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1
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Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer. World J Gastroenterol 2023; 29:1911-1941. [PMID: 37155531 PMCID: PMC10122790 DOI: 10.3748/wjg.v29.i13.1911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/02/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.
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Affiliation(s)
- Sheng-Nan Ren
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Zhan-Yi Zhang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Jie Guo
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Ren Wang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Fang-Fang Chen
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Bo Chen
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Dong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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2
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Ruan H, Xiong J. Value of carbon-ion radiotherapy for early stage non-small cell lung cancer. Clin Transl Radiat Oncol 2022; 36:16-23. [PMID: 35756194 PMCID: PMC9213230 DOI: 10.1016/j.ctro.2022.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 06/06/2022] [Accepted: 06/13/2022] [Indexed: 12/24/2022] Open
Abstract
Carbon-ion radiotherapy (CIRT) is an important part of modern radiotherapy. Compared to conventional photon radiotherapy modalities, CIRT brings two major types of advantages to physical and biological aspects respectively. The physical advantages include a substantial dose delivery to the tumoral area and a minimization of dose damage to the surrounding tissue. The biological advantages include an increase in double-strand breaks (DSBs) in DNA structures, an upturn in oxygen enhancement ratio and an improvement of radiosensitivity compared with X-ray radiotherapy. The two advantages of CIRT are that the therapy not only inflicts major cytotoxic lesions on tumor cells, but it also protects the surrounding tissue. According to annual diagnoses, lung cancer is the second most common cancer worldwide, followed by breast cancer. However, lung cancer is the leading cause of cancer death. Patients with stage I non-small cell lung cancer (NSCLC) who are optimally received the treatment of lobectomy. Some patients with comorbidities or combined cardiopulmonary insufficiency have been shown to be unable to tolerate the treatment when combined with surgery. Consequentially, radiotherapy may be the best treatment option for this patient category. Multiple radiotherapy options are available for these cases, such as stereotactic body radiotherapy (SBRT), volumetric modulated arc therapy (VMAT), and intensity-modulated radiotherapy (IMRT). Although these treatments have brought some clinical benefits to some patients, the resulting adverse events (AEs), which include cardiotoxicity and radiation pneumonia, cannot be ignored. The damage and toxicity to normal tissue also limit the increase of tumor dose. Due to the significant physical and biological advantages brought by CIRT, some toxicity induced by radiotherapy may be avoided with CIRT Bragg Peak. CIRT brought clinical benefits to lung cancer patients, especially geriatric patients. This review introduced the clinical efficacy and research results for non-small cell lung cancer (NSCLC) with CIRT.
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Affiliation(s)
- Hanguang Ruan
- Department of Radiation Oncology, Graduate School of Medicine, Gunma University, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
- Gunma University Heavy Ion Medical Center, 3-39-22, Showa-machi, Maebashi, Gunma 371-8511, Japan
- Department of Radiation Oncology, The Third Hospital of Nanchang, No 1248 Jiuzhou Avenue, Nanchang City 300002, China
| | - Juan Xiong
- Department of Radiation Oncology, Jiangxi Cancer Hospital, 519 East Beijing Road, Nanchang City 330029, China
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Darwis NDM, Horigome E, Li S, Adachi A, Oike T, Shibata A, Hirota Y, Ohno T. Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455. Cells 2022; 11:cells11111727. [PMID: 35681425 PMCID: PMC9179643 DOI: 10.3390/cells11111727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 05/16/2022] [Accepted: 05/23/2022] [Indexed: 02/05/2023] Open
Abstract
Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of LY2874455 remain unclear. In this study, we addressed this issue by using radioresistant human cancer cell lines H1703 (FGFR1 mutant), A549 (FGFR1–4 wild-type), and H1299 (FGFR1–4 wild-type). At an X-ray dose corresponding to 50%-clonogenic survival as the endpoint, 100 nM LY2874455 increased the sensitivity of H1703, A549, and H1299 cells by 31%, 62%, and 53%, respectively. The combination of X-rays and LY2874455 led to a marked induction of mitotic catastrophe, a hallmark of radiation-induced cell death. Furthermore, combination treatment suppressed the growth of A549 xenografts to a significantly greater extent than either X-rays or the drug alone without noticeable toxicity. This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation.
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Affiliation(s)
- Narisa Dewi Maulany Darwis
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
- Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital, Faculty of Medicine Universitas Indonesia, Jl. Diponegoro No. 71, Jakarta Pusat, DKI Jakarta 10430, Indonesia
| | - Eisuke Horigome
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
| | - Shan Li
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
| | - Akiko Adachi
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
| | - Takahiro Oike
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
- Gunma University Heavy Ion Medical Center, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Correspondence:
| | - Atsushi Shibata
- Signal Transduction Program, Gunma University Initiative for Advanced Research (GIAR), Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan;
| | - Yuka Hirota
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
| | - Tatsuya Ohno
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan; (N.D.M.D.); (E.H.); (S.L.); (A.A.); (Y.H.); (T.O.)
- Gunma University Heavy Ion Medical Center, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
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Liang S, Zhou G, Hu W. Research Progress of Heavy Ion Radiotherapy for Non-Small-Cell Lung Cancer. Int J Mol Sci 2022; 23:2316. [PMID: 35216430 PMCID: PMC8876478 DOI: 10.3390/ijms23042316] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/10/2022] [Accepted: 02/18/2022] [Indexed: 02/05/2023] Open
Abstract
Non-small-cell lung cancer (NSCLC) has a high incidence and poses a serious threat to human health. However, the treatment outcomes of concurrent chemoradiotherapy for non-small-cell lung cancer are still unsatisfactory, especially for high grade lesions. As a new cancer treatment, heavy ion radiotherapy has shown promising efficacy and safety in the treatment of non-small-cell lung cancer. This article discusses the clinical progress of heavy ion radiotherapy in the treatment of non-small-cell lung cancer mainly from the different cancer stages, the different doses of heavy ion beams, and the patient's individual factors, and explores the deficiency of heavy ion radiotherapy in the treatment of non-small-cell lung cancer and the directions of future research, in order to provide reference for the wider and better application of heavy ion radiotherapy in the future.
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Affiliation(s)
| | - Guangming Zhou
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China;
| | - Wentao Hu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China;
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5
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Li Y, Li X, Yang J, Wang S, Tang M, Xia J, Gao Y. Flourish of Proton and Carbon Ion Radiotherapy in China. Front Oncol 2022; 12:819905. [PMID: 35237518 PMCID: PMC8882681 DOI: 10.3389/fonc.2022.819905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Proton and heavy ion therapy offer superior relative biological effectiveness (RBE) in the treatment of deep-seated tumors compared with conventional photon radiotherapy due to its Bragg-peak feature of energy deposition in organs. Many proton and carbon ion therapy centers are active all over the world. At present, five particle radiotherapy institutes have been built and are receiving patient in China, mainly including Wanjie Proton Therapy Center (WPTC), Shanghai Proton Heavy Ion Center (SPHIC), Heavy Ion Cancer Treatment Center (HIMM), Chang Gung Memorial Hospital (CGMH), and Ruijin Hospital affiliated with Jiao Tong University. Many cancer patients have benefited from ion therapy, showing unique advantages over surgery and chemotherapy. By the end of 2020, nearly 8,000 patients had been treated with proton, carbon ion or carbon ion combined with proton therapy. So far, there is no systemic review for proton and carbon ion therapy facility and clinical outcome in China. We reviewed the development of proton and heavy ion therapy, as well as providing the representative clinical data and future directions for particle therapy in China. It has important guiding significance for the design and construction of new particle therapy center and patients’ choice of treatment equipment.
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Affiliation(s)
- Yue Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- *Correspondence: Yue Li,
| | - Xiaoman Li
- Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jiancheng Yang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Sicheng Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Meitang Tang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jiawen Xia
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Huizhou Research Center of Ion Science, Chinese Academy of Sciences, Huizhou, China
| | - Yunzhe Gao
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- School of Nuclear Science and Technology, University of Chinese Academy of Sciences, Beijing, China
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Petroni G, Cantley LC, Santambrogio L, Formenti SC, Galluzzi L. Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer. Nat Rev Clin Oncol 2022; 19:114-131. [PMID: 34819622 PMCID: PMC9004227 DOI: 10.1038/s41571-021-00579-w] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2021] [Indexed: 02/03/2023]
Abstract
A variety of targeted anticancer agents have been successfully introduced into clinical practice, largely reflecting their ability to inhibit specific molecular alterations that are required for disease progression. However, not all malignant cells rely on such alterations to survive, proliferate, disseminate and/or evade anticancer immunity, implying that many tumours are intrinsically resistant to targeted therapies. Radiotherapy is well known for its ability to activate cytotoxic signalling pathways that ultimately promote the death of cancer cells, as well as numerous cytoprotective mechanisms that are elicited by cellular damage. Importantly, many cytoprotective mechanisms elicited by radiotherapy can be abrogated by targeted anticancer agents, suggesting that radiotherapy could be harnessed to enhance the clinical efficacy of these drugs. In this Review, we discuss preclinical and clinical data that introduce radiotherapy as a tool to elicit or amplify clinically actionable signalling pathways in patients with cancer.
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Affiliation(s)
- Giulia Petroni
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Lewis C Cantley
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Laura Santambrogio
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Silvia C Formenti
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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7
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Molecular mechanisms of the anti-cancer drug, LY2874455, in overcoming the FGFR4 mutation-based resistance. Sci Rep 2021; 11:16593. [PMID: 34400727 PMCID: PMC8368202 DOI: 10.1038/s41598-021-96159-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 08/05/2021] [Indexed: 12/19/2022] Open
Abstract
In recent years, many strategies have been used to overcome the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) resistance caused by different mutations. LY2874455 (or 6LF) is a pan-FGFR inhibitor which is identified as the most efficient TKI for all resistant mutations in FGFRs. Here, we perform a comparative dynamics study of wild type (WT) and the FGFR4 V550L mutant for better understanding of the 6LF inhibition mechanism. Our results confirm that the pan-FGFR inhibitor 6LF can bind efficiently to both WT and V550L FGFR4. Moreover, the communication network analysis indicates that in apo-WT FGFR4, αD–αE loop behaves like a switch between open and close states of the substrate-binding pocket in searching of its ligand. In contrast, V550L mutation induces the active conformation of the FGFR4 substrate-binding pocket through disruption of αD–αE loop and αG helix anti-correlation. Interestingly, 6LF binding causes the rigidity of hinge and αD helix regions, which results in overcoming V550L induced resistance. Collectively, the results of this study would be informative for designing more efficient TKIs for more effective targeting of the FGFR signaling pathway.
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Molè MA, Coorens THH, Shahbazi MN, Weberling A, Weatherbee BAT, Gantner CW, Sancho-Serra C, Richardson L, Drinkwater A, Syed N, Engley S, Snell P, Christie L, Elder K, Campbell A, Fishel S, Behjati S, Vento-Tormo R, Zernicka-Goetz M. A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre. Nat Commun 2021; 12:3679. [PMID: 34140473 PMCID: PMC8211662 DOI: 10.1038/s41467-021-23758-w] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 05/11/2021] [Indexed: 01/02/2023] Open
Abstract
Following implantation, the human embryo undergoes major morphogenetic transformations that establish the future body plan. While the molecular events underpinning this process are established in mice, they remain unknown in humans. Here we characterise key events of human embryo morphogenesis, in the period between implantation and gastrulation, using single-cell analyses and functional studies. First, the embryonic epiblast cells transition through different pluripotent states and act as a source of FGF signals that ensure proliferation of both embryonic and extra-embryonic tissues. In a subset of embryos, we identify a group of asymmetrically positioned extra-embryonic hypoblast cells expressing inhibitors of BMP, NODAL and WNT signalling pathways. We suggest that this group of cells can act as the anterior singalling centre to pattern the epiblast. These results provide insights into pluripotency state transitions, the role of FGF signalling and the specification of anterior-posterior axis during human embryo development.
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Affiliation(s)
- Matteo A Molè
- Department of Physiology, Development and Neuroscience, Mammalian Embryo and Stem Cell Group, University of Cambridge, Cambridge, UK
- Babraham Institute, Babraham Research Campus, Cambridge, UK
| | | | - Marta N Shahbazi
- Department of Physiology, Development and Neuroscience, Mammalian Embryo and Stem Cell Group, University of Cambridge, Cambridge, UK
- MRC Laboratory of Molecular Biology, Cambridge, UK
| | - Antonia Weberling
- Department of Physiology, Development and Neuroscience, Mammalian Embryo and Stem Cell Group, University of Cambridge, Cambridge, UK
| | - Bailey A T Weatherbee
- Department of Physiology, Development and Neuroscience, Mammalian Embryo and Stem Cell Group, University of Cambridge, Cambridge, UK
| | - Carlos W Gantner
- Department of Physiology, Development and Neuroscience, Mammalian Embryo and Stem Cell Group, University of Cambridge, Cambridge, UK
| | | | - Lucy Richardson
- Herts & Essex Fertility Centre, Bishops College, Cheshunt, Herts, UK
| | - Abbie Drinkwater
- Herts & Essex Fertility Centre, Bishops College, Cheshunt, Herts, UK
| | - Najma Syed
- Herts & Essex Fertility Centre, Bishops College, Cheshunt, Herts, UK
| | - Stephanie Engley
- Herts & Essex Fertility Centre, Bishops College, Cheshunt, Herts, UK
| | | | | | | | | | - Simon Fishel
- CARE Fertility Group, Nottingham, UK
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
| | - Sam Behjati
- Wellcome Sanger Institute, Hinxton, UK.
- Cambridge University Hospital, NHS Foundation Trust, Cambridge, UK.
- Department of Paediatrics, University of Cambridge, Cambridge, UK.
| | | | - Magdalena Zernicka-Goetz
- Department of Physiology, Development and Neuroscience, Mammalian Embryo and Stem Cell Group, University of Cambridge, Cambridge, UK.
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
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Yoshimoto Y, Sasaki Y, Murata K, Noda SE, Miyasaka Y, Hamamoto J, Furuya M, Hirato J, Suzuki Y, Ohno T, Tokino T, Oike T, Nakano T. Mutation profiling of uterine cervical cancer patients treated with definitive radiotherapy. Gynecol Oncol 2020; 159:546-553. [PMID: 32951893 DOI: 10.1016/j.ygyno.2020.08.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To elucidate tumor mutation profiles associated with outcomes of uterine cervical cancer (UCC) patients treated with definitive radiotherapy. METHODS Ninety-eight patients with newly diagnosed and pathologically confirmed UCC (82 squamous cell carcinomas, 12 adenocarcinomas, and four adenosquamous carcinomas) who were treated with definitive radiotherapy were analyzed. DNA was extracted from pre-treatment tumor biopsy specimens. The exons of 409 cancer-related genes were sequenced using a next-generation sequencer. Genetic mutations were identified and analyzed for correlations with clinical outcome. RESULTS Recurrent mutations were observed in PIK3CA (35.7%), ARID1A (25.5%), NOTCH1 (19.4%), FGFR3 (16.3%), FBXW7 (19.4%), TP53 (13.3%), EP300 (12.2%), and FGFR4 (10.2%). The prevalence of mutations in FGFR family genes (i.e., FGFR1-4) was almost as high (24.5%) as that in PIK3CA and ARID1A, both of which are well-studied drivers of UCC. Fifty-five percent (21 of 38) of the identified FGFR mutations were located in the FGFR protein tyrosine kinase domain. Five-year progression-free survival (PFS) rates for FGFR mutation-positive patients (n = 24) were significantly worse than those for FGFR mutation-negative patients (n = 74) (43.9% vs. 68.5%, respectively; P = 0.010). Multivariate analysis identified FGFR mutations as significant predictors of worse 5 year PFS (P = 0.005), independent of clinicopathological variables. CONCLUSIONS FGFR mutations are associated with worse PFS in UCC patients treated with definitive radiotherapy. These results warrant further validation in prospective studies.
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Affiliation(s)
- Yuya Yoshimoto
- Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan; Department of Radiation Oncology, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Yasushi Sasaki
- Center for Medical Education, Sapporo Medical University, Sapporo, Japan
| | - Kazutoshi Murata
- Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan
| | - Shin-Ei Noda
- Department of Radiation Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Yuhei Miyasaka
- Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan
| | - Junko Hamamoto
- Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Mio Furuya
- Department of Pathology, Maebashi Red Cross Hospital, Maebashi, Japan; Department of Pathology, Gunma University Hospital, Maebashi, Japan
| | - Junko Hirato
- Department of Pathology, Gunma University Hospital, Maebashi, Japan; Department of Pathology, Public Tomioka General Hospital, Maebashi, Japan
| | - Yoshiyuki Suzuki
- Department of Radiation Oncology, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Tatsuya Ohno
- Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan
| | - Takashi Tokino
- Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takahiro Oike
- Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan.
| | - Takashi Nakano
- Department of Radiation Oncology, Gunma Graduate School of Medicine, Maebashi, Japan; National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan
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10
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Counteracting Radio-Resistance Using the Optimization of Radiotherapy. Int J Mol Sci 2020; 21:ijms21051767. [PMID: 32150868 PMCID: PMC7084332 DOI: 10.3390/ijms21051767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 12/23/2022] Open
Abstract
Radiotherapy is an essential component of cancer therapy and remains one of the most (cost-) effective treatment options available [...].
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11
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Bale TA. FGFR- gene family alterations in low-grade neuroepithelial tumors. Acta Neuropathol Commun 2020; 8:21. [PMID: 32085805 PMCID: PMC7035775 DOI: 10.1186/s40478-020-00898-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
The discovery of fibroblast growth factor receptor (FGFR) gene family alterations as drivers of primary brain tumors has generated significant excitement, both as potential therapeutic targets as well as defining hallmarks of histologic entities. However, FGFR alterations among neuroepithelial lesions are not restricted to high or low grade, nor to adult vs. pediatric-type tumors. While it may be tempting to consider FGFR-altered tumors as a unified group, this underlying heterogeneity poses diagnostic and interpretive challenges. Therefore, understanding the underlying biology of tumors harboring specific FGFR alterations is critical. In this review, recent evidence for recurrent FGFR alterations in histologically and biologically low-grade neuroepithelial tumors (LGNTs) is examined (namely FGFR1 tyrosine kinase domain duplication in low grade glioma, FGFR1-TACC1 fusions in extraventricular neurocytoma [EVN], and FGFR2-CTNNA3 fusions in polymorphous low-grade neuroepithelial tumor of the young [PLNTY]). Additionally, FGFR alterations with less well-defined prognostic implications are considered (FGFR3-TACC3 fusions, FGFR1 hotspot mutations). Finally, a framework for practical interpretation of FGFR alterations in low grade glial/glioneuronal tumors is proposed.
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Affiliation(s)
- Tejus A Bale
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Street, New York, NY, 10065, USA.
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12
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Abstract
The discovery of fibroblast growth factor receptor (FGFR) gene family alterations as drivers of primary brain tumors has generated significant excitement, both as potential therapeutic targets as well as defining hallmarks of histologic entities. However, FGFR alterations among neuroepithelial lesions are not restricted to high or low grade, nor to adult vs. pediatric-type tumors. While it may be tempting to consider FGFR-altered tumors as a unified group, this underlying heterogeneity poses diagnostic and interpretive challenges. Therefore, understanding the underlying biology of tumors harboring specific FGFR alterations is critical. In this review, recent evidence for recurrent FGFR alterations in histologically and biologically low-grade neuroepithelial tumors (LGNTs) is examined (namely FGFR1 tyrosine kinase domain duplication in low grade glioma, FGFR1-TACC1 fusions in extraventricular neurocytoma [EVN], and FGFR2-CTNNA3 fusions in polymorphous low-grade neuroepithelial tumor of the young [PLNTY]). Additionally, FGFR alterations with less well-defined prognostic implications are considered (FGFR3-TACC3 fusions, FGFR1 hotspot mutations). Finally, a framework for practical interpretation of FGFR alterations in low grade glial/glioneuronal tumors is proposed.
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Affiliation(s)
- Tejus A Bale
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Street, New York, NY, 10065, USA.
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