, Spain
- *Correspondence: Foysal Ahammad, ; Farhan Mohammad, ; Jesus Simal-Gandara,
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20
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New Genetic Technologies in Diagnosis and Treatment of Cancer of Unknown Primary. Cancers (Basel) 2022; 14:cancers14143429. [PMID: 35884492 PMCID: PMC9318615 DOI: 10.3390/cancers14143429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/28/2022] [Accepted: 07/05/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary The NGS and other molecular techniques creates huge hopes for effective CUP patients treatment and to select them for molecularly targeted therapies (agnostic therapies) and immunotherapy. Development of diagnostic technologies and biologically targeted therapies could make CUP’ patients access to modern therapies and change their outcome. Abstract Cancer of unknown primary (CUP) represents a rare oncological and heterogeneous disease in which one or more metastases are present, but the location of the primary site is unknown. Pathological diagnosis, using immunohistochemistry, of such metastatic materials is challenging and frequently does not allow for determining the tissue of origin (ToO). The selection of systemic therapy in patients with CUP is usually based on empiric grounds, and the prognosis is generally unfavourable. New molecular techniques could identify the tissue of origin and be used to select systemic agnostic therapies in various malignancies with specific molecular abnormalities. Targetable driver mutations or gene rearrangements in cancer cells may be identified using various molecular assays, of which particularly valuable are next-generation sequencing techniques. These assays may identify tumour sources and allow personalized treatments. However, current guidelines for CUP management do not recommend routine testing of gene expression and epigenetic factors. This is mainly due to the insufficient evidence supporting the improvement of CUP’s prognosis by virtue of this approach. This review summarizes the advantages and disadvantages of new genetic techniques in CUP diagnostics and proposes updating the recommendations for CUP management.
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21
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Xu T, Wang X, Wang Z, Deng T, Qi C, Liu D, Li Y, Ji C, Li J, Shen L. Molecular mechanisms underlying the resistance of BRAF V600E-mutant metastatic colorectal cancer to EGFR/BRAF inhibitors. Ther Adv Med Oncol 2022; 14:17588359221105022. [PMID: 35747165 PMCID: PMC9210093 DOI: 10.1177/17588359221105022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 05/16/2022] [Indexed: 11/16/2022] Open
Abstract
Background Combinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Methods Targeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS). Results In all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations (n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes (n = 6) were associated with worse PFS (p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes (n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression. Conclusion Multiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.
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Affiliation(s)
- Ting Xu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xicheng Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ting Deng
- National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Dan Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Congcong Ji
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 52 Fucheng Road, Haidian District, Beijing 100142, China
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22
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Roviello G, Lavacchi D, Antonuzzo L, Catalano M, Mini E. Liquid biopsy in colorectal cancer: No longer young, but not yet old. World J Gastroenterol 2022; 28:1503-1507. [PMID: 35582130 PMCID: PMC9048462 DOI: 10.3748/wjg.v28.i15.1503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/12/2021] [Accepted: 03/14/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. The treatment strategy employed in CRC patients is becoming highly dependent on molecular characteristics present at diagnosis and during treatment. Liquid biopsy is an emerging field in the management of this cancer, and its relevance as a potential diagnostic, prognostic, monitoring, and therapeutic tool makes it a viable strategy in the clinical management of CRC patients. Liquid biopsy also has certain limitations, but these limitations seem to be at the reach of near-future technological development. In this letter, we focus on the clinical perspectives of liquid biopsy in CRC with particular regard to the various biomarkers recently identified that have been shown to be potentially useful in multiple aspects of early stage or metastatic CRC.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze 50139, Italy
| | | | - Lorenzo Antonuzzo
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy
| | - Martina Catalano
- School of Human Health Sciences, University of Florence, Florence 50134, Italy
| | - Enrico Mini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze 50139, Italy
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23
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Angerilli V, Sabella G, Centonze G, Lonardi S, Bergamo F, Mangogna A, Pietrantonio F, Fassan M, Milione M. BRAF-mutated colorectal adenocarcinomas: Pathological heterogeneity and clinical implications. Crit Rev Oncol Hematol 2022; 172:103647. [PMID: 35248712 DOI: 10.1016/j.critrevonc.2022.103647] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 02/07/2023] Open
Abstract
Advances in molecular biology have markedly increased our understanding of the heterogeneous molecular landscape of colorectal cancer (CRC). Up to 15% of CRCs harbor the BRAF p.V600E somatic mutation (BRAFmt), a well-established negative prognostic marker in patients with metastatic CRC (mCRC). The BEACON CRC trial set a new standard of care in patients with progressive BRAFmt cancers, consisting of the combination of encorafenib and cetuximab. On these bases, BRAF mutational testing is now recommended in patients with mCRC. However, efforts are needed to further stratify patients carrying this mutation. Here, we discuss the heterogeneous pathologic and molecular landscape of BRAFmt CRCs, focusing on the promises and pitfalls of molecular diagnostics, on novel biomarkers to improve patients' stratification and on the current diagnostic scenario for CRC. We believe that a better stratification based on histopathological features and novel molecular biomarkers should be performed to optimize patient management and therapeutic decision-making.
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Affiliation(s)
| | - Giovanna Sabella
- Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Giovanni Centonze
- Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Sara Lonardi
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Francesca Bergamo
- Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, 34137 Trieste, Italy
| | | | - Matteo Fassan
- Department of Medicine, Surgical Pathology Unit, University of Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Massimo Milione
- Pathology Unit 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
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24
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Real-World Treatment Patterns and Clinical Outcomes for Standard of Care Regimens in Patients with Deficient MMR or MSI-High Metastatic Colorectal and Non-Colorectal Cancer: A Retrospective Chart Review Study in France. Adv Ther 2022; 39:1215-1229. [PMID: 35025060 DOI: 10.1007/s12325-021-01956-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/08/2021] [Indexed: 11/01/2022]
Abstract
INTRODUCTION There is limited evidence on the effectiveness of standard of care (SOC) treatments in previously treated patients with deficient mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic cancer. Immune checkpoints inhibitors (ICIs) have emerged as key treatments for dMMR/MSI-H tumors. However, clinical outcomes data with SOC regimens are still limited. Study objectives were to evaluate real-world treatment patterns and clinical outcomes in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and non-CRC receiving SOC regimens. Given the resulting small cohort of patients with metastatic non-CRC, only summary results are provided. METHODS Two French university hospitals participated in a retrospective chart review study in which adult patients with dMMR/MSI-H mCRC and non-CRC were enrolled. Treatment patterns, overall survival (OS) from the start of third-line (3L, for mCRC) or second-line (2L, for non-CRC) treatment, and the best overall response rate (BORR) were reported. RESULTS Thirty-six patients with dMMR/MSI-H mCRC were included. Almost all patients received combination treatments both in first-line (1L, 100%) and 2L (97%). For 3L and later, combination treatment was preferred over monotherapy but decreased in usage (75% at 3L and 57% at fourth-line, 4L). The BORR was 5.7% and median OS for patients with dMMR/MSI-H mCRC receiving 3L therapy was 9.0 months (95% confidence interval, CI 4.0-14.1); it decreased to 4.1 months (95% CI 4.0-9.0) when survival data of patients receiving ICIs at fourth or later lines were censored at progression date of prior treatment line. CONCLUSION Real-world clinical outcomes observed for patients with dMMR/MSI-H mCRC receiving 3L treatment(s) are suboptimal, suggesting a high unmet need that could be addressed with ICIs.
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25
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Clerk A, Meijles DN, Hardyman MA, Fuller SJ, Chothani SP, Cull JJ, Cooper ST, Alharbi HO, Vanezis K, Felkin LE, Markou T, Leonard SJ, Shaw SW, Rackham OJ, Cook SA, Glennon PE, Sheppard MN, Sembrat JC, Rojas M, McTiernan CF, Barton PJ, Sugden PH. Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo. Biochem J 2022; 479:401-424. [PMID: 35147166 PMCID: PMC8883496 DOI: 10.1042/bcj20210615] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/12/2022] [Accepted: 01/27/2022] [Indexed: 12/13/2022]
Abstract
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the 'RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a 'RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the 'RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.
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Affiliation(s)
- Angela Clerk
- School of Biological Sciences, University of Reading, Reading, U.K
| | - Daniel N. Meijles
- Molecular and Clinical Sciences Institute, St. George's University of London, London, U.K
| | | | | | - Sonia P. Chothani
- Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore City, Singapore
| | - Joshua J. Cull
- School of Biological Sciences, University of Reading, Reading, U.K
| | - Susanna T.E. Cooper
- Molecular and Clinical Sciences Institute, St. George's University of London, London, U.K
| | - Hajed O. Alharbi
- School of Biological Sciences, University of Reading, Reading, U.K
| | - Konstantinos Vanezis
- National Heart and Lung Institute, Imperial College London, London, U.K
- MRC London Institute of Medical Sciences, Imperial College London, London, U.K
| | - Leanne E. Felkin
- National Heart and Lung Institute, Imperial College London, London, U.K
- Cardiovascular Research Centre, Royal Brompton and Harefield Hospitals, London, U.K
| | - Thomais Markou
- School of Biological Sciences, University of Reading, Reading, U.K
| | | | - Spencer W. Shaw
- School of Biological Sciences, University of Reading, Reading, U.K
| | - Owen J.L. Rackham
- Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore City, Singapore
| | - Stuart A. Cook
- Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore City, Singapore
- MRC London Institute of Medical Sciences, Imperial College London, London, U.K
- National Heart Centre Singapore, Singapore City, Singapore
| | - Peter E. Glennon
- University Hospitals Coventry and Warwickshire, University Hospital Cardiology Department, Clifford Bridge Road, Coventry, U.K
| | - Mary N. Sheppard
- CRY Cardiovascular Pathology Department, St. George's Healthcare NHS Trust, London, U.K
| | - John C. Sembrat
- Division of Pulmonary, Allergy and Critical Care Medicine, and Dorothy P & Richard P Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh, Pittsburgh, U.S.A
| | - Mauricio Rojas
- Division of Pulmonary, Allergy and Critical Care Medicine, and Dorothy P & Richard P Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh, Pittsburgh, U.S.A
| | - Charles F. McTiernan
- Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, U.S.A
| | - Paul J. Barton
- National Heart and Lung Institute, Imperial College London, London, U.K
- Cardiovascular Research Centre, Royal Brompton and Harefield Hospitals, London, U.K
| | - Peter H. Sugden
- School of Biological Sciences, University of Reading, Reading, U.K
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26
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Bekele RT, Samant AS, Nassar AH, So J, Garcia EP, Curran CR, Hwang JH, Mayhew DL, Nag A, Thorner AR, Börcsök J, Sztupinszki Z, Pan CX, Bellmunt J, Kwiatkowski DJ, Sonpavde GP, Van Allen EM, Mouw KW. RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics. J Clin Invest 2021; 131:147849. [PMID: 34554931 DOI: 10.1172/jci147849] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 09/16/2021] [Indexed: 11/17/2022] Open
Abstract
Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.
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Affiliation(s)
- Raie T Bekele
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Amruta S Samant
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Amin H Nassar
- Brigham and Women's Hospital, Boston, Massachusetts, USA.,Department of Medical Oncology and
| | | | | | | | - Justin H Hwang
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Department of Medical Oncology and
| | - David L Mayhew
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Department of Medical Oncology and
| | - Anwesha Nag
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Aaron R Thorner
- Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Judit Börcsök
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | | | - Chong-Xian Pan
- VA Boston Healthcare System, Harvard Medical School, West Roxbury, Massachusetts, USA
| | - Joaquim Bellmunt
- Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - David J Kwiatkowski
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - Eliezer M Van Allen
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Department of Medical Oncology and
| | - Kent W Mouw
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Brigham and Women's Hospital, Boston, Massachusetts, USA
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27
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Giuliani J, Mantoan B, Bonetti A. Cost-effectiveness of encorafenib plus cetuximab in BRAF V600E-mutated colorectal cancer. J Oncol Pharm Pract 2021; 28:199-202. [PMID: 34581610 DOI: 10.1177/10781552211045006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Recently, the introduction of encorafenib in combination with cetuximab was considered as a practice changing in BRAFV600-mutated metastatic colorectal cancer. The aim of this paper was to assess the cost-effectiveness of encorafenib plus cetuximab in the second-line treatment of BRAFV600-mutated metastatic colorectal cancer. BEACON CRC Trail was considered. Incremental cost-effectiveness ratio was calculated as the ratio between the difference of the costs in the intervention and in the control groups (pharmacy costs) and the difference between the effect in the intervention and in the control groups (overall survival). Four hundred forty-one patients were included. Differences in costs between the two arms (encorafenib plus cetuximab vs FOLFIRI plus cetuximab) was 59 501 €, with a cost of 17 500 € per month of overall survival-gain. Combining pharmacological costs of drugs with the measure of efficacy represented by overall survival, at the actual prize encorafenib cannot be considered cost-effectiveness for second-line treatment of BRAFV600-mutated metastatic colorectal cancer.
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Affiliation(s)
- Jacopo Giuliani
- Department of Oncology, 18586Mater Salutis General Hospital, Italy
| | | | - Andrea Bonetti
- Department of Oncology, 18586Mater Salutis General Hospital, Italy
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28
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Diasio RB, Innocenti F, Offer SM. Pharmacogenomic-Guided Therapy in Colorectal Cancer. Clin Pharmacol Ther 2021; 110:616-625. [PMID: 34114648 DOI: 10.1002/cpt.2334] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 06/03/2021] [Indexed: 01/07/2023]
Abstract
Approximately 20 drugs have been shown to be effective for the treatment of colorectal cancer (CRC). These drugs are from several classes of agents and include cytotoxic drugs, therapeutics that target cell signaling pathways at the extracellular and/or intracellular levels, and combination therapies that contain multiple targeted agents and/or cytotoxic compounds. Targeted therapeutics can include monoclonal antibodies, fusion proteins, and small molecule drugs. The first introduced into clinical use was 5-fluorouracil in the early 1960s and remains the foundation for most CRC treatments in both adjuvant therapy and in advanced (metastatic) treatment regimens. As with other cancers, the consideration of biomarkers has the potential to improve CRC therapy through patient stratification. The biomarkers can include germline genetic markers, tumor-specific genetic markers, immune markers, and other biomarkers that can predict antitumor efficacy or the likelihood of toxicity prior to administration of a specific drug. Consistent with the benefit of considering biomarkers in treatment, many newer targeted therapies are developed and approved simultaneously with a companion diagnostic test to determine efficacy. This review will focus on biomarkers that have demonstrated clinical utility in CRC treatment; however, it is noted that many additional biomarkers have been theorized to contribute to drug response and/or toxicity based on known biological pathways but thus far have not attained widespread use in the clinic. The importance of pretreatment biomarker testing is expected to increase as future drug development will likely continue to focus on the concurrent development of companion diagnostics.
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Affiliation(s)
- Robert B Diasio
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.,Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota, USA
| | - Federico Innocenti
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Steven M Offer
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
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29
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Colardo M, Martella N, Pensabene D, Siteni S, Di Bartolomeo S, Pallottini V, Segatto M. Neurotrophins as Key Regulators of Cell Metabolism: Implications for Cholesterol Homeostasis. Int J Mol Sci 2021; 22:5692. [PMID: 34073639 PMCID: PMC8198482 DOI: 10.3390/ijms22115692] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/14/2022] Open
Abstract
Neurotrophins constitute a family of growth factors initially characterized as predominant mediators of nervous system development, neuronal survival, regeneration and plasticity. Their biological activity is promoted by the binding of two different types of receptors, leading to the generation of multiple and variegated signaling cascades in the target cells. Increasing evidence indicates that neurotrophins are also emerging as crucial regulators of metabolic processes in both neuronal and non-neuronal cells. In this context, it has been reported that neurotrophins affect redox balance, autophagy, glucose homeostasis and energy expenditure. Additionally, the trophic support provided by these secreted factors may involve the regulation of cholesterol metabolism. In this review, we examine the neurotrophins' signaling pathways and their effects on metabolism by critically discussing the most up-to-date information. In particular, we gather experimental evidence demonstrating the impact of these growth factors on cholesterol metabolism.
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Affiliation(s)
- Mayra Colardo
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Noemi Martella
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Daniele Pensabene
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Silvia Siteni
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Sabrina Di Bartolomeo
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
| | - Valentina Pallottini
- Department of Science, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy;
- Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Via del Fosso Fiorano 64, 00143 Rome, Italy
| | - Marco Segatto
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy; (M.C.); (N.M.); (D.P.); (S.D.B.)
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30
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Kan G, Wang Z, Sheng C, Chen G, Yao C, Mao Y, Chen S. Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004344. [PMID: 34026451 PMCID: PMC8132060 DOI: 10.1002/advs.202004344] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/28/2021] [Indexed: 05/09/2023]
Abstract
Colorectal cancer, one of the most commonly diagnosed cancers worldwide, is often accompanied by uncontrolled proliferation of tumor cells. Dyskerin pseudouridine synthase 1 (DKC1), screened using the genome-wide RNAi strategy, is a previously unidentified key regulator that promotes colorectal cancer cell proliferation. Enforced expression of DKC1, but not its catalytically inactive mutant D125A, accelerates cell growth in vitro and in vivo. DKC1 knockdown or its inhibitor pyrazofurin attenuates cell proliferation. Proteomics, RNA immunoprecipitation (RIP)-seq, and RNA decay analyses reveal that DKC1 binds to and stabilizes the mRNA of several ribosomal proteins (RPs), including RPL10A, RPL22L1, RPL34, and RPS3. DKC1 depletion significantly accelerates mRNA decay of these RPs, which mediates the oncogenic function of DKC1. Interestingly, these DKC1-regulated RPs also interact with HRAS and suppress the RAS/RAF/MEK/ERK pathway. Pyrazofurin and trametinib combination synergistically restrains colorectal cancer cell growth in vitro and in vivo. Furthermore, DKC1 is markedly upregulated in colorectal cancer tissues compared to adjacent normal tissues. Colorectal cancer patients with higher DKC1 expression has consistently poorer overall survival and progression-free survival outcomes. Taken together, these data suggest that DKC1 is an essential gene and candidate therapeutic target for colorectal cancer.
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Affiliation(s)
- Guangyan Kan
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Ziyang Wang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Chunjie Sheng
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Gong Chen
- Department of Colorectal SurgeryState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Chen Yao
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Yizhi Mao
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
| | - Shuai Chen
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouGuangdong510060P. R. China
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31
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Pisapia P, Pepe F, Iaccarino A, Sgariglia R, Nacchio M, Russo G, Gragnano G, Malapelle U, Troncone G. BRAF: A Two-Faced Janus. Cells 2020; 9:E2549. [PMID: 33260892 PMCID: PMC7760616 DOI: 10.3390/cells9122549] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/18/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022] Open
Abstract
Gain-of-function of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) is one of the most frequent oncogenic mutations in numerous cancers, including thyroid papillary carcinoma, melanoma, colon, and lung carcinomas, and to a lesser extent, ovarian and glioblastoma multiforme. This mutation aberrantly activates the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, thereby eliciting metastatic processes. The relevance of BRAF mutations stems from its prognostic value and, equally important, from its relevant therapeutic utility as an actionable target for personalized treatment. Here, we discuss the double facets of BRAF. In particular, we argue the need to implement diagnostic molecular algorithms that are able to detect this biomarker in order to streamline and refine diagnostic and therapeutic decisions.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (P.P.); (F.P.); (A.I.); (R.S.); (M.N.); (G.R.); (G.G.); (U.M.)
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32
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Sun Z, Qiu Z, Ma B, Wang Z. Encorafenib enhances TRAIL-induced apoptosis of colorectal cancer cells dependent on p53/PUMA signaling. Cytotechnology 2020; 73:63-70. [PMID: 33505114 DOI: 10.1007/s10616-020-00442-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/06/2020] [Indexed: 01/18/2023] Open
Abstract
TRAIL has been demonstrated to play a critical role in the apoptosis of colorectal cancer (CRC) cells, but drug resistance markedly restricts its therapeutic effects. Objectives: This study aims to investigate whether encorafenib can enhance TRAIL-induced apoptosis of colorectal cancer cells and the underlying mechanism. TRAIL was first used to induce CRC cells. CCK-8 assays were conducted for detecting cell viability of TRAIL-induced CRC cells with encorafenib treatment. Flow cytometry was used to detect the cell apoptosis of CRC cells and western blot was used to measure the expressions of apoptosis-related proteins. The expressions of DR4, DR5, p53, and PUMA were then evaluated by qPCR and western blot. After transfecting the interference plasmid of p53 into CRC cells, the expressions of PUMA and DR5 were further explored. TRAIL reduced the cell viability of CRC cells, and the inhibition was further reinforced under co-treatment of TRAIL and encorafenib. Encorafenib also triggered the promotion of CRC cell apoptosis induced by TRAIL. It was also found that encorafenib exerted its promoting effects on cell apoptosis of CRC cells via the elevation of DR5. Besides, encorafenib administration promoted the expression levels of p53 and PUMA in TRAIL-induced CRC cells. Furthermore, p53 knockdown attenuated the expression of PUMA and DR5 in TRAIL-induced CRC cells treated with encorafenib. This study indicates that encorafenib stimulates TRAIL-induced apoptosis of CRC cells dependent on p53/PUMA signaling, which may provide instructions for the treatment of CRC.
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Affiliation(s)
- Zhenqing Sun
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, N0.59, Haier Road, Laoshan District, Qingdao, 266100 Shandong China
| | - Zhigang Qiu
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, N0.59, Haier Road, Laoshan District, Qingdao, 266100 Shandong China
| | - Bin Ma
- Affiliated Hospital of Qingdao University, Qingdao, 266100 Shandong China
| | - Zhengkun Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, N0.59, Haier Road, Laoshan District, Qingdao, 266100 Shandong China
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33
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Parrozzani R, Lombardi G, Midena E, Londei D, Padovan M, Marchione G, Caccese M, Midena G, Zagonel V, Frizziero L. Ocular Side Effects of EGFR-Inhibitor ABT-414 in Recurrent Glioblastoma: A Long-Term Safety Study. Front Oncol 2020; 10:593461. [PMID: 33154952 PMCID: PMC7591744 DOI: 10.3389/fonc.2020.593461] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/28/2020] [Indexed: 11/27/2022] Open
Abstract
This study aimed to prospectively evaluate, on a long-term basis, corneal side effects secondary to compassionate administration of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in patients affected by EGFR-amplified recurrent glioblastoma. Fifteen patients with a median follow-up of 4.3 months after treatment discontinuation were enrolled. Each patient underwent full ophthalmologic examination including in vivo corneal confocal microscopy (CCM). No CTCAE grade 4 toxicity and four (27%) grade 3 toxicities were documented during treatment. Ocular symptoms (blurred vision, eye pain, photophobia) were experienced by all patients, reaching maximal severity after the second ABT-414 infusion, with persistence until treatment discontinuation. During treatment, CCM documented specific changes in the corneal epithelium and in the sub-basal nerve plexus layer fibers of all eyes. The median time of symptoms resolution after treatment discontinuation ranged from 38 days (eye pain) to 53 days (photophobia). The median time of signs resolution ranges from 14 days (corneal ulcer) to 38 days (superficial punctate epitheliopathy, corneal stroma edema and intraepithelial cysts). ABT-414 corneal side effects are detectable in all treated patients. Related symptoms are gradually experienced by all patients during treatment and although reversible, they are characterized by a relative prolonged persistence after treatment discontinuation.
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Affiliation(s)
| | - Giuseppe Lombardi
- Department of Oncology, Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy
| | - Edoardo Midena
- Department of Ophthalmology, University of Padova, Padova, Italy.,IRCCS-Fondazione Bietti, Rome, Italy
| | - Davide Londei
- Department of Ophthalmology, University of Padova, Padova, Italy
| | - Marta Padovan
- Department of Oncology, Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy
| | - Giulia Marchione
- Department of Ophthalmology, University of Padova, Padova, Italy
| | - Mario Caccese
- Department of Oncology, Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy
| | - Giulia Midena
- Unità Operativa Complessa Oftalmologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Vittorina Zagonel
- Department of Oncology, Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy
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Gong Y, Wang X, Zhu Z. Pseudomyxoma Peritonei Originating from Transverse Colon Mucinous Adenocarcinoma: A Case Report and Literature Review. Gastroenterol Res Pract 2020; 2020:5826214. [PMID: 32714388 PMCID: PMC7354658 DOI: 10.1155/2020/5826214] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/13/2020] [Accepted: 06/20/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Pseudomyxoma peritonei (PMP) is a rare neoplasm involving the peritoneum. Most PMPs are low-grade appendicular mucinous neoplasms (LAMNs). There have been no reports of PMP originating from a transverse colonic mucinous adenocarcinoma and causing metastatic mucinous adenocarcinoma. Case Presentation. We report a 46-year-old woman who presented with a right abdominal mass of more than 4-month duration. Transverse colonic mucinous adenocarcinoma, PMP, and ovarian metastatic mucinous adenocarcinoma were diagnosed. The patient's diet was normal, and she had no abdominal pain or bloating. The abdomen mass increased in the month before treatment. After chemotherapy, the transverse colon mass and ovarian giant cyst were resected and about 2000 mL of gelatinous tumor tissue was removed. Postoperative histology confirmed PMP from the transverse colonic mucinous adenocarcinoma, ovarian metastatic mucinous adenocarcinoma, and mesocolon metastatic cancer. Multiple lung metastases appeared 8 months after surgery. The patient died 29 months after surgery because of an inability to eat and poor nutrition. A systematic literature review of the management and outcome of all known similar cases is also presented. CONCLUSIONS This is the first report of PMP originating from a transverse colonic mucinous adenocarcinoma. It was diagnosed during resective surgery, involved ovarian metastasis, and survival was short. We did an extensive literature review in order to describe the clinical characteristics, histopathological findings, genetic profile, and potential treatments of PMP caused by nonappendiceal mucinous adenocarcinoma.
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Affiliation(s)
- Yingbo Gong
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Xin Wang
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Zhi Zhu
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
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