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Benli Y, Arıkan H, Akbulut-Çalışkan Ö. HER2-targeted therapy in colorectal cancer: a comprehensive review. Clin Transl Oncol 2025:10.1007/s12094-025-03887-0. [PMID: 40087250 DOI: 10.1007/s12094-025-03887-0] [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: 12/04/2024] [Accepted: 02/25/2025] [Indexed: 03/17/2025]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Despite treatment advancements in the last decades, CRC remains heterogeneous with significant clinical and genetic diversity. Human epidermal growth factor receptor 2 (HER2) proto-oncogene plays a critical role, as its amplification or overexpression leading to abnormal cell proliferation and tumorigenesis. HER2 overexpression or amplification is identified in 2-4% of metastatic CRCs (mCRC) patients, representing a potential therapeutic target. It is also associated with resistance against epidermal growth factor receptor (EGFR)-targeted therapies like cetuximab and panitumumab, for treatment of RAS wild-type mCRC. Although HER2-positive mCRC is rare, assessing HER2 levels is important. Furthermore, anti-HER2 therapies exhibited non-toxic profile and high efficacy in chemorefractory cases. This review delves into modern management of anti-HER2 therapies in CRC with a particular focus on recent advances and current knowledge about the prognostic and predictive value of HER2.
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Affiliation(s)
- Yeliz Benli
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Başkent University, 06790, Ankara, Turkey
| | - Helin Arıkan
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Başkent University, 06790, Ankara, Turkey
| | - Özge Akbulut-Çalışkan
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Başkent University, 06790, Ankara, Turkey.
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Cheng YC, Chen MY, Yadav VK, Pikatan NW, Fong IH, Kuo KT, Yeh CT, Tsai JT. Targeting FABP4/UCP2 axis to overcome cetuximab resistance in obesity-driven CRC with drug-tolerant persister cells. Transl Oncol 2025; 53:102274. [PMID: 39823981 PMCID: PMC11787020 DOI: 10.1016/j.tranon.2025.102274] [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: 08/18/2024] [Revised: 11/24/2024] [Accepted: 01/05/2025] [Indexed: 01/20/2025] Open
Abstract
Colorectal cancer (CRC) is closely linked to obesity, a condition that significantly impacts tumor progression and therapeutic resistance. Although cetuximab, an EGFR-targeting monoclonal antibody, is a cornerstone in metastatic CRC treatment, resistance often emerges, leading to poor outcomes. This study investigated the role of drug-tolerant persister (DTP) cells and their metabolic interactions within the tumor microenvironment (TME) in cetuximab resistance. Using patient-derived organoids and in vivo models, we identified the FABP4/UCP2 axis as a critical mediator of resistance. Organoids derived from cetuximab non-responders revealed upregulated FABP4 and UCP2 expression post-treatment. Coculture experiments with adipocytes showed that FABP4 and UCP2 promote lipid metabolic reprogramming, facilitating cancer cell survival in a dormant state. CRISPR/Cas9 mediated inhibition of FABP4 disrupted this metabolic interaction, sensitising resistant cells to cetuximab. In vivo, the FABP4 inhibitor BMS309403, either alone or in combination with cetuximab, significantly reduced tumor growth in resistant CRC models, highlighting its therapeutic potential. These findings establish the FABP4/UCP2 axis as a pivotal driver of cetuximab resistance in obesity-associated CRC and suggest that targeting this metabolic pathway could improve outcomes in DTP-resistant CRC patients.
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Affiliation(s)
- Yi-Chiao Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan
| | - Ming-Yao Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Vijesh Kumar Yadav
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Narpati Wesa Pikatan
- Division of Urology, Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Iat-Hang Fong
- Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan
| | - Kuang-Tai Kuo
- Department of Surgery, Division of Thoracic Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
| | - Chi-Tai Yeh
- Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan.
| | - Jo-Ting Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Radiology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
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Zhai K, Liu G, Cao C, Wang X. Jujuboside B inhibits proliferation and induces apoptosis and ferroptosis in colorectal cancer cells with potential involvement of the MAPK signaling pathway. Oncol Lett 2025; 29:162. [PMID: 39911154 PMCID: PMC11795164 DOI: 10.3892/ol.2025.14908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 01/07/2025] [Indexed: 02/07/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and life-threatening malignancies worldwide. Jujuboside B (JUB) is a bioactive compound derived from the seeds of Ziziphus jujuba, known for its potential anticancer properties. The present study aimed to investigate the association of JUB with inhibiting the proliferation, apoptosis and ferroptosis of human CRC cells with mitogen-activated protein kinase (MAPK) pathway regulation. First, the human CRC HCT116 cell line was treated with different concentrations of JUB. Subsequently, cell viability was evaluated using MTT assay and colony formation was assessed using a colony formation assay. Flow cytometry was used to detect cell apoptosis and the levels of reactive oxygen species. Western blotting was utilized to assess the expression levels of apoptosis-related proteins, ferroptosis regulators and MAPK pathway-related proteins. In addition, biochemical assay kits were used to evaluate the levels of malondialdehyde, glutathione, total iron and ferrous iron. The results demonstrated that cell viability and colony formation were markedly decreased after JUB treatment, whilst the level of apoptosis was notably increased in a concentration-dependent manner. Using electron microscopy, cells treated with JUB exhibited typical apoptotic bodies, as well as mitochondrial swelling and cristae disruption, further demonstrating JUB-induced cell apoptosis. Western blot analysis indicated that JUB treatment markedly reduced the expression of B-cell lymphoma-2 (Bcl-2) but notably increased the expression of Bcl-2 associated X-protein and cleaved caspase-3. Additionally, JUB induced ferroptosis and inhibited the MAPK signaling pathway in CRC cells. Collectively, the findings of the present study suggest that JUB has the potential to inhibit CRC cell proliferation and induce apoptosis through regulating the MAPK pathway. Therefore, JUB may be a promising therapeutic agent for the treatment of CRC.
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Affiliation(s)
- Ke Zhai
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Guodong Liu
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Ce Cao
- Department of Gastrointestinal Surgery, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
| | - Xiaolong Wang
- Department of Gastrointestinal Surgery, Zibo Central Hospital, Zibo, Shandong 255036, P.R. China
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Muradi Muhar A, Velaro AJ, Prananda AT, Nugraha SE, Halim P, Syahputra RA. Precision medicine in colorectal cancer: genomics profiling and targeted treatment. Front Pharmacol 2025; 16:1532971. [PMID: 40083375 PMCID: PMC11903709 DOI: 10.3389/fphar.2025.1532971] [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: 11/27/2024] [Accepted: 02/11/2025] [Indexed: 03/16/2025] Open
Abstract
Precision medicine has revolutionized the treatment of colorectal cancer by enabling a personalized approach tailored to each patient's unique genetic characteristics. Genomic profiling allows for the identification of specific mutations in genes such as KRAS, BRAF, and PIK3CA, which play a crucial role in cell signaling pathways that regulate cell proliferation, apoptosis, and differentiation. This information enables doctors to select targeted therapies that inhibit specific molecular pathways, maximizing treatment effectiveness and minimizing side effects. Precision medicine also facilitates adaptive monitoring of tumor progression, allowing for adjustments in therapy to maintain treatment effectiveness. While challenges such as high costs, limited access to genomic technology, and the need for more representative genomic data for diverse populations remain, collaboration between researchers, medical practitioners, policymakers, and the pharmaceutical industry is crucial to ensure that precision medicine becomes a standard of care accessible to all. With continued advances and support, precision medicine has the potential to improve treatment outcomes, reduce morbidity and mortality rates, and enhance the quality of life for colorectal cancer patients worldwide.
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Affiliation(s)
- Adi Muradi Muhar
- Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Adrian Joshua Velaro
- Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Arya Tjipta Prananda
- Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Sony Eka Nugraha
- Department of Pharmaceutical Biology, Universitas Sumatera Utara, Medan, Indonesia
| | - Princella Halim
- Department of Pharmacology, Universitas Sumatera Utara, Medan, Indonesia
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Sun F, Yao F, Zeng C, Zhao Y, Liang B, Li S, Wang Y, Wu Q, Shi Y, Yao Z, Wang J, Jiang Y, Gu C, Huang Q, Liao W, Huang N, Wang C, Rong X, Wu J, Tan Y, Peng J, Li Y, Shi M. Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation. J Immunother Cancer 2025; 13:e010126. [PMID: 39947814 PMCID: PMC11831272 DOI: 10.1136/jitc-2024-010126] [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: 07/18/2024] [Accepted: 01/07/2025] [Indexed: 02/19/2025] Open
Abstract
BACKGROUND Patients with microsatellite stable (MSS) colorectal cancer (CRC) often display resistance to immunotherapy. Epidermal growth factor receptor (EGFR)-targeted therapies have shown potential in enhancing immunotherapy, yet clinical benefits remain unfulfilled, which may relate to inadequate patient stratification. METHODS Circulating tumor cells and tumor tissues were collected from multicenter cohorts of patients with CRC receiving cetuximab to analyze EGFR variant type III (EGFRvIII) expression and immune infiltration. Syngeneic mouse models of EGFRvIII CRC were used to investigate the combined efficacy of adenosine inhibition and antiprogrammed cell death protein 1 (anti-PD-1). RESULTS EGFRvIII mutations are found in about 10% of MSS CRC and are associated with poor response to cetuximab therapy. EGFRvIII-mutated patients with CRC exhibit an adenosine-mediated immunosuppressive tumor microenvironment (TME) subtype. Combination therapy with adenosine inhibitors remodels the TME, reversing cetuximab resistance and enhancing anti-PD-1 efficacy in EGFRvIII CRC. CONCLUSIONS Our findings identified EGFRvIII-positive CRC as a distinct subtype characterized by adenosine-mediated immunosuppressive TME. Targeting adenosine significantly improved the efficacy of anti-PD-1 in MSS CRC.
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Affiliation(s)
- Fei Sun
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Fangzhen Yao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunting Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yang Zhao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Bishan Liang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shaowei Li
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yawen Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qijing Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yulu Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhiqi Yao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiao Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yu Jiang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunhui Gu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Na Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunlin Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoxiang Rong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jing Wu
- Department of Oncology, The First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Yujing Tan
- Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianjun Peng
- Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yong Li
- Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Lawal AO, Ogunniyi TJ, Oludele OI, Olorunfemi OA, Okesanya OJ, Ogaya JB, Manirambona E, Ahmed MM, Lucero-Prisno DE. Innovative laboratory techniques shaping cancer diagnosis and treatment in developing countries. Discov Oncol 2025; 16:137. [PMID: 39921787 PMCID: PMC11807038 DOI: 10.1007/s12672-025-01877-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 02/03/2025] [Indexed: 02/10/2025] Open
Abstract
Cancer is a major global health challenge, with approximately 19.3 million new cases and 10 million deaths estimated by 2020. Laboratory advancements in cancer detection have transformed diagnostic capabilities, particularly through the use of biomarkers that play crucial roles in risk assessment, therapy selection, and disease monitoring. Tumor histology, single-cell technology, flow cytometry, molecular imaging, liquid biopsy, immunoassays, and molecular diagnostics have emerged as pivotal tools for cancer detection. The integration of artificial intelligence, particularly deep learning and convolutional neural networks, has enhanced the diagnostic accuracy and data analysis capabilities. However, developing countries face significant challenges including financial constraints, inadequate healthcare infrastructure, and limited access to advanced diagnostic technologies. The impact of COVID-19 has further complicated cancer management in resource-limited settings. Future research should focus on precision medicine and early cancer diagnosis through sophisticated laboratory techniques to improve prognosis and health outcomes. This review examines the evolving landscape of cancer detection, focusing on laboratory research breakthroughs and limitations in developing countries, while providing recommendations for advancing tumor diagnostics in resource-constrained environments.
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Affiliation(s)
- Azeez Okikiola Lawal
- Department of Medical Laboratory Science, Kwara State University, Malete, Nigeria
| | | | | | | | - Olalekan John Okesanya
- Department of Public Health and Maritime Transport, University of Thessaly, Volos, Greece
| | - Jerico Bautista Ogaya
- Department of Medical Technology, Institute of Health Sciences and Nursing, Far Eastern University, Manila, Philippines
| | | | | | - Don Eliseo Lucero-Prisno
- Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK
- Research and Innovation Office, Southern Leyte State University, Leyte, Philippines
- Research and Development Office, Biliran Province State University, Biliran, Philippines
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Zhang L, Liu S, Ding K, Zeng B, Li B, Zhou J, Li J, Wang J, Su X, Sun R. Yanghe decoction inhibits inflammation-induced lung metastasis of colorectal cancer. JOURNAL OF ETHNOPHARMACOLOGY 2025; 340:119257. [PMID: 39694428 DOI: 10.1016/j.jep.2024.119257] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 12/07/2024] [Accepted: 12/15/2024] [Indexed: 12/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Positive deficiency and cancer toxicity are the main pathogenesis of colorectal cancer (CRC) lung metastasis. Yanghe decoction (YHD), a traditional Chinese medicine, has the effects of warming yang, tonifying blood, dispersing cold and clearing stagnation, adopting a treatment method that combines supporting the right and dispelling the wrong, which has remarkable efficacy in anti-tumor.Although, its precise mechanism of inhibiting the metastasis of colorectal cancer to the lung is still poorly understood. AIM OF THE STUDY This study aimed to elucidate the antitumor properties of YHD within the context of colorectal cancer lung metastasis. MATERIALS AND METHODS Ultrahigh-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) was utilized to analyze the chemical composition of YHD. The anticancer activity of YHD was evaluated in a CRC lung metastasis mouse model by quantifying pulmonary metastatic nodules. The effects of YHD on CRC cell proliferation, apoptosis, cell cycle progression, and invasion were assessed using CCK-8 assays, flow cytometry, and Transwell assays. YHD-mediated immune modulation in tumor-bearing mice was evaluated by analyzing antitumor immunity, immunosuppressive cells, and cytokines in peripheral blood and tumor tissue. Gut microbiota analysis was conducted to determine the impact of YHD on the gut microbiota in mice. RESULTS Our analysis identified 1801 chemical markers in YHD. CFA exacerbated lung metastasis in CRC, whereas oral administration of YHD significantly mitigated this effect, as evidenced by the reduced number of metastatic lung nodules in CRC tumor-bearing mice. In vitro experiments demonstrated that YHD inhibits CRC cell proliferation, induces apoptosis, and suppresses invasion. In the lung tissues of mice with CRC metastasis treated with CFA, there was a significant reduction in NK cells and IL-21, along with an increase in M2 macrophages and IL-6. Following YHD treatment, there was a notable increase in NK cells and IL-21, accompanied by a decrease in M2 macrophages and IL-6 in lung tissues. YHD administration was also associated with an increase in beneficial bacterial species such as Bacillus and a decrease in deleterious bacterial species such as Oscillibacter. CONCLUSION Our findings demonstrate that YHD inhibits lung metastasis in CRC by suppressing CRC cell proliferation and invasion, in addition to modulating the tumor microenvironment to favor antitumor immunity. These results provide a scientific basis for the clinical application of YHD in the treatment of CRC patients.
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Affiliation(s)
- Lu Zhang
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Songyu Liu
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Kai Ding
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Bin Zeng
- Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Bo Li
- Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China
| | - Jinyi Zhou
- Department of Neurosurgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China
| | - Jv Li
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Junliang Wang
- Scientific Research and Experimental Center, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Xiaosan Su
- Scientific Research and Experimental Center, Yunnan University of Chinese Medicine, Kunming, 650500, China.
| | - Ruifen Sun
- School of Nursing, Yunnan University of Chinese Medicine, Kunming, 650500, China.
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Shouki B, Abdelsalam A, Abdullah AS, Kanan A, Ahmed AS, Emad D, Volker H, Mohamed A, Aref C, Mohammed A, Dina H, Maroun K, Ajit V, Mervat M, Kakil R, Shereef E, Diaeddine T. Management of metastatic colorectal cancer: consensus in the Gulf Cooperation Council countries. Ther Adv Med Oncol 2025; 17:17588359241299324. [PMID: 39759829 PMCID: PMC11700394 DOI: 10.1177/17588359241299324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 10/25/2024] [Indexed: 01/07/2025] Open
Abstract
Colorectal cancer (CRC) represents a major public health challenge globally, particularly in the Gulf Cooperation Council (GCC) countries, where it is identified as the second most prevalent form of cancer. Despite advancements in management strategies, tailored guidelines specific to the Gulf region are lacking. This paper presents consensus recommendations developed by a panel of experts from the GCC countries to address this gap. The guidelines cover epidemiology, screening, biomarkers, and treatment strategies for metastatic CRC. Treatment guidelines emphasize tailored approaches based on tumor characteristics, including sidedness and molecular profiles. Furthermore, the importance of maintenance therapy and emerging biomarkers are discussed. These guidelines aim to improve CRC management and outcomes in the Gulf region.
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Affiliation(s)
- Bazarbashi Shouki
- King Faisal Specialist Hospital & Research Center, Riyadh, Kingdom of Saudi Arabia
| | | | | | - Alshammari Kanan
- King Abdulaziz Medical City, Ministry of National Guard for Health Affairs, Riyadh, Kingdom of Saudi Arabia
| | - Al Sherhi Ahmed
- King Saud bin Abdulaziz University for Health Sciences, Jeddah, Kingdom of Saudi Arabia
| | - Dawoud Emad
- Tawam Hospital, Al Ain, United Arab Emirates
| | - Heinemann Volker
- Cancer Center, CCC Munich—Comprehensive Cancer Center, Munich, Germany
| | | | - Chehal Aref
- Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
| | - Alghamdi Mohammed
- Oncology Center, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Hamza Dina
- Dubai Health Authority, Dubai, United Arab Emirates
| | | | - Venniyoor Ajit
- National Oncology Center, The Royal Hospital, Muscat, Sultanate of Oman
| | - Mahrous Mervat
- Prince Sultan Military Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Rasul Kakil
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | - Elsamany Shereef
- King Abdullah Medical City Oncology Center, Makkah, Kingdom of Saudi Arabia
| | - Trad Diaeddine
- Tawam Hospital, po box 15254, Al Ain, United Arab Emirates
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9
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de Moraes FCA, de Oliveira Rodrigues ALS, Priantti JN, Limachi-Choque J, Burbano RMR. Efficacy and Safety of Anti-EGFR Therapy Rechallenge in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. J Gastrointest Cancer 2024; 56:9. [PMID: 39436445 DOI: 10.1007/s12029-024-01128-1] [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: 09/10/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) represents the second leading cause of cancer-related mortality worldwide, with a significant portion of patients presenting with metastatic disease at diagnosis. Resistance to initial anti-EGFR therapy, a key treatment for RAS wild-type metastatic CRC, remains a major challenge. This study aimed to assess the efficacy and safety of rechallenge with anti-EGFR therapy in patients with metastatic CRC who have progressed after prior treatments. METHODS A systematic search was conducted across PubMed, Web of Science, Cochrane, and Scopus. Studies were included if they were randomized controlled trials (RCTs) or observational studies involving patients with EGFR-mutated metastatic CRC who received anti-EGFR therapy as a rechallenge. Endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events. Statistical analyses were performed using the DerSimonian/Laird random effect model, with heterogeneity assessed via I2 statistics. R, version 4.2.3, was used for statistical analyses. RESULTS Fourteen studies were included with 520 patients; 50.3% were male, and the median age was 63 years old. The median progression-free survival (mPFS) ranged between 2.4 and 4.9 months, while the median overall survival (mOS) ranged from 5 to 17.8 months. Our pooled analysis demonstrated an objective response rate (ORR) of 17.70% (95% CI, 8.58-26.82%) and a disease control rate (DCR) of 61.72% (95% CI, 53.32-70.11%), both with significant heterogeneity (I2, 84% and 80%, respectively; p < 0.01). In the subgroup analysis, cetuximab showed an ORR of 18.31% (95% CI, 4.67-31.94%), and panitumumab an ORR of 10.9% (95% CI, 0.00-26.82%), while the combination of both resulted in an ORR of 29.24% (95% CI, 0.00-65.84%). For DCR, cetuximab resulted in 62.1% (95% CI, 49.32-74.87%), panitumumab in 63.05% (95% CI, 52.13-73.97%), and the combination in 60.34% (95% CI, 31.92-88.77%), all with significant heterogeneity. Adverse events included anemia (15.39%), diarrhea (4.20%), hypomagnesemia (6.40%), neutropenia (22.57%), and skin rash (13.22%). CONCLUSIONS Rechallenge with anti-EGFR therapy in metastatic CRC patients shows moderate efficacy with manageable safety profiles. These findings highlight the need for careful patient selection and monitoring to optimize outcomes. Further studies are warranted to refine strategies for maximizing the therapeutic benefits of anti-EGFR rechallenge.
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10
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Kubaichuk K, Seitz T, Bergmann U, Glumoff V, Mennerich D, Kietzmann T. Ubiquitin-specific protease 10 determines colorectal cancer outcome by modulating epidermal growth factor signaling via inositol polyphosphate-4-phosphatase type IIB. Oncogenesis 2024; 13:37. [PMID: 39394169 PMCID: PMC11479595 DOI: 10.1038/s41389-024-00538-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 09/17/2024] [Accepted: 09/19/2024] [Indexed: 10/13/2024] Open
Abstract
Although there have been advances in understanding colorectal cancer (CRC) pathogenesis, significant gaps still exist, highlighting the need for deeper insights. Dysregulated protein homeostasis, including perturbations in the epidermal growth factor receptor (EGFR) pathway, remains a focal point in CRC pathogenesis. Within this context, the roles of ubiquitin ligases and deubiquitinases have attracted attention, but exploration of their precise contributions is still in its early stages. To address this gap, we investigated the involvement of the deubiquitinase USP10 in CRC. Our in vitro and in vivo study reveals a new paradigm in CRC biology and unravels a novel mechanistic axis, demonstrating for the first time the involvement of inositol polyphosphate 4-phosphatase type II B (INPP4B) in USP10-mediated CRC modulation. Specifically, our study demonstrates that the loss of USP10 results in reduced sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and osimertinib. This is accompanied by a decrease in the activation of the AKT1/PKB pathway upon EGF stimulation, which is mediated by INPP4B. Importantly, in vivo xenograft experiments validate these findings and highlight the crucial role of USP10, particularly in conjunction with INPP4B, in driving CRC progression. The findings enhance our understanding of CRC pathobiology and reveal a new regulatory axis involving USP10 and INPP4B in CRC progression. This unique insight identifies USP10 and INPP4B as potential therapeutic targets in CRC.
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Affiliation(s)
- Kateryna Kubaichuk
- Faculty of Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
| | - Timo Seitz
- Institute of Biomedicine, Faculty of Medicine, Food Sciences Unit, Faculty of Technology, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Ulrich Bergmann
- Faculty of Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
| | - Virpi Glumoff
- Faculty of Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
| | - Daniela Mennerich
- Faculty of Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
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11
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Tardito S, Matis S, Zocchi MR, Benelli R, Poggi A. Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance. Int J Mol Sci 2024; 25:7131. [PMID: 39000238 PMCID: PMC11241078 DOI: 10.3390/ijms25137131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 06/22/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, the need for new therapeutic strategies is still a challenge. Surgery and chemotherapy represent the first-line interventions; nevertheless, the prognosis for metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from the inhibition of the epidermal growth factor receptor (EGFR) pathway, by the anti-EGFR antibody, Cetuximab, or by specific tyrosine kinase inhibitors (TKI). Cetuximab, a mouse-human chimeric monoclonal antibody (mAb), binds to the extracellular domain of EGFR thus impairing EGFR-mediated signaling and reducing cell proliferation. TKI can affect the EGFR biochemical pathway at different steps along the signaling cascade. Apart from Cetuximab, other anti-EGFR mAbs have been developed, such as Panitumumab. Both antibodies have been approved for the treatment of KRAS-NRAS wild type mCRC, alone or in combination with chemotherapy. These antibodies display strong differences in activating the host immune system against CRC, due to their different immunoglobulin isotypes. Although anti-EGFR antibodies are efficient, drug resistance occurs with high frequency. Resistant tumor cell populations can either already be present before therapy or develop later by biochemical adaptations or new genomic mutations in the EGFR pathway. Numerous efforts have been made to improve the efficacy of the anti-EGFR mAbs or to find new agents that are able to block downstream EGFR signaling cascade molecules. Indeed, we examined the importance of analyzing the anti-EGFR antibody-drug conjugates (ADC) developed to overcome resistance and/or stimulate the tumor host's immunity against CRC growth. Also, patient-derived CRC organoid cultures represent a useful and feasible in vitro model to study tumor behavior and therapy response. Organoids can reflect tumor genetic heterogeneity found in the tissue of origin, representing a unique tool for personalized medicine. Thus, CRC-derived organoid cultures are a smart model for studying the tumor microenvironment and for the preclinical assay of anti-EGFR drugs.
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Affiliation(s)
- Samuele Tardito
- Center for Cancer and Immunology Research, Children’s National Hospital, Washington, DC 20010, USA;
| | - Serena Matis
- Molecular Oncology and Angiogenesis Unit, IRRCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Maria Raffaella Zocchi
- Department of Immunology, Transplant and Infectious Diseases, IRCCS Scientific Institute San Raffaele, 20132 Milan, Italy;
| | - Roberto Benelli
- Molecular Oncology and Angiogenesis Unit, IRRCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, IRRCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
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12
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Zhou Y, Wu S, Qu FJ. Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer. World J Gastrointest Oncol 2024; 16:2362-2379. [PMID: 38994135 PMCID: PMC11236217 DOI: 10.4251/wjgo.v16.i6.2362] [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: 12/07/2023] [Revised: 02/13/2024] [Accepted: 04/01/2024] [Indexed: 06/14/2024] Open
Abstract
More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.
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Affiliation(s)
- Yi Zhou
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
| | - Shuang Wu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
| | - Fan-Jie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian 116033, Liaoning Province, China
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13
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Tufail M, Wan WD, Jiang C, Li N. Targeting PI3K/AKT/mTOR signaling to overcome drug resistance in cancer. Chem Biol Interact 2024; 396:111055. [PMID: 38763348 DOI: 10.1016/j.cbi.2024.111055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/06/2024] [Accepted: 05/13/2024] [Indexed: 05/21/2024]
Abstract
This review comprehensively explores the challenge of drug resistance in cancer by focusing on the pivotal PI3K/AKT/mTOR pathway, elucidating its role in oncogenesis and resistance mechanisms across various cancer types. It meticulously examines the diverse mechanisms underlying resistance, including genetic mutations, feedback loops, and microenvironmental factors, while also discussing the associated resistance patterns. Evaluating current therapeutic strategies targeting this pathway, the article highlights the hurdles encountered in drug development and clinical trials. Innovative approaches to overcome resistance, such as combination therapies and precision medicine, are critically analyzed, alongside discussions on emerging therapies like immunotherapy and molecularly targeted agents. Overall, this comprehensive review not only sheds light on the complexities of resistance in cancer but also provides a roadmap for advancing cancer treatment.
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Affiliation(s)
- Muhammad Tufail
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Dong Wan
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Canhua Jiang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China; Institute of Oral Precancerous Lesions, Central South University, Changsha, China; Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Li
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China; Institute of Oral Precancerous Lesions, Central South University, Changsha, China; Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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14
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Hajjafari A, Sadr S, Rahdar A, Bayat M, Lotfalizadeh N, Dianaty S, Rezaei A, Moghaddam SP, Hajjafari K, Simab PA, Kharaba Z, Borji H, Pandey S. Exploring the integration of nanotechnology in the development and application of biosensors for enhanced detection and monitoring of colorectal cancer. INORG CHEM COMMUN 2024; 164:112409. [DOI: 10.1016/j.inoche.2024.112409] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/19/2024]
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15
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Chen N, He L, Zou Q, Deng H. HER2 targeted therapy in colorectal Cancer: Current landscape and future directions. Biochem Pharmacol 2024; 223:116101. [PMID: 38442793 DOI: 10.1016/j.bcp.2024.116101] [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: 08/31/2023] [Revised: 02/11/2024] [Accepted: 02/27/2024] [Indexed: 03/07/2024]
Abstract
Colorectal cancer (CRC) is one of the most common causes of tumor-related deaths globally. Despite recent improvements in the comprehensive therapy of malignancy, metastatic CRC continues to have a poor prognosis. Human epidermal growth factor receptor 2 (HER2) is an established oncogenic driver, which is successfully targeted for breast and gastric cancers. Approximately 5% of CRC patients carry somatic HER2 mutations or gene amplification. In 2019, the U.S. Food and Drug Administration have approved trastuzumab and pertuzumab in combination with chemotherapy for the treatment of HER2-positive metastatic CRC. This approval marked a significant milestone in the treatment of CRC, as HER2-positive patients now have access to targeted therapies that can improve their outcomes. Yet, assessment for HER2 overexpression/ amplification in CRC has not been standardized. The resistance mechanisms to anti-HER2 therapy have been not clearly investigated in CRC. Although many unknowns remain, an improved understanding of these anti-HER2 agents will be essential for advanced CRC. In this review, we provide an overview of the role of HER2 in CRC as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target, as well as the current progress and challenges in the field.
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Affiliation(s)
- Na Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China; Center of Science and Research, Chengdu Medical College, Chengdu, 610500, China
| | - Ling He
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Qiang Zou
- Center of Science and Research, Chengdu Medical College, Chengdu, 610500, China.
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, China.
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16
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Lawler T, Parlato L, Warren Andersen S. The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis. Front Oncol 2024; 14:1349572. [PMID: 38737895 PMCID: PMC11082351 DOI: 10.3389/fonc.2024.1349572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Background Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes. Methods We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC. Results In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent. Discussion A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.
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Affiliation(s)
- Thomas Lawler
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Shaneda Warren Andersen
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
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17
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Zhou YW, Zhao X, Ni L, Cao P, Leng WB, Zhu Q, Gou HF, Zhang J, Li XF, Qiu M. Dynamic ctDNA-based analysis of drug-resistant gene alterations at RAS/BRAF wild-type metastatic colorectal cancer patients after cetuximab plus chemotherapy as the first-line treatment. Int Immunopharmacol 2024; 131:111887. [PMID: 38503018 DOI: 10.1016/j.intimp.2024.111887] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND The purpose of this study was to explore the dynamic changes of genomic mutations and their correlations with the efficacy in metastatic colorectal cancer (mCRC) patients treated with cetuximab plus mFOLFOX as the first-line treatment. METHODS We included mCRC patients from January 2018 to October 2020 as a studied cohort which were treated with cetuximab plus mFOLFOX as first line therapy. Blood samples were collected for circulating tumor DNA (ctDNA) test at three timepoints: before the first-line therapy(baseline), at the time of first-line progression and at the time of second-line progression. Progression-free survival was considered as the primary endpoint while objective response rate and overall survival were determined as the secondary endpoints. RESULTS Totally 39 patients received first-line treatment, of which 25 patients entered the second-line treatment, while 10 patients entered the third-line treatment. The median follow-up time was 16.4 months (95 %CI, 14.8-19.3). Along the treatment from first-line progress disease (PD) to second-line PD, proportions of TP53 (12/18, 67 %), APC (10/18, 56 %), FBXW7 (3/18, 17 %), and AMER1 (2/18, 11 %) were gradually increased according to results of single nucleotide variation (SNV). CONCLUSIONS Resistant gene mutations caused by anti-EGFR drugs in RAS/BRAF wild-type mCRC patients can be observed by dynamic ctDNA analysis. TP53 and AMER1 mutations, tumor mutational burden (TMB) levels, and TP53/AMER1 co-mutation may predict the efficacy of the first-line cetuximab-contained treatment. Situations of genetic mutations were differentiated from first-line PD to second-line PD, which indicated that mutation detection may contribute to predict prognosis of mCRC patients.
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Affiliation(s)
- Yu-Wen Zhou
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Zhao
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Ni
- Department of Oncology, Mianyang Central Hospital, Sichuan Province, China
| | - Peng Cao
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Bing Leng
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Zhu
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu 610041, Sichuan Province, China
| | - Hong-Feng Gou
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu 610041, Sichuan Province, China
| | - Jiao Zhang
- Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, Suite C, 1310-1318, Xishan District, Wuxi City, Jiangsu 214104, China
| | - Xiao-Fen Li
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu 610041, Sichuan Province, China
| | - Meng Qiu
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China.
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18
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Veiga RN, de Azevedo ALK, de Oliveira JC, Gradia DF. Targeting EphA2: a promising strategy to overcome chemoresistance and drug resistance in cancer. J Mol Med (Berl) 2024; 102:479-493. [PMID: 38393661 DOI: 10.1007/s00109-024-02431-x] [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: 03/29/2023] [Revised: 01/24/2024] [Accepted: 02/11/2024] [Indexed: 02/25/2024]
Abstract
Erythropoietin-producing hepatocellular A2 (EphA2) is a vital member of the Eph tyrosine kinase receptor family and has been associated with developmental processes. However, it is often overexpressed in tumors and correlates with cancer progression and worse prognosis due to the activation of its noncanonical signaling pathway. Throughout cancer treatment, the emergence of drug-resistant tumor cells is relatively common. Since the early 2000s, researchers have focused on understanding the role of EphA2 in promoting drug resistance in different types of cancer, as well as finding efficient and secure EphA2 inhibitors. In this review, the current knowledge regarding induced resistance by EphA2 in cancer treatment is summarized, and the types of cancer that lead to the most cancer-related deaths are highlighted. Some EphA2 inhibitors were also investigated. Regardless of whether the cancer treatment has reached a drug-resistance stage in EphA2-overexpressing tumors, once EphA2 is involved in cancer progression and aggressiveness, targeting EphA2 is a promising therapeutic strategy, especially in combination with other target-drugs for synergistic effect. For that reason, monoclonal antibodies against EphA2 and inhibitors of this receptor should be investigated for efficacy and drug toxicity.
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Affiliation(s)
- Rafaela Nasser Veiga
- Laboratory of Human Cytogenetics and Oncogenetics, Postgraduate Program in Genetics. Department of Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil
| | - Alexandre Luiz Korte de Azevedo
- Laboratory of Human Cytogenetics and Oncogenetics, Postgraduate Program in Genetics. Department of Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil
| | - Jaqueline Carvalho de Oliveira
- Laboratory of Human Cytogenetics and Oncogenetics, Postgraduate Program in Genetics. Department of Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil
| | - Daniela Fiori Gradia
- Laboratory of Human Cytogenetics and Oncogenetics, Postgraduate Program in Genetics. Department of Genetics, Universidade Federal Do Paraná, Rua Coronel Francisco Heráclito Dos Santos, 100, Jardim das AméricasCuritiba, CEP, 81531-980, Brazil.
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Hassan AF, Hussein O, Al-Barazenji T, Allouch A, Kamareddine L, Malki A, Moustafa AA, Khalil A. The effect of novel nitrogen-based chalcone analogs on colorectal cancer cells: Insight into the molecular pathways. Heliyon 2024; 10:e27002. [PMID: 38463818 PMCID: PMC10923686 DOI: 10.1016/j.heliyon.2024.e27002] [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: 07/03/2023] [Revised: 02/12/2024] [Accepted: 02/22/2024] [Indexed: 03/12/2024] Open
Abstract
In colorectal cancer (CRC), aberrations in KRAS are associated with aggressive tumorigenesis and an overall low survival rate because of chemoresistance and adverse effects. Ergo, complementary, and integrative medicines are being considered for CRC treatment. Among which is the use of natural chalcones that are known to exhibit anti-tumor activities in KRAS mutant CRC subtypes treatment regimens. Consequently, we examine the effect of two novel compounds (DK13 and DK14) having chalcones with nitrogen mustard moiety on CRC cell lines (HCT-116 and LoVo) with KRAS mutation. These compounds were synthesized in our lab and previously reported to exhibit potent activity against breast cancer cells. Our data revealed that DK13 and DK14 treatment suppress cell growth, disturb the progression of cell cycle, and trigger apoptosis in CRC cell lines. Besides, treatment with both compounds impedes cell invasion and colony formation in both cell lines as compared to 5-FU; this is accompanied by up and down regulations of E-cadherin and Vimentin, respectively. At the molecular level, both compounds deregulate the expression and phosphorylation of β-catenin, Akt and mTOR, which are the main likely molecular mechanisms underlying these biological occurrences. Our findings present DK13 and DK14 as novel chemotherapies against CRC, through β-catenin/Akt/mTOR signaling pathways.
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Affiliation(s)
- Arij Fouzat Hassan
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Ola Hussein
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Tara Al-Barazenji
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Asma Allouch
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Layla Kamareddine
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
- Biomedical Research Centre, Qatar University, Doha, Qatar
| | - Ahmed Malki
- Department of Biomedical Science, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Ala‐Eddin Al Moustafa
- Biomedical Research Centre, Qatar University, Doha, Qatar
- College of Medicine, QU Health, Qatar University, Doha, Qatar
- Oncology Department, McGill University, Montreal, QC, Canada
| | - Ashraf Khalil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
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20
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Gmeiner WH. Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment. Cancers (Basel) 2024; 16:1029. [PMID: 38473386 PMCID: PMC10930828 DOI: 10.3390/cancers16051029] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/24/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.
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Affiliation(s)
- William H Gmeiner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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21
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Lawler T, Parlato L, Warren Andersen S. Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review. Cancer Causes Control 2024; 35:223-239. [PMID: 37688643 PMCID: PMC11090693 DOI: 10.1007/s10552-023-01783-y] [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: 03/21/2023] [Accepted: 08/21/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE African Americans have the highest colorectal cancer (CRC) mortality of all racial groups in the USA, which may relate to differences in healthcare access or advanced stage at diagnosis. Recent evidence indicates that differences in tumor characteristics may also underlie disparities in mortality. To highlight recent findings and areas for investigation, we completed the first systematic review of racial disparities in CRC tumor prognostic markers, including clinicopathological markers, microsatellite instability (MSI), oncogene mutations, and novel markers, including cancer stem cells and immune markers. METHODS Relevant studies were identified via PubMed, limited to original research published within the last 10 years. Ninety-six articles were identified that compared the prevalence of mortality-related CRC tumor characteristics in African Americans (or other African ancestry populations) to White cases. RESULTS Tumors from African ancestry cases are approximately 10% more likely to contain mutations in KRAS, which confer elevated mortality and resistance to epidermal growth factor receptor inhibition. Conversely, African Americans have approximately 50% lower odds for BRAF-mutant tumors, which occur less frequently but have similar effects on mortality and therapeutic resistance. There is less consistent evidence supporting disparities in mutations for other oncogenes, including PIK3CA, TP53, APC, NRAS, HER2, and PTEN, although higher rates of PIK3CA mutations and lower prevalence of MSI status for African ancestry cases are supported by recent evidence. Although emerging evidence suggests that immune markers reflecting anti-tumor immunity in the tumor microenvironment may be lower for African American cases, there is insufficient evidence to evaluate disparities in other novel markers, cancer stem cells, microRNAs, and the consensus molecular subtypes. CONCLUSION Higher rates of KRAS-mutant tumors in in African Americans may contribute to disparities in CRC mortality. Additional work is required to understand whether emerging markers, including immune cells, underlie the elevated CRC mortality observed for African Americans.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
- University of Wisconsin-Madison, Suite 1007B, WARF, 610 Walnut Street, Madison, WI, 53726, USA.
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22
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Dailah HG, Hommdi AA, Koriri MD, Algathlan EM, Mohan S. Potential role of immunotherapy and targeted therapy in the treatment of cancer: A contemporary nursing practice. Heliyon 2024; 10:e24559. [PMID: 38298714 PMCID: PMC10828696 DOI: 10.1016/j.heliyon.2024.e24559] [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: 04/29/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 02/02/2024] Open
Abstract
Immunotherapy and targeted therapy have emerged as promising therapeutic options for cancer patients. Immunotherapies induce a host immune response that mediates long-lived tumor destruction, while targeted therapies suppress molecular mechanisms that are important for tumor maintenance and growth. In addition, cytotoxic agents and targeted therapies regulate immune responses, which increases the chances that these therapeutic approaches may be efficiently combined with immunotherapy to ameliorate clinical outcomes. Various studies have suggested that combinations of therapies that target different stages of anti-tumor immunity may be synergistic, which can lead to potent and more prolonged responses that can achieve long-lasting tumor destruction. Nurses associated with cancer patients should have a better understanding of the immunotherapies and targeted therapies, such as their efficacy profiles, mechanisms of action, as well as management and prophylaxis of adverse events. Indeed, this knowledge will be important in establishing care for cancer patients receiving immunotherapies and targeted therapies for cancer treatment. Moreover, nurses need a better understanding regarding targeted therapies and immunotherapies to ameliorate outcomes in patients receiving these therapies, as well as management and early detection of possible adverse effects, especially adverse events associated with checkpoint inhibitors and various other therapies that control T-cell activation causing autoimmune toxicity. Nurses practice in numerous settings, such as hospitals, home healthcare agencies, radiation therapy facilities, ambulatory care clinics, and community agencies. Therefore, as compared to other members of the healthcare team, nurses often have better opportunities to develop the essential rapport in providing effective nurse-led patient education, which is important for effective therapeutic outcomes and continuance of therapy. In this article, we have particularly focused on providing a detailed overview on targeted therapies and immunotherapies used in cancer treatment, management of their associated adverse events, and the impact as well as strategies of nurse-led patient education.
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Affiliation(s)
- Hamad Ghaleb Dailah
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Abdullah Abdu Hommdi
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Mahdi Dafer Koriri
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Essa Mohammed Algathlan
- Research and Scientific Studies Unit, College of Nursing, Jazan University, Jazan, 45142, Saudi Arabia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Centre, Jazan University, Jazan, Saudi Arabia
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
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23
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Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R, Srivastava V. Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:41-99. [PMID: 38663962 DOI: 10.1016/bs.ircmb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.
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Affiliation(s)
- Afza Ahmad
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Saleha Siddiqui
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Muskan Chadha
- Department of Nutrition and Dietetics, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Ratnakar Shukla
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vivek Srivastava
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Greater Noida, Uttar Pradesh, India.
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24
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Abbass EM, Al-Karmalawy AA, Sharaky M, Khattab M, Alzahrani AYA, Hassaballah AI. Rational design and eco-friendly one-pot multicomponent synthesis of novel ethylidenehydrazineylthiazol-4(5H)-ones as potential apoptotic inducers targeting wild and mutant EGFR-TK in triple negative breast cancer. Bioorg Chem 2024; 142:106936. [PMID: 37890211 DOI: 10.1016/j.bioorg.2023.106936] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/15/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023]
Abstract
A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.
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Affiliation(s)
- Eslam M Abbass
- Department of Chemistry, Faculty of Science, Ain Shams University, Abbassiya 11566, Cairo, Egypt
| | - Ahmed A Al-Karmalawy
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
| | - Marwa Sharaky
- Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | - Muhammad Khattab
- Office of Research, University of Western Australia, Perth, Australia; Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, Egypt
| | | | - Aya I Hassaballah
- Department of Chemistry, Faculty of Science, Ain Shams University, Abbassiya 11566, Cairo, Egypt
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25
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Chauhan S, Sharma S. Recent Approaches on Molecular Markers, Treatment and Novel Drug Delivery System Used for the Management of Colorectal Cancer: A Comprehensive Review. Curr Pharm Biotechnol 2024; 25:1969-1985. [PMID: 38275054 DOI: 10.2174/0113892010270975231208113157] [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: 08/23/2023] [Revised: 09/29/2023] [Accepted: 10/16/2023] [Indexed: 01/27/2024]
Abstract
Colorectal cancer affects 1 in 25 females and 1 in 24 males, making it the third most frequent cancer with over 6,08,030 deaths worldwide, despite advancements in detection and treatments, including surgery, chemotherapeutics, radiotherapy, and immune therapeutics. Novel potential agents have increased survival in acute and chronic disease conditions, with a higher risk of side effects and cost. However, metastatic disease has an insignificant long-term diagnosis, and significant challenges remain due to last-stage diagnosis and treatment failure. Early detection, survival, and treatment efficacy are all improved by biomarkers. The advancement of cancer biomarkers' molecular pathology and genomics during the last three decades has improved therapy. Clinically useful prognostic biomarkers assist clinical judgment, for example, by predicting the success of EGFR-inhibiting antibodies in the presence of KRAS gene mutations. Few biomarkers are currently used in clinical settings, so further research is still needed. Nanocarriers, with materials like Carbon nanotubes and gold nanoparticles, provide targeted CRC drug delivery and diagnostics. Light-responsive drugs with gold and silica nanoparticles effectively target and destroy CRC cells. We evaluate the potential use of the long non-coding RNA (non-coding RNA) oncogene plasmacytoma variant translocation 1 (PVT1) as a diagnostic, prognostic, and therapeutic biomarker, along with the latest nanotech breakthroughs in CRC diagnosis and treatment.
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Affiliation(s)
- Sonia Chauhan
- Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, U.P, 201306, India
| | - Sakshi Sharma
- Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, U.P, 201306, India
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26
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Wu JB, Li XJ, Liu H, Liu YJ, Liu XP. Association of KRAS, NRAS, BRAF and PIK3CA gene mutations with clinicopathological features, prognosis and ring finger protein 215 expression in patients with colorectal cancer. Biomed Rep 2023; 19:104. [PMID: 38025833 PMCID: PMC10646763 DOI: 10.3892/br.2023.1686] [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: 06/28/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
The relationships of KRAS, NRAS, BRAF and PIK3CA gene mutations with the clinicopathological features and prognosis of colorectal cancer (CRC) in patient are lacking. Furthermore, the role of ring finger protein 215 (RNF215) in CRC patients with KRAS, NRAS, BRAF and PIK3CA mutations remains unclear. In the present study, 182 surgical resection specimens from patients with primary CRC for retrospective analysis, were collected. KRAS/NRAS/BRAF/PIK3CA gene mutations were confirmed by an amplification-refractory mutation system. Immunohistochemistry (IHC) was conducted to confirm KRAS, NRAS, BRAF and PIK3CA protein expression. RNF215 expression in patients with CRC was evaluated using TIMER 2.0 database and IHC. The individual mutation rates of KRAS, NRAS, BRAF and PIK3CA were 40.7% (74/182), 4.4% (8/182), 4.4% (8/182) and 3.3% (6/182), respectively. The KRAS exon 2 mutation rate was the highest (61.5%, 64/104), and these mutations mainly occurred at codons 12 and 13. KRAS/NRAS/BRAF/PIK3CA wild-type CRC patients had significantly longer overall survival and disease-free survival than mutated KRAS/NRAS/BRAF/PIK3CA CRC patients (P<0.05). Overall, 45.4% (5/11) of patients with PIK3CA mutations had concomitant KRAS mutations. The KRAS/NRAS/BRAF/PIK3CA gene mutation rate in patients with lymph node metastasis (76.1%, 35/46) was significantly higher than that in patients without lymph node metastasis (50.8%, 69/136) (P=0.0027). There were no significant differences in IHC expression between patients with and without KRAS, NRAS, BRAF and PIK3CA mutations (P>0.05). The TIMER 2.0 analysis showed that RNF215 expression was significantly higher in the mutated BRAF group than in the wild-type BRAF group in CRC (P<0.05). In conclusion, KRAS is the most commonly mutated gene, and KRAS mutations may be a poor prognostic factor for patients with CRC. KRAS wild-type patient resistance may be related to PIK3CA gene mutations, although this needs further verification in larger cohorts. BRAF mutations may be associated with RNF215 expression in patients with CRC.
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Affiliation(s)
- Jing-Bo Wu
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, P.R. China
| | - Xiao-Jing Li
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, P.R. China
| | - Hui Liu
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, P.R. China
| | - Yong-Juan Liu
- Department of Pathology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, P.R. China
| | - Xiu-Ping Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
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27
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Tsai CW, Chang WS, Yueh TC, Wang YC, Chin YT, Yang MD, Hung YC, Mong MC, Yang YC, Gu J, Bau DT. The Significant Impacts of Interleukin-8 Genotypes on the Risk of Colorectal Cancer in Taiwan. Cancers (Basel) 2023; 15:4921. [PMID: 37894288 PMCID: PMC10605288 DOI: 10.3390/cancers15204921] [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: 09/06/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
Interleukin-8 (IL-8), a pro-inflammatory cytokine, is upregulated in CRC and plays an important role in its development and progression. Genetic variants in the IL-8 gene may impact the risk of CRC by modulating IL-8 levels. Our primary objective was to investigate the role of IL-8 genotypes in the development of CRC. To accomplish this, we employed the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the genotypes of IL-8 rs4017, rs2227306, rs2227543, and rs1126647 in 362 CRC patients and 362 controls. Additionally, we evaluated the interactions between these genotypes and factors such as age, gender, smoking, alcohol consumption, and body mass index (BMI) status in relation to the risk of CRC. Furthermore, we utilized quantitative reverse transcription-PCR to measure the serum IL-8. The results demonstrated a significant difference in the distribution of rs4017 genotypes between the control and case groups (p for trend = 0.0059). Logistic regression analysis revealed that individuals with variant AA genotype had a 1.92-fold higher CRC risk (95% confidence interval [CI] = 1.28-2.89, p = 0.0023). Moreover, carriers of the IL-8 rs4017 AT + AA genotypes exhibited a significant association with CRC risk (odds ratio [OR] = 1.39, 95% CI = 1.02-1.91, p = 0.0460). Additionally, individuals with IL-8 rs4017 AA genotype displayed significantly elevated serum IL-8 compared to those with TT genotype at a 1.73-fold level (p < 0.0001), indicating a correlation between genotype and phenotype. In conclusion, the genotypes of IL-8 rs4017, along with their associated expression levels, can potentially serve as predictive markers for the risk of CRC.
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Affiliation(s)
- Chia-Wen Tsai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan; (C.-W.T.); (W.-S.C.); (Y.-C.W.); (Y.-T.C.); (Y.-C.H.)
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
| | - Wen-Shin Chang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan; (C.-W.T.); (W.-S.C.); (Y.-C.W.); (Y.-T.C.); (Y.-C.H.)
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
| | - Te-Cheng Yueh
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
- Division of Colon and Rectal Surgery, Department of Surgery, Taichung Armed Forces General Hospital, Taichung 41152, Taiwan
- National Defense Medical Center, Taipei 11490, Taiwan
| | - Yun-Chi Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan; (C.-W.T.); (W.-S.C.); (Y.-C.W.); (Y.-T.C.); (Y.-C.H.)
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
| | - Yu-Ting Chin
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan; (C.-W.T.); (W.-S.C.); (Y.-C.W.); (Y.-T.C.); (Y.-C.H.)
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
| | - Mei-Due Yang
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
- Department of General Surgery, China Medical University Hospital, Taichung 404332, Taiwan
| | - Yi-Chih Hung
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan; (C.-W.T.); (W.-S.C.); (Y.-C.W.); (Y.-T.C.); (Y.-C.H.)
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
| | - Mei-Chin Mong
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 41354, Taiwan; (M.-C.M.); (Y.-C.Y.)
| | - Ya-Chen Yang
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 41354, Taiwan; (M.-C.M.); (Y.-C.Y.)
| | - Jian Gu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Da-Tian Bau
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan; (C.-W.T.); (W.-S.C.); (Y.-C.W.); (Y.-T.C.); (Y.-C.H.)
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan; (T.-C.Y.); (M.-D.Y.)
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 41354, Taiwan
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Huang JL, Liang L, Xie PE, Sun WL, Wang L, Cai ZW. Cucurbitacin B induces apoptosis in colorectal cells through reactive oxygen species generation and endoplasmic reticulum stress pathways. Exp Ther Med 2023; 26:484. [PMID: 37753296 PMCID: PMC10518646 DOI: 10.3892/etm.2023.12183] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 08/01/2023] [Indexed: 09/28/2023] Open
Abstract
Cucurbitacin B (CuB) is a member of the cucurbitacin family, which has shown potent anticancer pharmacological activity. Prolonged or severe endoplasmic reticulum stress (ERS) induces apoptosis; therefore, the present study investigated whether CuB may activate the ERS pathway to induce apoptosis. HT-29 and SW620 colorectal cancer (CRC) cells were treated with a range of concentrations of CuB for 48 h, and the viability and proliferation of cells were determined using Cell Counting Kit 8 (CCK8) and colony formation assays. Subsequently, the appropriate CuB concentration (5 µM) was selected for treatment of CRC cells for 48 h. Western blot analysis was used to measure the expression levels of ERS-related proteins, flow cytometry was used to evaluate apoptosis, the dichlorodihydrofluorescein diacetate fluorescent probe was used to detect reactive oxygen species (ROS) production, and the relationship between ROS and ERS was determined by western blot analysis. Furthermore, flow cytometry was used to evaluate apoptosis after treatment with the ERS inhibitor 4-phenylbutyric acid, the ROS inhibitor N-acetylcysteine and following knockdown of CHOP expression. In addition, western blot analysis was performed to measure Bax and Bcl2 protein expression levels, and a CCK8 assay was performed to evaluate the viability of cells following knockdown of CHOP. Notably, CuB treatment increased apoptosis and inhibited cell proliferation in CRC cell lines, and these effects were mediated by ROS and ROS-regulated activation of the PERK and XBP1 ERS pathways. In conclusion, CuB may induce apoptosis in HT-29 and SW620 CRC cells via ROS and ERS.
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Affiliation(s)
- Jian-Lan Huang
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
| | - Li Liang
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
| | - Pei-En Xie
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
| | - Wei-Liang Sun
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
| | - Li Wang
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
| | - Zheng-Wen Cai
- Department of Medical Oncology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530007, P.R. China
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29
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Dobbs Spendlove M, M. Gibson T, McCain S, Stone BC, Gill T, Pickett BE. Pathway2Targets: an open-source pathway-based approach to repurpose therapeutic drugs and prioritize human targets. PeerJ 2023; 11:e16088. [PMID: 37790614 PMCID: PMC10544355 DOI: 10.7717/peerj.16088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/22/2023] [Indexed: 10/05/2023] Open
Abstract
Background Recent efforts to repurpose existing drugs to different indications have been accompanied by a number of computational methods, which incorporate protein-protein interaction networks and signaling pathways, to aid with prioritizing existing targets and/or drugs. However, many of these existing methods are focused on integrating additional data that are only available for a small subset of diseases or conditions. Methods We have designed and implemented a new R-based open-source target prioritization and repurposing method that integrates both canonical intracellular signaling information from five public pathway databases and target information from public sources including OpenTargets.org. The Pathway2Targets algorithm takes a list of significant pathways as input, then retrieves and integrates public data for all targets within those pathways for a given condition. It also incorporates a weighting scheme that is customizable by the user to support a variety of use cases including target prioritization, drug repurposing, and identifying novel targets that are biologically relevant for a different indication. Results As a proof of concept, we applied this algorithm to a public colorectal cancer RNA-sequencing dataset with 144 case and control samples. Our analysis identified 430 targets and ~700 unique drugs based on differential gene expression and signaling pathway enrichment. We found that our highest-ranked predicted targets were significantly enriched in targets with FDA-approved therapeutics for colorectal cancer (p-value < 0.025) that included EGFR, VEGFA, and PTGS2. Interestingly, there was no statistically significant enrichment of targets for other cancers in this same list suggesting high specificity of the results. We also adjusted the weighting scheme to prioritize more novel targets for CRC. This second analysis revealed epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), and two mitogen-activated protein kinases (MAPK14 and MAPK3). These observations suggest that our open-source method with a customizable weighting scheme can accurately prioritize targets that are specific and relevant to the disease or condition of interest, as well as targets that are at earlier stages of development. We anticipate that this method will complement other approaches to repurpose drugs for a variety of indications, which can contribute to the improvement of the quality of life and overall health of such patients.
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Affiliation(s)
- Mauri Dobbs Spendlove
- Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States of America
| | - Trenton M. Gibson
- Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States of America
| | - Shaney McCain
- Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States of America
| | - Benjamin C. Stone
- Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States of America
| | | | - Brett E. Pickett
- Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States of America
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30
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Akbarzadeh-Khiavi M, Safary A, Omidi Y. Targeting long non-coding RNAs as new modulators in anti-EGFR resistance mechanisms. BIOIMPACTS : BI 2023; 14:27696. [PMID: 38327631 PMCID: PMC10844586 DOI: 10.34172/bi.2023.27696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 07/15/2023] [Accepted: 08/22/2023] [Indexed: 02/09/2024]
Abstract
Epidermal growth factor receptor (EGFR) is a cell surface protein that plays a vital role in regulating cell growth and division. However, certain tumors, such as colorectal cancer (CRC), can exhibit an overexpression of EGFR, resulting in uncontrolled cell growth and tumor progression. To address this issue, therapies targeting and inhibiting EGFR activity have been developed to suppress cancer growth. Nevertheless, resistance to these therapies poses a significant obstacle in cancer treatment. Recent research has focused on comprehending the underlying mechanisms contributing to anti-EGFR resistance and identifying new targets to overcome this striking challenge. Long non-coding RNAs (lncRNAs) are a class of RNA molecules that do not encode proteins but play pivotal roles in gene regulation and cellular processes. Emerging evidence suggests that lncRNAs may participate in modulating resistance to anti-EGFR therapies in CRC. Consequently, combining lncRNA targeting with the existing treatment modalities could potentially yield improved clinical outcomes. Illuminating the involvement of lncRNAs in anti-EGFR resistance mechanisms of cancer cells can provide valuable insights into the development of novel anti-EGFR therapies in several solid tumors.
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Affiliation(s)
- Mostafa Akbarzadeh-Khiavi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azam Safary
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
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31
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Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathol Res Pract 2023; 248:154616. [PMID: 37379710 DOI: 10.1016/j.prp.2023.154616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
Colorectal cancer (CRC) is comprised of transformed cells and non-malignant cells including cancer-associated fibroblasts (CAF), endothelial vasculature cells, and tumor-infiltrating cells. These nonmalignant cells, as well as soluble factors (e.g., cytokines), and the extracellular matrix (ECM), form the tumor microenvironment (TME). In general, the cancer cells and their surrounding TME can crosstalk by direct cell-to-cell contact and via soluble factors, such as cytokines (e.g., chemokines). TME not only promotes cancer progression through growth-promoting cytokines but also provides resistance to chemotherapy. Understanding the mechanisms of tumor growth and progression and the roles of chemokines in CRC will likely suggest new therapeutic targets. In this line, a plethora of reports has evidenced the critical role of chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis in CRC pathogenesis. In the current review, we take a glimpse into the role of the CXCR4/CXCL12 axis in CRC growth, metastasis, angiogenesis, drug resistance, and immune escape. Also, a summary of recent reports concerning targeting CXCR4/CXCL12 axis for CRC management and therapy has been delivered.
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Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Rabia Noor
- Amna Inayat Medical College, Lahore, Pakistan
| | - Ali Alsalamy
- College of Medical Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 75471, Aljouf, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of Research & Innovation, Uttaranchal University, Dehradun 248007, India
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Cann CG, LaPelusa MB, Cimino SK, Eng C. Molecular and genetic targets within metastatic colorectal cancer and associated novel treatment advancements. Front Oncol 2023; 13:1176950. [PMID: 37409250 PMCID: PMC10319053 DOI: 10.3389/fonc.2023.1176950] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Colorectal cancer results in the deaths of hundreds of thousands of patients worldwide each year, with incidence expected to rise over the next two decades. In the metastatic setting, cytotoxic therapy options remain limited, which is reflected in the meager improvement of patient survival rates. Therefore, focus has turned to the identification of the mutational composition inherent to colorectal cancers and development of therapeutic targeted agents. Herein, we review the most up to date systemic treatment strategies for metastatic colorectal cancer based on the actionable molecular alterations and genetic profiles of colorectal malignancies.
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Affiliation(s)
- Christopher G. Cann
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Michael B. LaPelusa
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sarah K. Cimino
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cathy Eng
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
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Manzi J, Hoff CO, Ferreira R, Pimentel A, Datta J, Livingstone AS, Vianna R, Abreu P. Targeted Therapies in Colorectal Cancer: Recent Advances in Biomarkers, Landmark Trials, and Future Perspectives. Cancers (Basel) 2023; 15:cancers15113023. [PMID: 37296986 DOI: 10.3390/cancers15113023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/30/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
In 2022, approximately 600,000 cancer deaths were expected; more than 50,000 of those deaths would be from colorectal cancer (CRC). The CRC mortality rate in the US has decreased in recent decades, with a 51% drop between 1976 and 2014. This drop is attributed, in part, to the tremendous therapeutic improvements, especially after the 2000s, in addition to increased social awareness regarding risk factors and diagnostic improvement. Five-fluorouracil, irinotecan, capecitabine, and later oxaliplatin were the mainstays of mCRC treatment from the 1960s to 2002. Since then, more than a dozen drugs have been approved for the disease, betting on a new chapter in medicine, precision oncology, which uses patient and tumor characteristics to guide the therapeutic choice. Thus, this review will summarize the current literature on targeted therapies, highlighting the molecular biomarkers involved and their pathways.
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Affiliation(s)
- Joao Manzi
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Camilla O Hoff
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Raphaella Ferreira
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Agustin Pimentel
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Jashodeep Datta
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Alan S Livingstone
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
| | - Rodrigo Vianna
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
| | - Phillipe Abreu
- Miami Transplant Institute, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA
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Keshavarz F, Dorfaki M, Bardania H, Khosravani F, Nazari P, Ghalamfarsa G. Quercetin-loaded Liposomes Effectively Induced Apoptosis and Decreased the Epidermal Growth Factor Receptor Expression in Colorectal Cancer Cells: An In Vitro Study. IRANIAN JOURNAL OF MEDICAL SCIENCES 2023; 48:321-328. [PMID: 37791331 PMCID: PMC10542927 DOI: 10.30476/ijms.2022.95272.2658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/09/2022] [Accepted: 08/10/2022] [Indexed: 10/05/2023]
Abstract
Background Quercetin is a flavonoid having anti-cancer properties; however, it has low stability, insufficient bioavailability, and poor solubility. This study aimed to load quercetin on nanoliposomes to enhance its efficiency against SW48 colorectal cancer cells. The cytotoxicity of free-quercetin and quercetin-loaded nanoliposomes on the expression of the epidermal growth factor receptor (EGER) gene was investigated. Methods This present in vitro study was conducted at Yasuj University of Medical Sciences (Yasuj, Iran) in 2021. In this in vitro study, the lipid thin-film hydration method was used to synthesize quercetin-loaded liposomes. Additionally, high-performance liquid chromatography (HPLC) analyses, dynamic light scattering (DLS), and transmission electron microscopy (TEM) investigations were used to characterize nanomaterials. Following that, MTT, flow cytometry, and real-time PCR were used to investigate the cytotoxicity of quercetin-loaded liposomes on the colorectal cancer cells SW48 cell line, the incidence of apoptosis, and the expression of the EGFR gene in these cells. Statistical analysis was performed using the SPSS (version 26.0), and the graphs were created with the GraphPad Prism version 8.4.3. P<0.05 was considered statistically significant. Results The nanoparticles were spherical, homogenous, and 150±10 nm in size. According to HPLC, Quercetin had a 98% loading capacity. Although both free quercetin and quercetin-loaded liposomes indicated significant cytotoxicity against cancer cells (P˂0.001), the combined form was significantly more active (P=0.008). 50 µg/mL of this compound reduced the viability of SW48 cells by more than 80% (IC50 10.65 µg/mL), while the viability of cells treated with free quercetin was only 66% (IC50 18.74 µg/mL). The apoptosis was nearly doubled in the cells treated with quercetin-loaded nanoliposomes compared to free quercetin (54.8% versus 27.6%). EGFR gene expression, on the other hand, was significantly lower in cells treated with quercetin-loaded liposomes than the quercetin alone (P=0.006). Conclusion When combined with nanoliposomes, quercetin had greater anti-proliferative, apoptotic, and anti-EGFR expression than free quercetin.
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Affiliation(s)
- Fatemeh Keshavarz
- Department of Immunology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Dorfaki
- Department of Immunology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hasan Bardania
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fatemeh Khosravani
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Paria Nazari
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Ghasem Ghalamfarsa
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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Son S, Kim H, Lim H, Lee JH, Lee KM, Shin I. CCN3/NOV promotes metastasis and tumor progression via GPNMB-induced EGFR activation in triple-negative breast cancer. Cell Death Dis 2023; 14:81. [PMID: 36737605 PMCID: PMC9898537 DOI: 10.1038/s41419-023-05608-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/05/2023]
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC patients typically exhibit unfavorable outcomes due to its rapid growth and metastatic potential. Here, we found overexpression of CCN3 in TNBC patients. We identified that CCN3 knockdown diminished cancer stem cell formation, metastasis, and tumor growth in vitro and in vivo. Mechanistically, ablation of CCN3 reduced activity of the EGFR/MAPK pathway. Transcriptome profiling revealed that CCN3 induces glycoprotein nonmetastatic melanoma protein B (GPNMB) expression, which in turn activates the EGFR pathway. An interrogation of the TCGA dataset further supported the transcriptional regulation of GPNMB by CCN3. Finally, we showed that CCN3 activates Wnt signaling through a ligand-dependent or -independent mechanism, which increases microphthalmia-associated transcription factor (MITF) protein, a transcription factor inducing GPNMB expression. Together, our findings demonstrate the oncogenic role of CCN3 in TNBC, and we propose CCN3 as a putative therapeutic target for TNBC.
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Affiliation(s)
- Seogho Son
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Hyungjoo Kim
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Hogeun Lim
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Joo-Hyung Lee
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
| | - Kyung-Min Lee
- Department of Life Science, Hanyang University, Seoul, 04763, Korea
- Natural Science Institute, Hanyang University, Seoul, 04763, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, 04763, Korea
| | - Incheol Shin
- Department of Life Science, Hanyang University, Seoul, 04763, Korea.
- Natural Science Institute, Hanyang University, Seoul, 04763, Korea.
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, 04763, Korea.
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Liu T, Jiang S, Teng X, Zhong L, Liu M, Jin Y, Dong M. A comparison of panitumumab and cetuximab in the treatment of KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Immunopharmacol Immunotoxicol 2023; 45:1-9. [PMID: 35950851 DOI: 10.1080/08923973.2022.2112222] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
AIM Cetuximab and panitumumab are common antibodies against epidermal growth factor receptor (EGFR) that can be used in combination with chemotherapy for the treatment of metastatic colorectal cancer (mCRC). Although these two drugs are considered to be very similar, differences in the efficacy and safety of cetuximab and panitumumab are still unclear. We conducted this meta-analysis to explore the effects and adverse reactions of cetuximab and panitumumab in the treatment of mCRC. METHODS We searched PubMed, the Cochrane Library, Embase, Web of Science, China national knowledge infrastructure (CNKI) and WanFang databases to identify records related to the efficacy and safety of cetuximab and panitumumab in the treatment of mCRC. The search terms were "cetuximab," "panitumumab," and "colorectal cancer." The deadline of searching was April 2022. Review manager 5.4 software was used to perform the statistical analysis for this meta-analysis. Pooled hazard ratio (HR) with 95% confidence intervals (CI) were calculated to evaluate the overall survival (OS) and progression free survival (PFS) of cetuximab and panitumumab in the treatment of mCRC. RESULTS There was no significant difference in OS, PFS, and response rate (RR) between cetuximab arm and panitumumab arm (OS: HR = 0.91, 95% CI = 0.81-1.03, p = .14; PFS: HR = 0.92, 95% CI = 0.83-1.02, p = .11; RR: OR = 1.22, 95% CI = 0.96-1.61, p = .14). We also did not observe any statistical difference between both arms in incidence of acneiform rash, severe acneiform rash, diarrhea, and severe diarrhea (acneiform rash: OR = 1.09, 95% CI = 0.84-1.42, p = .51; severe acneiform rash: OR = 1.50, 95% CI = 0.80-2.81, p = .21; diarrhea: OR = 1.08, 95% CI = 0.82-1.42, p = .58; severe diarrhea: OR = 0.90, 95% CI = 0.44-1.84, p = .77). The incidence of paronychia was decreased in the panitumumab arm, but that of hypomagnesemia and severe hypomagnesemia were decreased in the cetuximab arm. (paronychia: OR = 0.74, 95% CI = 0.55-1.00, p = .05; hypomagnesemia: OR = 1.85, 95% CI =1.41-2.41, p < .00001; severe hypomagnesemia: OR = 2.66, 95% CI = 1.52-4.67, p = .0006). CONCLUSION There was no significant difference in OS, PFS and RR between the cetuximab arm and panitumumab arm in the treatment of mCRC. For adverse reactions, the incidence of paronychia was decreased in the panitumumab arm, and the incidence of hypomagnesemia was deceased in the cetuximab arm.
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Affiliation(s)
- Tong Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Shuai Jiang
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xue Teng
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Lu Zhong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Mengmeng Liu
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yao Jin
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
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Zhang Q, Zheng Y, Liu J, Tang X, Wang Y, Li X, Li H, Zhou X, Tang S, Tang Y, Wang X, He H, Li T. CircIFNGR2 enhances proliferation and migration of CRC and induces cetuximab resistance by indirectly targeting KRAS via sponging to MiR-30b. Cell Death Dis 2023; 14:24. [PMID: 36639711 PMCID: PMC9839739 DOI: 10.1038/s41419-022-05536-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 12/18/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023]
Abstract
Currently the clinical efficacy of colorectal cancer (CRC) which is the most common malignant tumors over the world has not reached an ideal level. Cetuximab, the monoclonal antibody targeting the extracellular domain of EGFR, has shown its great efficacy in the promotion of apoptosis and the inhibition of tumor cells-like characteristics in numerous cancers. However certain KRAS wild-type CRC patients unexpectedly show cetuximab resistance and the specific mechanism remains unclear. Circular RNAs (circRNAs) as the promising novel type of biomarkers in the cancer diagnosis and therapy, have been reported to be related with the drug resistance. In this study, with wondering the mechanism of cetuximab resistance in KRAS wild-type CRC patients, we evaluate the impact of circIFNGR2 on CRC and detect the association among circIFNGR2, miR-30b and KRAS via various experiments such as RT-qPCR, immunohistochemistry, luciferase assays, cell functional experiments and xenograft model. We conclude that circIFNGR2 induces cetuximab resistance in colorectal cancer cells by indirectly regulating target gene KRAS by sponging miR-30b at the post-transcriptional level. It is thus suggested that inhibition of circIFNGR2 can be a promising therapeutic strategy for malignant CRC patients with cetuximab resistance.
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Affiliation(s)
- Qi Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yifeng Zheng
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Jiajia Liu
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xiaoxiao Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yuan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xianzheng Li
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Huibin Li
- Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China
| | - Xiaoying Zhou
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Shiru Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Yitao Tang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China
| | - Xiaoyan Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
| | - Han He
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Tingting Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
- Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
- State Key Laboratory of Oncology in Southern China, Department of Experimental, Guangzhou, Guangdong, China.
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Gogoi P, Kaur G, Singh NK. Nanotechnology for colorectal cancer detection and treatment. World J Gastroenterol 2022; 28:6497-6511. [PMID: 36569271 PMCID: PMC9782835 DOI: 10.3748/wjg.v28.i46.6497] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/28/2022] [Accepted: 11/18/2022] [Indexed: 12/08/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related mortality in the United States. Across the globe, people in the age group older than 50 are at a higher risk of CRC. Genetic and environmental risk factors play a significant role in the development of CRC. If detected early, CRC is preventable and treatable. Currently, available screening methods and therapies for CRC treatment reduce the incidence rate among the population, but the micrometastasis of cancer may lead to recurrence. Therefore, the challenge is to develop an alternative therapy to overcome this complication. Nanotechnology plays a vital role in cancer treatment and offers targeted chemotherapies directly and selectively to cancer cells, with enhanced therapeutic efficacy. Additionally, nanotechnology elevates the chances of patient survival in comparison to traditional chemotherapies. The potential of nanoparticles includes that they may be used simultaneously for diagnosis and treatment. These exciting properties of nanoparticles have enticed researchers worldwide to unveil their use in early CRC detection and as effective treatment. This review discusses contemporary methods of CRC screening and therapies for CRC treatment, while the primary focus is on the theranostic approach of nanotechnology in CRC treatment and its prospects. In addition, this review aims to provide knowledge on the advancement of nanotechnology in CRC and as a starting point for researchers to think about new therapeutic approaches using nanotechnology.
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Affiliation(s)
- Purnima Gogoi
- Integrative Biosciences Center, OVAS, Wayne State University School of Medicine, Detroit, MI 48202, United States
| | - Geetika Kaur
- Integrative Biosciences Center, OVAS, Wayne State University School of Medicine, Detroit, MI 48202, United States
| | - Nikhlesh K Singh
- Integrative Biosciences Center, OVAS, Wayne State University School of Medicine, Detroit, MI 48202, United States
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Kilroy MK, Park S, Feroz W, Patel H, Mishra R, Alanazi S, Garrett JT. HER3 Alterations in Cancer and Potential Clinical Implications. Cancers (Basel) 2022; 14:cancers14246174. [PMID: 36551663 PMCID: PMC9776947 DOI: 10.3390/cancers14246174] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
In recent years, the third member of the HER family, kinase impaired HER3, has become a target of interest in cancer as there is accumulating evidence that HER3 plays a role in tumor growth and progression. This review focuses on HER3 activation in bladder, breast, colorectal, and lung cancer disease progression. HER3 mutations occur at a rate up to ~10% of tumors dependent on the tumor type. With patient tumors routinely sequenced for gene alterations in recent years, we have focused on HER3 mutations in bladder, breast, colon, and lung cancers particularly in response to targeted therapies and the potential to become a resistance mechanism. There are currently several HER3 targeting drugs in the pipeline, possibly improving outcomes for cancer patients with tumors containing HER3 activation and/or alterations.
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Affiliation(s)
- Mary Kate Kilroy
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
| | - SoYoung Park
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
- Cancer Research Scholars Program, College of Allied Health Sciences, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Wasim Feroz
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Hima Patel
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Rosalin Mishra
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Samar Alanazi
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Joan T. Garrett
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
- Correspondence:
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Doleschal B, Petzer A, Rumpold H. Current concepts of anti-EGFR targeting in metastatic colorectal cancer. Front Oncol 2022; 12:1048166. [PMID: 36465407 PMCID: PMC9714621 DOI: 10.3389/fonc.2022.1048166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/26/2022] [Indexed: 11/07/2023] Open
Abstract
Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.
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Affiliation(s)
- Bernhard Doleschal
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Andreas Petzer
- Department of Internal Medicine I for Hematology With Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz, Linz, Austria
| | - Holger Rumpold
- Gastrointestinal Cancer Center, Ordensklinikum Linz, Linz, Austria
- Johannes Kepler University Linz, Medical Faculty, Linz, Austria
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Eradication of KRAS mutant colorectal adenocarcinoma by PEGylated gold nanoparticles-cetuximab conjugates through ROS-dependent apoptosis. Colloids Surf A Physicochem Eng Asp 2022. [DOI: 10.1016/j.colsurfa.2022.129890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Bazzichetto C, Milella M, Zampiva I, Simionato F, Amoreo CA, Buglioni S, Pacelli C, Le Pera L, Colombo T, Bria E, Zeuli M, Del Bufalo D, Sperduti I, Conciatori F. Interleukin-8 in Colorectal Cancer: A Systematic Review and Meta-Analysis of Its Potential Role as a Prognostic Biomarker. Biomedicines 2022; 10:biomedicines10102631. [PMID: 36289899 PMCID: PMC9599846 DOI: 10.3390/biomedicines10102631] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/09/2022] [Accepted: 10/16/2022] [Indexed: 12/05/2022] Open
Abstract
Among soluble actors that have emerged as druggable factors, the chemokine interleukin-8 (IL-8) has emerged as a possible determinant of response to immunotherapy and targeted treatment in several cancer types; however, its prognostic/predictive role in colorectal cancer (CRC) remains to be established. We: (i) conducted a systematic review of published literature on IL-8 expression in CRC; (ii) searched public transcriptomics databases; (iii) investigated IL-8 expression, by tumor and infiltrating cells, in a series of CRC samples; and (iv) carried out a meta-analysis of published literature correlating IL-8 expression and CRC prognosis. IL-8 possesses an important role as a mediator of the bidirectional crosstalk between tumor/stromal cells. Transcriptomic analysis indicated that specific IL-8 transcripts were significantly overexpressed in CRC compared to normal colon mucosa. Moreover, in our series we observed a statistically significant correlation between PTEN-loss and IL-8 expression by infiltrating mononuclear and tumor cells. In total, 12 papers met our meta-analysis inclusion criteria, demonstrating that high IL-8 levels significantly correlated with shorter overall survival and progression-free survival. Sensitivity analysis demonstrated a highly significant correlation with outcome for circulating, but not for tissue-detected, IL-8. IL-8 is overexpressed in CRC tissues and differentially produced by tumor or stromal components depending on CRC genetic background. Moreover, circulating IL-8 represents a strong prognostic factor in CRC, suggesting its use in the refining of prognostic CRC assessment and potentially the tailoring of therapeutic strategies in individual CRC patients.
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Affiliation(s)
- Chiara Bazzichetto
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
- Correspondence: (C.B.); (M.M.); Tel.: +39-06-52665185 (C.B.)
| | - Michele Milella
- Section of Oncology, Department of Medicine, University of Verona-School of Medicine and Verona University Hospital Trust, 37134 Verona, Italy
- Correspondence: (C.B.); (M.M.); Tel.: +39-06-52665185 (C.B.)
| | - Ilaria Zampiva
- Section of Oncology, Department of Medicine, University of Verona-School of Medicine and Verona University Hospital Trust, 37134 Verona, Italy
| | | | | | - Simonetta Buglioni
- Pathology Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Chiara Pacelli
- Department of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, 00185 Rome, Italy
| | - Loredana Le Pera
- Servizio Grandi Strumentazioni e Core Facilities, Istituto Superiore di Sanità (ISS), 00161 Rome, Italy
| | - Teresa Colombo
- Institute of Molecular Biology and Pathology-National Research Council (IBPM-CNR), 00185 Rome, Italy
| | - Emilio Bria
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Massimo Zeuli
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Donatella Del Bufalo
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Isabella Sperduti
- Biostatistics Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Fabiana Conciatori
- Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
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43
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Korkmaz M, Karakurt Eryilmaz M, Karaağaç M, Araz M, Çeneli Ö, Artaç M. Ibrutinib and panitumumab used in combination safely in a patient with metachronous colorectal cancer and chronic lymphocytic leukemia. Anticancer Drugs 2022; 33:765-767. [PMID: 35946528 DOI: 10.1097/cad.0000000000001333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Ibrutinib is a Bruton tyrosine kinase inhibitor used in the treatment of chronic lymphocytic leukemia (CLL). Panitumumab, an mAb for epidermal growth factor receptor, is used in the treatment of metastatic colorectal cancer (CRC). We wanted to present our case where we used ibrutinib and panitumumab in combination in a patient with metachronous CLL and CRC. A 58-year-old male patient with a diagnosis of CLL was receiving ibrutinib treatment and primary rectal cancer was detected. FOLFOX + panitumumab were started when metastasis was detected in the lung after neoadjuvant chemoradiotherapy for rectal cancer. The patients used ibrutinib and panitumumab in combination. There was no cumulative or unexpected toxicity due to the combination of both antineoplastic agents. The most important point to be considered in the use of combined drugs is the evaluation of drug-drug interactions. Toxic effects of the combination of ibrutinib and cetuximab have been reported in a patient with metastatic CRC. We used ibrutinib together with panitumumab in our case and we did not encounter any cumulative or unexpected side effects during the treatment.
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Affiliation(s)
| | | | | | | | - Özcan Çeneli
- Department of Hematology, Necmettin Erbakan University School of Medicine, Konya, Turkey
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44
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Alfaro Alfaro ÁE, Murillo Castillo B, Cordero García E, Tascón J, Morales AI. Colon Cancer Pharmacogenetics: A Narrative Review. PHARMACY 2022; 10:95. [PMID: 36005935 PMCID: PMC9413567 DOI: 10.3390/pharmacy10040095] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/22/2022] [Accepted: 07/27/2022] [Indexed: 12/16/2022] Open
Abstract
Currently, metastatic colon cancer is treated with monotherapeutic regimens such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX), capecitabine and oxaliplatin (CapeOX), and leucovorin, fluorouracil, and irinotecan hydrochloride (FOLFIRI). Other treatments include biological therapies and immunotherapy with drugs such as bevacizumab, panitumumab, cetuximab, and pembrolizumab. After the research, it was found that some mutations make those treatments not as effective in all patients. In this bibliographic review, we investigated the pharmacogenetic explanations for how mutations in the genes coding for rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) reduce the effectiveness of these treatments and allow the continued proliferation of tumors. Furthermore, we note that patients with mutations in the dihydropyrimidine dehydrogenase (DPDY) gene usually require lower doses of therapies such as 5-fluorouracyl (5-FU) and capecitabine to avoid severe adverse effects. Some other mutations in the thymidylate synthase gene (TSYM), methylenetetrahydrofolate reductase gene (MTHFR), and ATP binding cassette transporter B (ABCB1 and ABCB2) affect efficacy and security of the treatments. It is important to address the clinical implication of the oncologist in the study of gene mutations than can influence in the antitumoral response and safety of colon cancer treatments.
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Affiliation(s)
| | | | | | - Javier Tascón
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana I. Morales
- Toxicology Unit, Universidad de Salamanca, 37007 Salamanca, Spain
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45
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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46
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Morindone from Morinda citrifolia as a potential antiproliferative agent against colorectal cancer cell lines. PLoS One 2022; 17:e0270970. [PMID: 35819953 PMCID: PMC9275698 DOI: 10.1371/journal.pone.0270970] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 06/21/2022] [Indexed: 11/30/2022] Open
Abstract
There is an increasing demand in developing new, effective, and affordable anti-cancer against colon and rectal. In this study, our aim is to identify the potential anthraquinone compounds from the root bark of Morinda citrifolia to be tested in vitro against colorectal cancer cell lines. Eight potential anthraquinone compounds were successfully isolated, purified and tested for both in-silico and in-vitro analyses. Based on the in-silico prediction, two anthraquinones, morindone and rubiadin, exhibit a comparable binding affinity towards multitargets of β-catenin, MDM2-p53 and KRAS. Subsequently, we constructed a 2D interaction analysis based on the above results and it suggests that the predicted anthraquinones from Morinda citrifolia offer an attractive starting point for potential antiproliferative agents against colorectal cancer. In vitro analyses further indicated that morindone and damnacanthal have significant cytotoxicity effect and selectivity activity against colorectal cancer cell lines.
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47
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Clonal evolution and expansion associated with therapy resistance and relapse of colorectal cancer. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2022; 790:108445. [PMID: 36371022 DOI: 10.1016/j.mrrev.2022.108445] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 11/01/2022] [Accepted: 11/07/2022] [Indexed: 11/10/2022]
Abstract
Colorectal cancer (CRC) arises by a continuous process of genetic diversification and clonal evolution. Multiple genes and pathways have a role in tumor initiation and progression. The gradual accumulation of genetic and epigenetic processes leads to the establishment of adenoma and cancer. The important 'driver' mutations in tumor suppressor genes (such as TP53, APC, and SMAD4) and oncogenes (such as KRAS, NRAS, MET, and PIK3CA) confer selective growth advantages and cause CRC advancement. Clonal evolution induced by therapeutic pressure, as well as intra-tumoral heterogeneity, has been a great challenge in the treatment of metastatic CRC. Tumors often develop resistance to treatments as a result of intra-tumor heterogeneity, clonal evolution, and selection. Hence, the development of a multidrug personalized approach should be prioritized to pave the way for therapeutics repurposing and combination therapy to arrest tumor progression. This review summarizes how selective drug pressure can impact tumor evolution, resulting in the formation of polyclonal resistance mechanisms, ultimately promoting cancer progression. Current strategies for targeting clonal evolution are described. By understanding sources and consequences of tumor heterogeneity, customized and effective treatment plans to combat drug resistance may be devised.
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48
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Hamdan A, Ewing A. Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis. J Pathol 2022; 257:479-493. [PMID: 35355264 PMCID: PMC9321913 DOI: 10.1002/path.5901] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/16/2022] [Accepted: 03/28/2022] [Indexed: 11/15/2022]
Abstract
Structural variants (SVs) represent a major source of aberration in tumour genomes. Given the diversity in the size and type of SVs present in tumours, the accurate detection and interpretation of SVs in tumours is challenging. New classes of complex structural events in tumours are discovered frequently, and the definitions of the genomic consequences of complex events are constantly being refined. Detailed analyses of short-read whole-genome sequencing (WGS) data from large tumour cohorts facilitate the interrogation of SVs at orders of magnitude greater scale and depth. However, the inherent technical limitations of short-read WGS prevent us from accurately detecting and investigating the impact of all the SVs present in tumours. The expanded use of long-read WGS will be critical for improving the accuracy of SV detection, and in fully resolving complex SV events, both of which are crucial for determining the impact of SVs on tumour progression and clinical outcome. Despite the present limitations, we demonstrate that SVs play an important role in tumourigenesis. In particular, SVs contribute significantly to late-stage tumour development and to intratumoural heterogeneity. The evolutionary trajectories of SVs represent a window into the clonal dynamics in tumours, a comprehensive understanding of which will be vital for influencing patient outcomes in the future. Recent findings have highlighted many clinical applications of SVs in cancer, from early detection to biomarkers for treatment response and prognosis. As the methods to detect and interpret SVs improve, elucidating the full breadth of the complex SV landscape and determining how these events modulate tumour evolution will improve our understanding of cancer biology and our ability to capitalise on the utility of SVs in the clinical management of cancer patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Alhafidz Hamdan
- MRC Human Genetics Unit, Institute of Genetics and CancerUniversity of EdinburghEdinburghUK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and CancerUniversity of EdinburghEdinburghUK
| | - Ailith Ewing
- MRC Human Genetics Unit, Institute of Genetics and CancerUniversity of EdinburghEdinburghUK
- Cancer Research UK Edinburgh Centre, Institute of Genetics and CancerUniversity of EdinburghEdinburghUK
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49
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
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50
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Lyu N, Pedersen B, Shklovskaya E, Rizos H, Molloy MP, Wang Y. SERS characterization of colorectal cancer cell surface markers upon anti-EGFR treatment. EXPLORATION (BEIJING, CHINA) 2022; 2:20210176. [PMID: 37323700 PMCID: PMC10190927 DOI: 10.1002/exp.20210176] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/11/2022] [Indexed: 06/16/2023]
Abstract
Colorectal cancer (CRC) is the third most diagnosed and the second lethal cancer worldwide. Approximately 30-50% of CRC are driven by mutations in the KRAS oncogene, which is a strong negative predictor for response to anti-epidermal growth factor receptor (anti-EGFR) therapy. Examining the phenotype of KRAS mutant and wild-type (WT) CRC cells in response to anti-EGFR treatment may provide significant insights into drug response and resistance. Herein, surface-enhanced Raman spectroscopy (SERS) assay was applied to phenotype four cell surface proteins (EpCAM, EGFR, HER2, HER3) in KRAS mutant (SW480) and WT (SW48) cells over a 24-day time course of anti-EGFR treatment with cetuximab. Cell phenotypes were obtained using Raman reporter-coated and antibody-conjugated gold nanoparticles (SERS nanotags), where a characteristic Raman spectrum was generated upon single laser excitation, reflecting the presence of the targeted surface marker proteins. Compared to the KRAS mutant cells, KRAS WT cells were more sensitive to anti-EGFR treatment and displayed a significant decrease in HER2 and HER3 expression. The SERS results were validated with flow cytometry, confirming the SERS assay is promising as an alternative method for multiplexed characterization of cell surface biomarkers using a single laser excitation system.
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Affiliation(s)
- Nana Lyu
- ARC Center of Excellence for Nanoscale BioPhotonics and School of Natural Sciences, Faculty of Science and EngineeringMacquarie UniversitySydneyNew South WalesAustralia
| | - Bernadette Pedersen
- Department of Biomedical Sciences, Faculty of Medicine, Health and Human SciencesMacquarie UniversitySydneyNew South WalesAustralia
| | - Elena Shklovskaya
- Department of Biomedical Sciences, Faculty of Medicine, Health and Human SciencesMacquarie UniversitySydneyNew South WalesAustralia
| | - Helen Rizos
- Department of Biomedical Sciences, Faculty of Medicine, Health and Human SciencesMacquarie UniversitySydneyNew South WalesAustralia
| | - Mark P. Molloy
- Bowel Cancer and Biomarker Laboratory, School of Medical Sciences, Kolling InstituteThe University of SydneySydneyNew South WalesAustralia
| | - Yuling Wang
- ARC Center of Excellence for Nanoscale BioPhotonics and School of Natural Sciences, Faculty of Science and EngineeringMacquarie UniversitySydneyNew South WalesAustralia
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