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Ma K, Mao Q, Fei B, Ni T, Zhang Z, Ni H. Metabolic reprogramming and immune microenvironment characteristics in laryngeal carcinoma: advances in immunotherapy. Front Immunol 2025; 16:1589243. [PMID: 40370437 PMCID: PMC12075248 DOI: 10.3389/fimmu.2025.1589243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Accepted: 04/08/2025] [Indexed: 05/16/2025] Open
Abstract
Laryngeal squamous cell carcinoma (LSCC) is a prevalent malignancy with high mortality and recurrence rates, necessitating novel therapeutic strategies. Recent research highlights the pivotal role of metabolic reprogramming and immune microenvironment alterations in LSCC pathogenesis, providing promising avenues for targeted therapy. This review summarizes the metabolic characteristics of LSCC, including glycolysis, lipid metabolism, and amino acid biosynthesis, and their implications for tumor progression and therapeutic resistance. Additionally, this review further describes the tumor microenvironment's immunosuppressive landscape, including immune checkpoint regulation, tumor-associated macrophages, and T-cell dysfunction. The integration of metabolic and immune-targeted strategies represents a promising frontier in LSCC treatment, warranting further investigation.
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Affiliation(s)
- Kexin Ma
- Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Qingjie Mao
- Department of Otolaryngology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Bing Fei
- Department of Otolaryngology Head and Neck Surgery, Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, China
| | - Tingting Ni
- Department of Oncology, Nantong Tumor Hospital, Nantong, China
| | - Zhenxin Zhang
- Department of Otolaryngology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Haosheng Ni
- Department of Otolaryngology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, China
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Akhunzianov AA, Rozhina EV, Filina YV, Rizvanov AA, Miftakhova RR. Resistance to Radiotherapy in Cancer. Diseases 2025; 13:22. [PMID: 39851486 PMCID: PMC11764699 DOI: 10.3390/diseases13010022] [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: 12/13/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 01/26/2025] Open
Abstract
Radiation therapy or radiotherapy is a medical treatment that uses high doses of ionizing radiation to eliminate cancer cells and shrink tumors. It works by targeting the DNA within the tumor cells restricting their proliferation. Radiotherapy has been used for treating cancer for more than 100 years. Along with surgery and chemotherapy, it is one of the three main and most common approaches used in cancer therapy. Nowadays, radiotherapy has become a standard treatment option for a wide range of cancers around the world, including lung, breast, cervical, and colorectal cancers. Around 50% of all patients will require radiotherapy, 60% of whom are treated with curative intent. Moreover, it is commonly used for palliative treatment. Radiotherapy provides 5-year local control and overall survival benefit in 10.4% and 2.4% of all cancer patients, respectively. The highest local control benefit is reported for cervical (33%), head and neck (32%), and prostate (26%) cancers. But no benefit is observed in pancreas, ovary, liver, kidney, and colon cancers. Such relatively low efficiency is related to the development of radiation resistance, which results in cancer recurrence, metastatic dissemination, and poor prognosis. The identification of radioresistance biomarkers allows for improving the treatment outcome. These biomarkers mainly include proteins involved in metabolism and cell signaling pathways.
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Affiliation(s)
- Almaz A. Akhunzianov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Elvira V. Rozhina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Yuliya V. Filina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, 420111 Kazan, Russia
| | - Regina R. Miftakhova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
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3
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Nair LM, Ravikumar R, Rafi M, Poulose JV, Jose N, Pisharody K, Thommachan KC. Anti‑epidermal growth factor receptor monoclonal antibody therapy in locally advanced head and neck cancer: A systematic review of phase III clinical trials. MEDICINE INTERNATIONAL 2024; 4:41. [PMID: 38873325 PMCID: PMC11170331 DOI: 10.3892/mi.2024.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 04/03/2024] [Indexed: 06/15/2024]
Abstract
The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m2 weekly, instead of the standard doses of 100 mg/m2 every 3 weeks or 40 mg/m2 every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.
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Affiliation(s)
- Lekha Madhavan Nair
- Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India
| | - Rejnish Ravikumar
- Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India
| | - Malu Rafi
- Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India
| | - Jissy Vijo Poulose
- Department of Palliative Medicine, DEAN Foundation Hospice and Palliative Care Centre, Chennai, Tamil Nadu 600010, India
| | - Nijo Jose
- Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India
| | - Krishnapriya Pisharody
- Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala 695011, India
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Kermorgant S. Rationale for Cotargeting Hepatocyte Growth Factor and Epidermal Growth Factor Receptor in Recurrent/Metastatic Head and Neck Cancer. J Clin Oncol 2023:JCO2300460. [PMID: 37319388 DOI: 10.1200/jco.23.00460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/03/2023] [Accepted: 05/10/2023] [Indexed: 06/17/2023] Open
Affiliation(s)
- Stéphanie Kermorgant
- Spatial Signalling Group, Barts Cancer Institute-a CR-UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, London, United Kingdom
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Li Q, Tie Y, Alu A, Ma X, Shi H. Targeted therapy for head and neck cancer: signaling pathways and clinical studies. Signal Transduct Target Ther 2023; 8:31. [PMID: 36646686 PMCID: PMC9842704 DOI: 10.1038/s41392-022-01297-0] [Citation(s) in RCA: 103] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/27/2022] [Accepted: 12/13/2022] [Indexed: 01/17/2023] Open
Abstract
Head and neck cancer (HNC) is malignant, genetically complex and difficult to treat and is the sixth most frequent cancer, with tobacco, alcohol and human papillomavirus being major risk factors. Based on epigenetic data, HNC is remarkably heterogeneous, and treatment remains challenging. There is a lack of significant improvement in survival and quality of life in patients with HNC. Over half of HNC patients experience locoregional recurrence or distal metastasis despite the current multiple traditional therapeutic strategies and immunotherapy. In addition, resistance to chemotherapy, radiotherapy and some targeted therapies is common. Therefore, it is urgent to explore more effective and tolerable targeted therapies to improve the clinical outcomes of HNC patients. Recent targeted therapy studies have focused on identifying promising biomarkers and developing more effective targeted therapies. A well understanding of the pathogenesis of HNC contributes to learning more about its inner association, which provides novel insight into the development of small molecule inhibitors. In this review, we summarized the vital signaling pathways and discussed the current potential therapeutic targets against critical molecules in HNC, as well as presenting preclinical animal models and ongoing or completed clinical studies about targeted therapy, which may contribute to a more favorable prognosis of HNC. Targeted therapy in combination with other therapies and its limitations were also discussed.
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Affiliation(s)
- Qingfang Li
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Tie
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Aqu Alu
- grid.13291.380000 0001 0807 1581Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Huashan Shi
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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Rawat S, Jain RK, Verma C. Cetuximab Concurrent with Radiotherapy in Unresectable, Locally Advanced Squamous Cell Carcinoma of Head and Neck: Real-World Evidence from a Tertiary Care Hospital. Indian J Otolaryngol Head Neck Surg 2022; 74:1857-1863. [PMID: 36452647 PMCID: PMC9702132 DOI: 10.1007/s12070-020-01877-y] [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: 04/01/2020] [Accepted: 04/29/2020] [Indexed: 12/24/2022] Open
Abstract
Cetuximab (EGFR-targeted IgG1 monoclonal antibody) has shown to improve the treatment outcomes in head and neck cancer. The evidence on the beneficial outcomes of cetuximab with radiotherapy (RT) in unresectable patients of locally advanced squamous cell carcinoma of head and neck (LA-SCCHN) is limited in real-life practice. The present study evaluated the treatment outcomes of cetuximab concurrent with RT in Indian patients with unresectable LA-SCCHN. We retrospectively reviewed fifty-one patients with unresectable LA-SCCHN between January 2013 and December 2017, who were treated with cetuximab concurrently with RT. Tumor response and disease-free survival (DFS) were estimated. Tumor response using RECIST (1.1) criteria reported complete response in 66.7%, partial response in 31.4% and progressive disease in 1.9% of the patients. The overall response rate was 98%. The 1-year and 2-year DFS was 85% and 69% respectively. The median DFS was significantly better in stage 3 than stage 4. The most common toxicity observed was mucositis and skin reactions (grade 3). Cetuximab concurrent with RT was effective in Indian patients with unresectable, LA-SCCHN and had an acceptable toxicity profile in real-life practice. The real-life beneficial evidence of the combination is consistent with the results documented in the randomized controlled trials.
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Affiliation(s)
- Shyamji Rawat
- Department of Radiation Oncology, NSCB Medical College and Government Hospital, Jabalpur, Madhya Pradesh 482003 India
| | - Rajesh Kumar Jain
- Department of Radiation Oncology, NSCB Medical College and Government Hospital, Jabalpur, Madhya Pradesh 482003 India
| | - Chandraprakash Verma
- Department of Radiation Oncology, NSCB Medical College and Government Hospital, Jabalpur, Madhya Pradesh 482003 India
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Imai C, Saeki H, Yamamoto K, Ichikawa A, Arai M, Tawada A, Suzuki T, Takiguchi Y, Hanazawa T, Ishii I. Radiotherapy plus cetuximab for locally advanced squamous cell head and neck cancer in patients with cisplatin-ineligible renal dysfunction: A retrospective study. Oncol Lett 2022; 23:152. [PMID: 35836484 PMCID: PMC9258593 DOI: 10.3892/ol.2022.13271] [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: 12/14/2021] [Accepted: 02/22/2022] [Indexed: 11/05/2022] Open
Abstract
Clinical trials have not fully demonstrated the efficacy and safety of radiotherapy plus cetuximab for locally advanced squamous cell head and neck cancer (LA-SCCHN) in patients with cisplatin-ineligible renal dysfunction. Patients who received radiotherapy plus cetuximab for LA-SCCHN at Chiba University Hospital (Chiba, Japan) between July 2013 and October 2018 were retrospectively reviewed. Background characteristics and locoregional control and overall survival rates were compared between patients with and without renal dysfunction. Survival was examined using Kaplan-Meier analysis and an adjusted Cox proportional hazards model. Kaplan-Meier analysis demonstrated that overall survival was shorter in patients with creatinine clearance of <45 ml/min (P=0.041; log-rank test). However, there was no difference in the locoregional control rate (P=0.477; log-rank test). Adjusted Cox analysis revealed that the risk of death was increased by 2.52-fold (hazard ratio, 2.52; 95% confidence interval, 1.01-6.30; P=0.048) if creatinine clearance was <45 ml/min. Moderate to severe renal dysfunction did not affect the locoregional control rate in patients with LA-SCCHN treated with radiotherapy plus cetuximab but was an adverse prognostic factor.
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Affiliation(s)
- Chiaki Imai
- Division of Pharmacy, Chiba University Hospital, Chiba, Chiba 260-8677, Japan
| | - Hiromi Saeki
- Division of Pharmacy, Chiba University Hospital, Chiba, Chiba 260-8677, Japan
| | - Kohei Yamamoto
- Division of Pharmacy, Chiba University Hospital, Chiba, Chiba 260-8677, Japan
| | - Ayano Ichikawa
- Division of Pharmacy, Chiba University Hospital, Chiba, Chiba 260-8677, Japan
| | - Makoto Arai
- Department of Gastroenterology, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Chiba 276-8524, Japan
| | - Akinobu Tawada
- Department of Nursing, Faculty of Health Care Sciences, Chiba Prefectural University of Health Sciences, Chiba, Chiba 261-0014, Japan
| | - Takaaki Suzuki
- Division of Pharmacy, Chiba University Hospital, Chiba, Chiba 260-8677, Japan
| | - Yuichi Takiguchi
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670, Japan
| | - Toyoyuki Hanazawa
- Department of Otorhinolaryngology/Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Chiba 260-8670, Japan
| | - Itsuko Ishii
- Division of Pharmacy, Chiba University Hospital, Chiba, Chiba 260-8677, Japan
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Campbell G, Glazer TA, Kimple RJ, Bruce JY. Advances in Organ Preservation for Laryngeal Cancer. Curr Treat Options Oncol 2022; 23:594-608. [PMID: 35303749 PMCID: PMC9405127 DOI: 10.1007/s11864-022-00945-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/30/2021] [Indexed: 12/11/2022]
Abstract
OPINION STATEMENT At the University of Wisconsin, all treatment of head and neck cancer patients begins with discussion at our multi-disciplinary tumor board. Most patients with T4 disease, with existing laryngeal dysfunction, considered unlikely to complete definitive CRT or who have a high risk of persistent aspiration after non-operative management undergo total laryngectomy. A laryngeal sparing approach is attempted on most other patients. Radiotherapy is delivered over 6.5 weeks, preferably with concurrent weekly cisplatin. If the patient is hesitant of chemotherapy or has contraindications to cisplatin, concurrent cetuximab may be offered. Patients treated with RT alone are often treated to the same dose, but via an accelerated schedule by adding a 6th fraction per week. The 6th fraction is given by delivering two treatments at least 6 h apart on a weekday of the patient's choosing. We consider the following to be major risk factors for clinically significant weight loss during treatment: a 10% or greater loss of weight in the 6 months prior to starting treatment, delivery of concurrent cisplatin, and treatment of the bilateral neck with radiation. Patients who have 2-3 of these characteristics are often given gastrostomy tubes prophylactically. Patients are seen 2 weeks after completion of therapy, and then every 3 months after completion for 2 years. A CT neck and PET-CT are performed at the first 3-month visit. They are seen twice in year three, and then yearly until years 5-7. At each of these visits, we have a low threshold to present the patient at our multidisciplinary tumor board for consideration of salvage laryngectomy if there are signs of progression.
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Affiliation(s)
- Graham Campbell
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Tiffany A Glazer
- Department of Surgery - Otolaryngology-Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, USA
| | - Randall J Kimple
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.,University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, USA
| | - Justine Yang Bruce
- Department of Medicine - Medical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA. .,University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, USA.
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Lin SH, Willers H, Krishnan S, Sarkaria JN, Baumann M, Lawrence TS. Moving Beyond the Standard of Care: Accelerate Testing of Radiation-Drug Combinations. Int J Radiat Oncol Biol Phys 2021; 111:1131-1139. [PMID: 34454045 PMCID: PMC9159468 DOI: 10.1016/j.ijrobp.2021.08.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 08/09/2021] [Indexed: 12/28/2022]
Abstract
Radiation therapy is a major treatment modality used in > 60% of cancer patients as definitive local treatment for inoperable locoregionally confined tumors and as palliative therapy. Although cytotoxic chemotherapy enhances the effectiveness of treatment, the benefit over radiation therapy alone is modest. There is a need to enhance the effectiveness of local tumor control over what sequentially or concurrently administered cytotoxic chemotherapy provides. Although many biological pathways are known to enhance the effectiveness of radiation therapy, there is currently a paucity of drugs approved for use in combination. Several clinical trials have tested the effectiveness of combining targeted agents or immunotherapies with radiation therapy, but the results of these trials have been negative, likely stemming from the relative lack of preclinical evidence using appropriate experimental standardization or model systems. Accelerating the identification of agents tested in an appropriate clinical context and experimental systems or models would greatly enhance the potential to bring forward early testing of drugs that would not only be safe but also more effective. This article provides an overview of the opportunities and challenges of developing therapeutics to combine with radiation therapy, and some guidance toward preclinical and early clinical testing to improve the chance that advanced phase testing of drug-radiation combinations would be successful in the long term.
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Affiliation(s)
- Steven H Lin
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Henning Willers
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Sunil Krishnan
- Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, Florida
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, Minnesota
| | | | - Theodore S Lawrence
- Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
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Rassamegevanon T, Feindt L, Koi L, Müller J, Freudenberg R, Löck S, Sihver W, Çevik E, Kühn AC, von Neubeck C, Linge A, Pietzsch HJ, Kotzerke J, Baumann M, Krause M, Dietrich A. Molecular Response to Combined Molecular- and External Radiotherapy in Head and Neck Squamous Cell Carcinoma (HNSCC). Cancers (Basel) 2021; 13:cancers13225595. [PMID: 34830750 PMCID: PMC8615625 DOI: 10.3390/cancers13225595] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 11/03/2021] [Indexed: 01/11/2023] Open
Abstract
Simple Summary Our previous preclinical trial in a head and neck squamous cell carcinoma (HNSCC) xenograft model showed a high potential for the improvement of curative treatment outcome upon the combination treatment of a radiolabeled (Yttrium-90) anti-EGFR antibody (Cetuximab) and external radiotherapy. We aim to elucidate the molecular response of HNSCC tumors upon this combination. Here, we show that the combination treatment leads to an increasing number and complexity of DNA double strand breaks. The upregulation of p21cip1/waf1 expression and cleaved caspase-3 suggest a blockage of cell cycle transition and an induction of programmed cell death. Collectively, a complex interplay between molecular mechanisms involved in cell death induction, cell cycle arrest, and DNA double strand break repair accounts for the beneficial potential using Yttrium-90-Cetuximab in combination with external radiotherapy. Abstract Combination treatment of molecular targeted and external radiotherapy is a promising strategy and was shown to improve local tumor control in a HNSCC xenograft model. To enhance the therapeutic value of this approach, this study investigated the underlying molecular response. Subcutaneous HNSCC FaDuDD xenografts were treated with single or combination therapy (X-ray: 0, 2, 4 Gy; anti-EGFR antibody (Cetuximab) (un-)labeled with Yttrium-90 (90Y)). Tumors were excised 24 h post respective treatment. Residual DNA double strand breaks (DSB), mRNA expression of DNA damage response related genes, immunoblotting, tumor histology, and immunohistological staining were analyzed. An increase in number and complexity of residual DNA DSB was observed in FaDuDD tumors exposed to the combination treatment of external irradiation and 90Y-Cetuximab relative to controls. The increase was observed in a low oxygenated area, suggesting the expansion of DNA DSB damages. Upregulation of genes encoding p21cip1/waf1 (CDKN1A) and GADD45α (GADD45A) was determined in the combination treatment group, and immunoblotting as well as immunohistochemistry confirmed the upregulation of p21cip1/waf1. The increase in residual γH2AX foci leads to the blockage of cell cycle transition and subsequently to cell death, which could be observed in the upregulation of p21cip1/waf1 expression and an elevated number of cleaved caspase-3 positive cells. Overall, a complex interplay between DNA damage repair and programmed cell death accounts for the potential benefit of the combination therapy using 90Y-Cetuximab and external radiotherapy.
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Affiliation(s)
- Treewut Rassamegevanon
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany; (T.R.); (S.L.); (C.v.N.); (A.L.); (M.K.)
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
| | - Louis Feindt
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Lydia Koi
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology—OncoRay, 01328 Dresden, Germany
| | - Johannes Müller
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology—OncoRay, 01328 Dresden, Germany
| | - Robert Freudenberg
- Department of Nuclear Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (R.F.); (J.K.)
| | - Steffen Löck
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany; (T.R.); (S.L.); (C.v.N.); (A.L.); (M.K.)
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Wiebke Sihver
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany; (W.S.); (H.-J.P.)
| | - Enes Çevik
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology—OncoRay, 01328 Dresden, Germany
- School of Medicine, Koç University, Istanbul 34450, Turkey
| | - Ariane Christel Kühn
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- B CUBE—Center for Molecular Bioengineering, Technische Universität Dresden, 01307 Dresden, Germany
| | - Cläre von Neubeck
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany; (T.R.); (S.L.); (C.v.N.); (A.L.); (M.K.)
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Department of Particle Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
| | - Annett Linge
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany; (T.R.); (S.L.); (C.v.N.); (A.L.); (M.K.)
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany
| | - Hans-Jürgen Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany; (W.S.); (H.-J.P.)
| | - Jörg Kotzerke
- Department of Nuclear Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany; (R.F.); (J.K.)
| | - Michael Baumann
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
| | - Mechthild Krause
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany; (T.R.); (S.L.); (C.v.N.); (A.L.); (M.K.)
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology—OncoRay, 01328 Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany
| | - Antje Dietrich
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany; (T.R.); (S.L.); (C.v.N.); (A.L.); (M.K.)
- German Cancer Research Center (DKFZ), 69192 Heidelberg, Germany;
- OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany; (L.F.); (L.K.); (J.M.); (E.Ç.); (A.C.K.)
- Correspondence: ; Tel.: +49-351-458-7404
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11
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Obaid G, Samkoe K, Tichauer K, Bano S, Park Y, Silber Z, Hodge S, Callaghan S, Guirguis M, Mallidi S, Pogue B, Hasan T. Is Tumor Cell Specificity Distinct from Tumor Selectivity In Vivo?: A Quantitative NIR Molecular Imaging Analysis of Nanoliposome Targeting. NANO RESEARCH 2021; 14:1344-1354. [PMID: 33717420 PMCID: PMC7951968 DOI: 10.1007/s12274-020-3178-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
The significance and ability for receptor targeted nanoliposomes (tNLs) to bind to their molecular targets in solid tumors in vivo has been questioned, particularly as the efficiency of their tumor accumulation and selectivity is not always predictive of their efficacy or molecular specificity. This study presents, for the first time, in situ NIR molecular imaging-based quantitation of the in vivo specificity of tNLs for their target receptors, as opposed to tumor selectivity, which includes influences of enhanced tumor permeability and retention. Results show that neither tumor delivery nor selectivity (tumor-to-normal ratio) of cetuximab and IRDye conjugated tNLs correlate with EGFR expression in U251, U87 and 9L tumors, and in fact underrepresent their imaging-derived molecular specificity by up to 94.2%. Conversely, their in vivo specificity, which we quantify as the concentration of tNL-reported tumor EGFR provided by NIR molecular imaging, correlates positively with EGFR expression levels in vitro and ex vivo (Pearson's r= 0.92 and 0.96, respectively). This study provides a unique opportunity to address the problematic disconnect between tNL synthesis and in vivo specificity. The findings encourage their continued adoption as platforms for precision medicine, and facilitates intelligent synthesis and patient customization in order to improve safety profiles and therapeutic outcomes.
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Affiliation(s)
- Girgis Obaid
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S
- Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75080, U.S
| | - Kimberley Samkoe
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 037551, U.S
| | - Kenneth Tichauer
- Armour College of Engineering, Illinois Institute of Technology, Chicago, Illinois 60616, U.S
| | - Shazia Bano
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S
| | - Yeonjae Park
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 037551, U.S
| | - Zachary Silber
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S
| | - Sassan Hodge
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 037551, U.S
| | - Susan Callaghan
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S
| | - Mina Guirguis
- Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75080, U.S
| | - Srivalleesha Mallidi
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S
| | - Brian Pogue
- Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire 037551, U.S
| | - Tayyaba Hasan
- Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, U.S
- Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, U.S
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12
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Taberna M, Oliva M, Mesía R. Cetuximab-Containing Combinations in Locally Advanced and Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Front Oncol 2019; 9:383. [PMID: 31165040 PMCID: PMC6536039 DOI: 10.3389/fonc.2019.00383] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 04/24/2019] [Indexed: 12/29/2022] Open
Abstract
Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy.
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Affiliation(s)
- Miren Taberna
- Medical Oncology Department, Catalan Institute of Oncology, ONCOBELL, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.,Medicine Department, Barcelona University, Barcelona, Spain
| | - Marc Oliva
- Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Ricard Mesía
- B-ARGO Group, Medical Oncology Department, Catalan Institute of Oncology, Badalona, Spain
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13
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Toulany M. Targeting DNA Double-Strand Break Repair Pathways to Improve Radiotherapy Response. Genes (Basel) 2019; 10:genes10010025. [PMID: 30621219 PMCID: PMC6356315 DOI: 10.3390/genes10010025] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 12/07/2018] [Accepted: 12/27/2018] [Indexed: 12/13/2022] Open
Abstract
More than half of cancer patients receive radiotherapy as a part of their cancer treatment. DNA double-strand breaks (DSBs) are considered as the most lethal form of DNA damage and a primary cause of cell death and are induced by ionizing radiation (IR) during radiotherapy. Many malignant cells carry multiple genetic and epigenetic aberrations that may interfere with essential DSB repair pathways. Additionally, exposure to IR induces the activation of a multicomponent signal transduction network known as DNA damage response (DDR). DDR initiates cell cycle checkpoints and induces DSB repair in the nucleus by non-homologous end joining (NHEJ) or homologous recombination (HR). The canonical DSB repair pathways function in both normal and tumor cells. Thus, normal-tissue toxicity may limit the targeting of the components of these two pathways as a therapeutic approach in combination with radiotherapy. The DSB repair pathways are also stimulated through cytoplasmic signaling pathways. These signaling cascades are often upregulated in tumor cells harboring mutations or the overexpression of certain cellular oncogenes, e.g., receptor tyrosine kinases, PIK3CA and RAS. Targeting such cytoplasmic signaling pathways seems to be a more specific approach to blocking DSB repair in tumor cells. In this review, a brief overview of cytoplasmic signaling pathways that have been reported to stimulate DSB repair is provided. The state of the art of targeting these pathways will be discussed. A greater understanding of the underlying signaling pathways involved in DSB repair may provide valuable insights that will help to design new strategies to improve treatment outcomes in combination with radiotherapy.
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Affiliation(s)
- Mahmoud Toulany
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Roentgenweg 11, 72076 Tuebingen, Germany.
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14
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Corvò R, Antognoni P, Sanguineti G. Biological Predictors of Response to Radiotherapy in Head and Neck Cancer: Recent Advances and Emerging Perspectives. TUMORI JOURNAL 2018; 87:355-63. [PMID: 11989586 DOI: 10.1177/030089160108700601] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The study of new biological parameters has received considerable attention in radiotherapy during the last decade due to their potential value in predicting treatment response in squamous cell carcinoma of the head and neck (SCC-HN) and the foreseen possibility of selecting altered fractionation radiotherapy for the individual patient. Although there are established clinical parameters in SCC-HN patients that relate to radiation response (extent of disease, hemoglobin level), recent advances with direct measurement of tumor oxygenation, inherent radiosensitivity and proliferation rate have increased the promise of individualization of treatment strategy according to these radiobiologically based parameters. Molecular research has now identified a host of new biological parameters with potential predictive utility; oncogenes, tumor suppressor genes, cell-cycle control genes, apoptosis genes and angiogenesis genes have been extensively studied and correlated with radiation response. Moreover, study of the epidermal growth factor receptor signal-transduction system as a possible response modulator has recently fostered molecular strategies which employ blockade of the receptor to down-regulate tumor growth. This article briefly reviews and analyzes the main controversial issues and drawbacks that hinder the general use of biological parameters for predicting tumor response to radiotherapy. It highlights the future perspectives of radiotherapy predictive assay research and the need to shift from single-parameter analysis to multiparametric studies which take into account several potential predictors that together are involved in different biological and clinical pathways.
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Affiliation(s)
- R Corvò
- UO Oncologia Radioterapica, Istituto Nazionale per la Ricerca sul Cancro, Genoa.
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15
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Mahabadi S, Labeed FH, Hughes MP. Dielectrophoretic analysis of treated cancer cells for rapid assessment of treatment efficacy. Electrophoresis 2018; 39:1104-1110. [PMID: 29405335 DOI: 10.1002/elps.201700488] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 01/26/2018] [Accepted: 01/30/2018] [Indexed: 12/21/2022]
Abstract
Whilst personalized medicine (where interventions are precisely tailored to a patient's genotype and phenotype, as well as the nature and state of the disease) is regarded as an optimal form of treatment, the time and cost associated with it means it remains inaccessible to the greater public. A simpler alternative, stratified medicine, identifies groups of patients who are likely to respond to a given treatment. This allows appropriate treatments to be selected at the start of therapy, avoiding the common "trial and error" approach of replacing a therapy only once it is demonstrated to be ineffective in the patient. For stratification to be effective, tests are required that rapidly predict treatment effectiveness. Most tests use genetic analysis to identify drug targets, but these can be expensive and may not detect changes in the phenotype that affect drug sensitivity. An alternative method is to assess the whole-cell phenotype by evaluating drug response using cells from a biopsy. We assessed dielectrophoresis to assess drug efficacy on short timescales and at low cost. To explore the principle of assessing drug efficacy we examined two cell lines (one expressing EGFR, one not) with the drug Iressa. We then further explored the sensitive cells using combinations of chemotherapeutic and radiotherapeutic therapies. Our results compare with known effects of these cell/treatment combination, and offer the additional benefit over methods such as TUNEL of detecting drug effects such as cell cycle arrest, which do not cause cell death.
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Affiliation(s)
- Sina Mahabadi
- Centre for Biomedical Engineering, Department of Mechanical Engineering Sciences, University of Surrey, Guildford, UK
| | - Fatima H Labeed
- Centre for Biomedical Engineering, Department of Mechanical Engineering Sciences, University of Surrey, Guildford, UK
| | - Michael P Hughes
- Centre for Biomedical Engineering, Department of Mechanical Engineering Sciences, University of Surrey, Guildford, UK
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16
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Huang A, Yao J, Liu T, Lin Z, Zhang S, Zhang T, Ma H. 53BP1 loss suppresses the radiosensitizing effect of icotinib hydrochloride in colorectal cancer cells. Int J Radiat Biol 2018; 94:327-334. [PMID: 29388453 DOI: 10.1080/09553002.2018.1434322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND This study aimed to investigate the influence of the expression of P53-binding protein 1 (53BP1), a key component in DNA damage repair pathways, on the radiosensitizing effect of icotinib hydrochloride in colorectal cancer and to elucidate the mechanisms underlying this influence. MATERIALS AND METHODS Real-time RT-PCR and Western blotting were performed to verify the gene-knockout effect of 53BP1 small hairpin RNA (ShRNA), and colony formation assay was employed to investigate the influence of 53BP1 downregulation on the radiosensitizing effect of icotinib hydrochloride in HCT116 cells. Cell apoptosis, cell cycle distributions, and histone H2AX (γ-H2AX) fluorescence foci after 53BP1 knockdown were evaluated. Relative protein expression in the ataxia telangiectasia mutated kinase (ATM)-checkpoint kinase-2 (CHK2)-P53 pathway was measured by Western blot analysis to unravel the molecular mechanisms linking the pathway to the above phenomena. RESULTS Icotinib hydrochloride increased the radiosensitivity of HCT116 cells; however, this effect was suppressed by the downregulation of 53BP1 expression, a change that inhibited cell apoptosis, increased the percentage of HCT116 cells arrested in S-phase and inhibited the protein expression of key molecules in the ATM-CHK2-P53 apoptotic pathway. CONCLUSION Our studies confirmed that the loss of 53BP1 serves as a negative regulator of the radiosensitizing effect of icotinib in part by suppressing the ATM-CHK2-P53 apoptotic pathway.
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Affiliation(s)
- Ai Huang
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Jing Yao
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Tao Liu
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Zhenyu Lin
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Sheng Zhang
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Tao Zhang
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
| | - Hong Ma
- a Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China
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17
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Kriegs M, Kasten-Pisula U, Riepen B, Hoffer K, Struve N, Myllynen L, Braig F, Binder M, Rieckmann T, Grénman R, Petersen C, Dikomey E, Rothkamm K. Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests. Oncotarget 2018; 7:45122-45133. [PMID: 27281611 PMCID: PMC5216710 DOI: 10.18632/oncotarget.9161] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 04/18/2016] [Indexed: 12/28/2022] Open
Abstract
The increase in cellular radiosensitivity by EGF receptor (EGFR) inhibition has been shown to be attributable to the induction of a G1-arrest in p53-proficient cells. Because EGFR targeting in combination with radiotherapy is used to treat head and neck squamous cell carcinomas (HNSCC) which are predominantly p53 mutated, we tested the effects of EGFR targeting on cellular radiosensitivity, proliferation, apoptosis, DNA repair and cell cycle control using a large panel of HNSCC cell lines. In these experiments EGFR targeting inhibited signal transduction, blocked proliferation and induced radiosensitization but only in some cell lines and only under normal (pre-plating) conditions. This sensitization was not associated with impaired DNA repair (53BP1 foci) or induction of apoptosis. However, it was associated with the induction of a lasting G2-arrest. Both, the radiosensitization and the G2-arrest were abrogated if the cells were re-stimulated (delayed plating) with actually no radiosensitization being detectable in any of the 14 tested cell lines. Therefore we conclude that EGFR targeting can induce a reversible G2 arrest in p53 deficient HNSCC cells, which does not consequently result in a robust cellular radiosensitization. Together with recent animal and clinical studies our data indicate that EGFR inhibition is no effective strategy to increase the radiosensitivity of HNSCC cells.
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Affiliation(s)
- Malte Kriegs
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Ulla Kasten-Pisula
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Britta Riepen
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Konstantin Hoffer
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Nina Struve
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Laura Myllynen
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Friederike Braig
- Department of Oncology and Hematology, BMT with section Pneumology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Mascha Binder
- Department of Oncology and Hematology, BMT with section Pneumology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Thorsten Rieckmann
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.,Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Reidar Grénman
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, 20521 Turku, Finland
| | - Cordula Petersen
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Ekkehard Dikomey
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
| | - Kai Rothkamm
- Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany
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18
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Shin HK, Kim MS, Lee JK, Lee SS, Ji YH, Kim JI, Jeong JH. Combination Effect of Cetuximab with Radiation in Colorectal Cancer Cells. TUMORI JOURNAL 2018; 96:713-20. [DOI: 10.1177/030089161009600513] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Colorectal cancer (CRC) is one of the commonest malignant disorders and frequently associated with high expression of epidermal growth factor receptor (EGFR), resulting in advanced disease and a poor prognosis. In this study, we investigated the radiosensitizing effects of the selective EGFR inhibitor cetuximab in human CRC cell lines. Methods Four human CRC cell lines, CaCo-2, HCT-8, LoVo, and WiDr, were treated with cetuximab and/or radiation. The effects on cell proliferation and viability were measured by MTT and annexin-V staining, and clonogenic survival assay. The in vivo effect on the growth of CRC xenografts was assessed in athymic nude mice. Results Cetuximab in combination with radiation significantly inhibited the in vitro proliferation of CRC cells, with a concomitant increase in cell death, except in WiDr cells. Clonogenic survival assay confirmed that cetuximab worked as a radiosensitizer in three cetuximab-sensitivie CRC cells. However, no correlations were found between the radiosensitivity and EGFR expression level or mutation status of EGFR signaling molecules. In nude mice bearing CRC cell xenografts, cetuximab plus radiation significantly inhibited the tumor growth over either agent alone. Interestingly, the WiDr xenograft was also sensitive to cetuximab and/or radiation in vivo, suggesting host-mediated effects of cetuximab. Conclusions Cetuximab enhanced the radiosensitivity of CRC cells in vitro and efficiently inhibited xenograft tumor growth. This study provided a rationale for the clinical application of the selective EGFR inhibitor cetuximab in combination with radiation in CRC. Free full text available at www.tumorionline.it
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Affiliation(s)
| | - Mi-Sook Kim
- Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul
| | - Jin Kyung Lee
- Department of Laboratory Medicine, Korea Institute of Radiological and Medical Sciences, Seoul
| | - Seung-Sook Lee
- Department of Experimental Pathology, Korea Institute of Radiological and Medical Sciences, Seoul
| | | | - Jong-Il Kim
- Department of Food and Microbial Technology, Seoul Women's University, Seoul, Korea
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Afatinib, an Irreversible EGFR Family Inhibitor, Shows Activity Toward Pancreatic Cancer Cells, Alone and in Combination with Radiotherapy, Independent of KRAS Status. Target Oncol 2017; 11:371-81. [PMID: 26668065 DOI: 10.1007/s11523-015-0403-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has shown modest activity in most patients. OBJECTIVE Here we investigated the activity of afatinib, a second-generation irreversible pan-EGFR family kinase inhibitor, alone or in combination with ionizing radiation, toward pancreatic cancer cells. METHODS The influence of afatinib on cell proliferation, cell cycle distribution, clonogenic survival, nuclear fragmentation, ploidy, and centrosome amplification following irradiation was determined. Expression and phosphorylation of HER receptors, Akt, DNA-PKcs, and ERK1/2 was characterized by Western blot analysis. RESULTS Afatinib was growth-inhibitory for all three cell lines but cytotoxic only toward BxPC3 (KRAS (wt)) and Capan-2 (KRAS (mut)) cells, both of which express high levels of EGFR, HER2, and HER3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells, prevented the radio-induced phosphorylation of Akt, and induced mitotic catastrophe following irradiation. In comparison, Panc-1 cells (KRAS (mut)) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization. LIMITATIONS These results must be confirmed in vivo. CONCLUSIONS Afatinib showed cytotoxic and radiosensitizing effects toward a subset of pancreatic cancer cells which was closely correlated with expression of EGFR, HER2, and HER3 receptors, but not with KRAS status.
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Koi L, Löck S, Linge A, Thurow C, Hering S, Baumann M, Krause M, Gurtner K. EGFR-amplification plus gene expression profiling predicts response to combined radiotherapy with EGFR-inhibition: A preclinical trial in 10 HNSCC-tumour-xenograft models. Radiother Oncol 2017; 124:496-503. [PMID: 28807520 DOI: 10.1016/j.radonc.2017.07.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/03/2017] [Accepted: 07/06/2017] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND PURPOSE Improvement of the results of radiotherapy by EGFR inhibitors is modest, suggesting significant intertumoural heterogeneity of response. To identify potential biomarkers, a preclinical trial was performed on ten different human squamous cell carcinoma xenografts of the head and neck (HNSCC) studying in vivo and ex vivo the effect of fractionated irradiation and EGFR inhibition. Local tumour control and tumour growth delay were correlated with potential biomarkers, e.g. EGFR gene amplification and radioresponse-associated gene expression profiles. MATERIAL AND METHODS Local tumour control 120days after end of irradiation was determined for fractionated radiotherapy alone (30f, 6weeks) or after simultaneous EGFR-inhibition with cetuximab. The EGFR gene amplification status was determined using FISH. Gene expression analyses were performed using an in-house gene panel. RESULTS Six out of 10 investigated tumour models showed a significant increase in local tumour control for the combined treatment of cetuximab and fractionated radiotherapy compared to irradiation alone. For 3 of the 6 responding tumour models, an amplification of the EGFR gene could be demonstrated. Gene expression profiling of untreated tumours revealed significant differences between amplified and non-amplified tumours as well as between responder and non-responder tumours to combined radiotherapy and cetuximab. CONCLUSION The EGFR amplification status, in combination with gene expression profiling, may serve as a predictive biomarker for personalized interventional strategies regarding combined treatment of cetuximab and fractionated radiotherapy and should, as a next step, be clinically validated.
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Affiliation(s)
- Lydia Koi
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany
| | - Steffen Löck
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Annett Linge
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), partner site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Germany
| | - Cedric Thurow
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany
| | - Sandra Hering
- Institute for Legal Medicine, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
| | - Michael Baumann
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Germany
| | - Mechthild Krause
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany; German Cancer Consortium (DKTK), partner site Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Germany
| | - Kristin Gurtner
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Germany; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), partner site Dresden, Germany.
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Crosby T, Hurt CN, Falk S, Gollins S, Staffurth J, Ray R, Bridgewater JA, Geh JI, Cunningham D, Blazeby J, Roy R, Maughan T, Griffiths G, Mukherjee S. Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer. Br J Cancer 2017; 116:709-716. [PMID: 28196063 PMCID: PMC5355926 DOI: 10.1038/bjc.2017.21] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 01/03/2017] [Accepted: 01/16/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The SCOPE-1 study tested the role of adding cetuximab to conventional definitive chemoradiotherapy (dCRT), and demonstrated greater toxicity and worse survival outcomes. We present the long-term outcomes and patterns of recurrence. METHODS SCOPE-1 was a phase II/III trial in which patients were randomised to cisplatin 60 mg m-2 (day 1) and capecitabine 625 mg m-2 bd (days 1-21) for four cycles +/- cetuximab 400 mg m-2 day 1 then by 250 mg m-2 weekly. Radiotherapy consisted of 50 Gy/25# given concurrently with cycles 3 and 4. Recruitment was between February 2008 and February 2012, when the IDMC recommended closure on the basis of futility. RESULTS About 258 patients (dCRT=129; dCRT+cetuximab (dCRT+C)=129) were recruited from 36 centres. About 72.9% (n=188) had squamous cell histology. The median follow-up (IQR) was 46.2 (35.9-48.3) months for surviving patients. The median overall survival (OS; months; 95% CI) was 34.5 (24.7-42.3) in dCRT and 24.7 (18.6-31.3) in dCRT+C (hazard ratio (HR)=1.25, 95% CIs: 0.93-1.69, P=0.137). Median progression-free survival (PFS; months; 95% CI) was 24.1 (15.3-29.9) and 15.9 (10.7-20.8) months, respectively (HR=1.28, 95% CIs: 0.94-1.75; P=0.114). On multivariable analysis only earlier stage, full-dose RT, and higher cisplatin dose intensity were associated with improved OS. CONCLUSIONS The mature analysis demonstrates that the dCRT regimen used in the study provided useful survival outcomes despite its use in patients who were largely unfit for surgery or who had inoperable disease. Given the competing risk of systemic and local failure, future studies should continue to focus on enhancing local control as well as optimising systemic therapy.
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Affiliation(s)
- T Crosby
- Velindre Cancer Centre, Velindre Hospital, Cardiff CF14 2TL, UK
| | - C N Hurt
- Wales Cancer Trials Unit, Cardiff University, Cardiff CF14 4YS, UK
| | - S Falk
- Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8ED, UK
| | - S Gollins
- North Wales Cancer Treatment Centre, Conwy and Denbighshire NHS Trust, Rhyl LL18 5UJ, UK
| | - J Staffurth
- Velindre Cancer Centre, Velindre Hospital, Cardiff CF14 2TL, UK
| | - R Ray
- Wales Cancer Trials Unit, Cardiff University, Cardiff CF14 4YS, UK
| | - J A Bridgewater
- UCL Cancer Institute, University College London, London WC1E 6BT, UK
| | - J I Geh
- Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust Birmingham B15 2GW, UK
| | - D Cunningham
- The Royal Marsden Hospital NHS Foundation Trust, London SM2 5PT, UK
| | - J Blazeby
- Centre for Surgical Research, University of Bristol, Bristol BS8 2PS, UK
| | - R Roy
- Diana Princess of Wales Hospital, Northern Lincolnshire and Goole NHS Foundation Trust, Grimsby DN33 2BA, UK
| | - T Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK
| | - G Griffiths
- Southampton Clinical Trials Unit, University of Southampton, Southampton SO16 6YD, UK
| | - S Mukherjee
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK
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Psyrri A, Seiwert TY, Jimeno A. Molecular pathways in head and neck cancer: EGFR, PI3K, and more. Am Soc Clin Oncol Educ Book 2016:246-55. [PMID: 23714515 DOI: 10.14694/edbook_am.2013.33.246] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The treatment of head and neck squamous cell carcinoma (HNSCC) is set to undergo rapid changes, as novel treatment targets informed by genomic profiling and novel molecularly targeted therapies continue to make strides. In this review we provide an overview of the latest developments regarding (1) EGFR targeting for HNSCC, (2) PI3K as a novel treatment target, and (3) newly described key genetic events in HNSCC such as NOTCH1 mutations and emerging candidate targets including ALK1 and hedgehog. The first molecular targeting strategy to demonstrate a survival advantage for patients with HNSCC has emerged in the context of EGFR biology. Cetuximab remains the only U.S. Food and Drug Administration (FDA)-approved targeted therapy available for HNSCC, but EGFR as a target has not been individualized in this disease. The PI3K-AKT pathway is downstream of EGFR and is emerging as potentially one of the most important pathways in HNSCC. PIK3CA is the most frequently mutated oncogene for HNSCC (approximately 20%) and may play a role for both HPV-negative and HPV-positive tumors. Multiple therapeutic strategies targeting PI3K are being explored, and multiple agents either alone or in combination are in development. NOTCH1 is a key tumor suppressor gene and its genetic alterations lead to abnormal pathway activation. ALK1 is a novel target involved in angiogenesis, and efficacy in patients with HNSCC was documented in an early inhibitor trial. The hedgehog pathway modulates EGFR dependence and epithelial to mesenchymal transition (EMT), a key invasion and drug-resistance mechanism in HNSCC.
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Affiliation(s)
- Amanda Psyrri
- From the Department of Medicine, Section of Medical Oncology, Attikon University Hospital, Athens, Greece; Department of Medicine, University of Chicago School of Medicine and Biological Sciences, Chicago, IL; Division of Medical Oncology, University of Colorado School of Medicine, Denver, CO
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Alorabi M, Shonka NA, Ganti AK. EGFR monoclonal antibodies in locally advanced head and neck squamous cell carcinoma: What is their current role? Crit Rev Oncol Hematol 2016; 99:170-179. [PMID: 26797287 DOI: 10.1016/j.critrevonc.2015.12.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 10/25/2015] [Accepted: 12/15/2015] [Indexed: 01/29/2023] Open
Abstract
Treatment options for locally advanced squamous cell carcinoma of the head and neck (SCCHN) include either surgical resection followed by radiation or chemoradiation, or definitive chemoradiation for which single-agent cisplatin is the best studied and established. The increasing understanding of the molecular biology of SCCHN has led to an interest in the development of targeted therapies. The epidermal growth factor receptor (EGFR) is over-expressed in nearly 80-90% of cases of SCCHN and correlates with poor prognosis and resistance to radiation. Preclinical evidence showed that blocking EGFR restores radiation sensitivity and enhances cytotoxicity. This finding led to clinical trials evaluating this class of agents and the approval of cetuximab in combination with radiation for the treatment of locally advanced SCCHN. This review is focused on the anti-EGFR monoclonal antibodies and their role either with radiotherapy or chemoradiation in unresectable LA SCCHN.
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Affiliation(s)
- Mohamed Alorabi
- Department of Clinical Oncology, Ain Shams University Hospitals, Cairo, Egypt
| | - Nicole A Shonka
- Division of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Apar Kishor Ganti
- Division of Oncology-Hematology, Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE 68198-7680, USA.
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24
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Pancari P, Mehra R. Systemic therapy for squamous cell carcinoma of the head and neck. Surg Oncol Clin N Am 2016; 24:437-54. [PMID: 25979393 DOI: 10.1016/j.soc.2015.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The use of systemic therapy as part of curative treatment and palliation is an evolving paradigm for squamous cell cancer of the head and neck (SCCHN), which historically has been treated with local modalities. At present, the treatment armamentarium includes traditional cytotoxic therapy, targeted biological agents, and emerging immunotherapeutics. This article discusses the use of all of these systemic approaches for the curative and palliative treatment of SCCHN.
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Affiliation(s)
- Philip Pancari
- Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Ranee Mehra
- Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
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25
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Achell Nava L, Hierro Orozco S, Maya Talamantes EI. Manejo y prevención de efectos secundarios al empleo de un anticuerpo monoclonal inhibidor de la señal de los receptores del factor de crecimiento epidérmico. GACETA MEXICANA DE ONCOLOGÍA 2016. [DOI: 10.1016/j.gamo.2015.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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26
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Mountzios G. Optimal management of the elderly patient with head and neck cancer: Issues regarding surgery, irradiation and chemotherapy. World J Clin Oncol 2015; 6:7-15. [PMID: 25667910 PMCID: PMC4318746 DOI: 10.5306/wjco.v6.i1.7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer (HNC) represents the sixth most common malignancy and accounts for approximately 6% of new cancer cases annually worldwide. As life expectancy constantly increases, the onset of HNC in patients older than 65 years of age at diagnosis is not rare and up to one fourth of cases occurs in patients older that 70 years at age. Because elderly cancer patients are severely under-represented in clinical trials, there is a clear need to address the particular aspects of this specific patient group, especially in the context of novel multidisciplinary therapeutic approaches. The frailty of elderly patients with HNC is attributed to the high incidence of smoking and alcohol abuse in this malignancy and the presence of substantial cardiovascular, respiratory or metabolic comorbidities. In the current work, I provide an overview of current and emerging treatment approaches, in elderly patients with HNC. In particular, I discuss modern surgical approaches that improve radical excision rates while preserving functionality, the incorporation of modern radiotherapeutic techniques and the introduction of novel chemotherapeutic combinations and molecular targeted agents in an effort to reduce toxicity without compromising efficacy. Finally, there is an urgent need to increase accrual and active participation of elderly patients with HNC in clinical trials, including biomarker evaluation in biopsy specimens towards an individualized therapeutic approach.
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27
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Bowles DW, McDermott JD, Jimeno A. Novel treatments for head and neck squamous cell carcinoma: preclinical identification and clinical investigation. Future Oncol 2015; 10:1065-80. [PMID: 24941990 DOI: 10.2217/fon.14.18] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Classically, it is a disease related to tobacco and alcohol use; an increasing number of patients are being diagnosed with HNSCC caused by infection with the human papillomavirus. New deep-sequencing techniques have confirmed the importance of p53 and EGF receptor in HNSCC development, and have identified pathways of critical importance, such as PI3K/mTOR and NOTCH. Increasing knowledge of key molecular features has lead to new therapeutic avenues for HNSCC. Novel therapies under investigation in HNSCC include antibody and small molecule inhibitors of EGF receptor and its family members, PI3K inhibitors, antiangiogenic agents, immunotherapies and agents interacting with early developmental pathways such as Hedgehog.
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Affiliation(s)
- Daniel W Bowles
- Division of Medical Oncology, University of Colorado School of Medicine, CO, USA
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Ma H, Bi J, Liu T, Ke Y, Zhang S, Zhang T. Icotinib hydrochloride enhances the effect of radiotherapy by affecting DNA repair in colorectal cancer cells. Oncol Rep 2014; 33:1161-70. [PMID: 25572529 DOI: 10.3892/or.2014.3699] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 11/27/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to explore the efficacy and mechanism of the radiosensitisation of icotinib hydrochloride (IH), a novel oral epidermal growth factor receptor-tyrosine kinase activity inhibitor, by evaluating the changes in tumour cell double-strand breaks (DSBs) repair, cell cycle and apoptosis following a combination of IH and radiotherapy (RT) in human colorectal adenocarcinoma cell lines. The HT29 and HCT116 human CRC cell lines were treated with IH and/or radiation. Effects on cell viability and cell cycle progression were measured by MTT, a clonogenic survival assay, and flow cytometry. Immunofluorescent staining and western blot analysis were applied to detect the expression of γ-H2AX and 53BP1 in the different treatment groups. Finally, the in vivo effect on the growth of CRC xenografts was assessed in athymic nude mice. IH inhibited the proliferation and enhanced the radiosensitivity in HT29 and HCT116 CRC cells lines. IH combined with radiation increased cell cycle arrest in the G2/M phase compared to the other treatments in the HT29 cell line (P<0.05). Similarly, cell cycle arrest occurred in the HCT116 cell line, although this increase did not result in significant differences in the RT group (P>0.05). IH combined with radiation significantly inhibited the expression of γ-H2AX and 53BP1 based on results of immunofluorescent staining and western blot analysis. In vivo, IH plus radiation significantly inhibited the tumour growth compared to either agent independently. In conclusion, IH significantly increased the radiosensitivity of HT29 and HCT116 cells in vitro and in vivo. Radiation combined with EGFR blockade inhibited tumour proliferation, increased apoptosis, prolonged G2/M arrest and significantly enhanced DNA injury in colorectal cancer. These data support the clinical trials of biologically targeted and conventional therapies in the treatment of cancer.
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Affiliation(s)
- Hong Ma
- Cancer Center of Wuhan Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Jianping Bi
- Cancer Center of Wuhan Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Tao Liu
- Cancer Center of Wuhan Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Yang Ke
- Cancer Center of Wuhan Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Sheng Zhang
- Cancer Center of Wuhan Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
| | - Tao Zhang
- Cancer Center of Wuhan Union Hospital, TongJi Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
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Li CF, Chen LB, Li DD, Yang L, Zhang BG, Jin JP, Zhang Y, Zhang B. Dual‑sensitive HRE/Egr1 promoter regulates Smac overexpression and enhances radiation‑induced A549 human lung adenocarcinoma cell death under hypoxia. Mol Med Rep 2014; 10:1108-1116. [PMID: 24842518 DOI: 10.3892/mmr.2014.2233] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 04/04/2014] [Indexed: 11/05/2022] Open
Abstract
The aim of this study was to construct an expression vector carrying the hypoxia/radiation dual‑sensitive chimeric hypoxia response element (HRE)/early growth response 1 (Egr‑1) promoter in order to overexpress the therapeutic second mitochondria‑derived activator of caspases (Smac). Using this expression vector, the present study aimed to explore the molecular mechanism underlying radiotherapy‑induced A549 human lung adenocarcinoma cell death and apoptosis under hypoxia. The plasmids, pcDNA3.1‑Egr1‑Smac (pE‑Smac) and pcDNA3.1‑HRE/Egr-1‑Smac (pH/E‑Smac), were constructed and transfected into A549 human lung adenocarcinoma cells using the liposome method. CoCl2 was used to chemically simulate hypoxia, followed by the administration of 2 Gy X‑ray irradiation. An MTT assay was performed to detect cell proliferation and an Annexin V‑fluorescein isothiocyanate apoptosis detection kit was used to detect apoptosis. Quantitative polymerase chain reaction and western blot analyses were used for the detection of mRNA and protein expression, respectively. Infection with the pE‑Smac and pH/E‑Smac plasmids in combination with radiation and/or hypoxia was observed to enhance the expression of Smac. Furthermore, Smac overexpression was found to enhance the radiation‑induced inhibition of cell proliferation and promotion of cycle arrest and apoptosis. The cytochrome c/caspase‑9/caspase‑3 pathway was identified to be involved in this regulation of apoptosis. Plasmid infection in combination with X‑ray irradiation was found to markedly induce cell death under hypoxia. In conclusion, the hypoxia/radiation dual‑sensitive chimeric HRE/Egr‑1 promoter was observed to enhance the expression of the therapeutic Smac, as well as enhance the radiation‑induced inhibition of cell proliferation and promotion of cycle arrest and apoptosis under hypoxia. This apoptosis was found to involve the mitochondrial pathway.
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Affiliation(s)
- Chang-Feng Li
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Li-Bo Chen
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Dan-Dan Li
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Lei Yang
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Bao-Gang Zhang
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Jing-Peng Jin
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Ying Zhang
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Bin Zhang
- Endoscopy Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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Ricci F, Paradisi A, Silveri SL, Sampogna F, Miccichè F, Bonomo PL, DiNapoli N, Valentini V, Capizzi R, Guerriero C. Adverse skin reactions during treatment with cetuximab plus radiotherapy: Multidisciplinary approach to minimize radio-chemotherapy interruption. J DERMATOL TREAT 2014; 26:183-7. [DOI: 10.3109/09546634.2014.927815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Yuan JW, Qiu HY, Wang PF, Makawana JA, Yang YA, Zhang F, Yin Y, Lin J, Wang ZC, Zhu HL. Synthesis of caffeic acid amides bearing 2,3,4,5-tetra-hydrobenzo[b][1,4]dioxocine moieties and their biological evaluation as antitumor agents. Molecules 2014; 19:7269-86. [PMID: 24896265 PMCID: PMC6271756 DOI: 10.3390/molecules19067269] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 05/26/2014] [Accepted: 05/27/2014] [Indexed: 11/16/2022] Open
Abstract
A series of caffeic acid amides D1-D17 bearing 2,3,4,5-tetrahydrobenzo-[b][1,4]dioxocine units has been synthesized and their biological activities evaluated for potential antiproliferative and EGFR inhibitory activity. Of all the compounds studied, compound D9 showed the most potent inhibitory activity (IC50 = 0.79 μM for HepG2 and IC50 = 0.36 μM for EGFR). The structures of compounds were confirmed by 1H-NMR, ESI-MS and elemental analysis. Among all, the structure of compound D9 ((E)-N-(4-ethoxyphenyl)-3-(2,3,4,5-tetrahydrobenzo[b][1,4]dioxocin-8-yl)acrylamide) was also determined by single-crystal X-ray diffraction analysis. Compound D9 was found to be a potential antitumor agent according to biological activity, molecular docking, apoptosis assay and inhibition of HepG2.
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Affiliation(s)
- Ji-Wen Yuan
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Han-Yue Qiu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Peng-Fei Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Jigar A Makawana
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Yong-An Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Fei Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Yong Yin
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Jie Lin
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Zhong-Chang Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
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Lin SH, Komaki RU. Molecular Target Treatment for Personalized Radiotherapy in Lung Cancer. Lung Cancer 2014. [DOI: 10.1002/9781118468791.ch25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Ingargiola M, Runge R, Heldt JM, Freudenberg R, Steinbach J, Cordes N, Baumann M, Kotzerke J, Brockhoff G, Kunz-Schughart LA. Potential of a Cetuximab-based radioimmunotherapy combined with external irradiation manifests in a 3-D cell assay. Int J Cancer 2014; 135:968-80. [PMID: 24615356 DOI: 10.1002/ijc.28735] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Revised: 12/04/2013] [Accepted: 01/08/2014] [Indexed: 12/22/2022]
Abstract
Targeting epidermal growth factor receptor (EGFR)-overexpressing tumors with radiolabeled anti-EGFR antibodies is a promising strategy for combination with external radiotherapy. In this study, we evaluated the potential of external plus internal irradiation by [(90) Y]Y-CHX-A″-DTPA-C225 (Y-90-C225) in a 3-D environment using FaDu and SAS head and neck squamous cell carcinoma (HNSCC) spheroid models and clinically relevant endpoints such as spheroid control probability (SCP) and spheroid control dose 50% (SCD50 , external irradiation dose inducing 50% loss of spheroid regrowth). Spheroids were cultured using a standardized platform. Therapy response after treatment with C225, CHX-A"-DTPA-C225 (DTPA-C225), [(90) Y]Y-CHX-A"-DTPA (Y-90-DTPA) and Y-90-C225 alone or in combination with X-ray was evaluated by long-term monitoring (60 days) of spheroid integrity and volume growth. Penetration kinetics into spheroids and EGFR binding capacities on spheroid cells were identical for unconjugated C225 and Y-90-C225. Spheroid-associated radioactivity upon exposure to the antibody-free control conjugate Y-90-DTPA was negligible. Determination of the SCD50 demonstrated higher intrinsic radiosensitivity of FaDu as compared with SAS spheroids. Treatment with unconjugated C225 alone did not affect spheroid growth and cell viability. Also, C225 treatment after external irradiation showed no additive effect. However, the combination of external irradiation with Y-90-C225 (1 µg/ml, 24 hr) resulted in a considerable benefit as reflected by a pronounced reduction of the SCD50 from 16 Gy to 9 Gy for SAS spheroids and a complete loss of regrowth for FaDu spheroids due to the pronounced accumulation of internal dose caused by the continuous exposure to cell-bound radionuclide upon Y-90-C225-EGFR interaction.
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Affiliation(s)
- M Ingargiola
- OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany; Institute of Radiooncology, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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Merlano M, Mattiot VP. Future chemotherapy and radiotherapy options in head and neck cancer. Expert Rev Anticancer Ther 2014; 6:395-403. [PMID: 16503856 DOI: 10.1586/14737140.6.3.395] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chemoradiation is a standard approach to advanced unresectable head and neck cancer, although the optimum combination regimen remains controversial. However, in the past few years, chemoradiation has been successfully extended from the treatment of unresectable disease to the postsurgical therapy of high-risk patients and its value as an organ preservation procedure is under evaluation. More recently, molecular-targeted therapies have emerged, which interfere with mechanisms of chemo- and radioresistance, and preliminary data are promising. Their use in the combined treatment of head and neck cancer will hopefully further improve the value of chemoradiation in the clinical setting.
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Affiliation(s)
- Marco Merlano
- Department of Clinical Oncology, S. Croce General Hospital, Via M. Coppino 26, 12100 Cuneo, Italy.
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Rosenthal DI, Blanco AI. Head and neck squamous cell carcinoma: optimizing the therapeutic index. Expert Rev Anticancer Ther 2014; 5:501-14. [PMID: 16001957 DOI: 10.1586/14737140.5.3.501] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The four recent noteworthy strategies aimed at improving therapeutic outcomes for the curative treatment of head and neck squamous cancers include the development of altered fractionation regimens, integration of chemotherapy, incorporation of intensity-modulated radiation therapy and introduction of targeted biologic therapy. Clinical investigations during the last 30 years have demonstrated the benefits of biologically sound altered fractionation and concurrent chemoradiation regimens in improving locoregional control and overall survival. These results have contributed to redefining the standard of care, with the caveat that proper patient selection for those who will benefit from potentially toxic combined modality treatment regimens remains controversial. These benefits have come at the expense of increased acute toxicity (i.e., mucositis) and sometimes at the expense of late toxicity (i.e., fibrosis and dysphagia). There are two additional developments that may help to further widen the therapeutic ratio. Intensity-modulated radiation therapy allows for the delivery of a highly conformal 3D radiation dose distribution around intended targets, thereby limiting the volumes of mucosa receiving a high dose per fraction and high total doses. The technical basis for intensity-modulated radiation therapy delivery reopens many fractionation questions that are still being addressed and challenges us to determine which of these is optimal for use with intensity-modulated radiation therapy alone or in combination with concurrent sensitizers. Finally, combined radiation therapy and biologic therapies directed at targets expressed predominately or exclusively by tumor cells have the promise to help increase tumor cell kill, while at least not substantially increasing normal tissue toxicity. These strategies are reviewed in a clinical context.
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Affiliation(s)
- David I Rosenthal
- Department of Radiation Oncology, 097, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
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A phase I study of nelfinavir concurrent with temozolomide and radiotherapy in patients with glioblastoma multiforme. J Neurooncol 2013; 116:365-372. [PMID: 24194293 DOI: 10.1007/s11060-013-1303-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 10/21/2013] [Indexed: 10/26/2022]
Abstract
We conducted a phase I trial to examine the maximally tolerated dose (MTD) of the oral protease inhibitor nelfinavir (NFV) in combination with temozolomide and concurrent radiotherapy in patients with glioblastoma and to gather preliminary data for response. The study was conducted in patients with newly diagnosed glioblastoma after surgical resection. Patients were treated with standard radiotherapy (6,000 cGy to the gross tumor volume), temozolomide (75 mg/m(2) daily) together with daily oral NFV starting 7-10 days prior to chemoradiotherapy continuing for the duration of chemoradiation for 6 weeks. Temozolomide (150-200 mg/m(2)) was resumed 4 weeks after completion of chemoradiotherapy. Two dose levels of NFV were investigated: 625 mg twice daily (bid) and 1,250 mg bid in a cohort escalation design. A total of 21 patients were enrolled. At the maximum tolerated dose, 18 subjects were enrolled to further evaluate toxicity and for preliminary estimate of efficacy for further phase II study. No dose-limiting toxicity was noted at 625 mg bid. At 1,250 mg bid, 3 dose-limiting episodes of hepatotoxicity were noted and one dose-limiting episode of diarrhea. The MTD for this study was 1,250 mg bid. NFV (1,250 mg bid) concurrent with temozolomide and radiotherapy is tolerated in most patients with glioblastoma. At the 1,250 mg bid dose level, patients should be monitored for hepatotoxicity and GI side effects.
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Liu WW, Liu Y, Liang S, Wu JH, Wang ZC, Gong SL. Hypoxia- and radiation-induced overexpression of Smac by an adenoviral vector and its effects on cell cycle and apoptosis in MDA-MB-231 human breast cancer cells. Exp Ther Med 2013; 6:1560-1564. [PMID: 24255691 PMCID: PMC3829727 DOI: 10.3892/etm.2013.1351] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 10/10/2013] [Indexed: 12/22/2022] Open
Abstract
A conditionally replicative adenoviral (CRAd) vector, designated as CRAd.pEgr-1-Smac, that promotes the overexpression of second mitochondria-derived activator of caspase (Smac) when stimulated by hypoxia and radiation was constructed. MDA-MB-231 cells were transfected with CRAd.pEgr-1-Smac and treated with 4-Gy X-rays. The hypoxic status in cancer cells was mimicked with the chemical reagent CoCl2. Smac protein expression was measured by a western blotting assay and cell proliferation was detected with the MTT assay. The cell cycle progression and apoptotic percentage were measured by flow cytometry with PI and Annexin V-FITC staining kits, respectively, following the irradiation of the transfected cells with 4-Gy X-rays. The results showed that CRAd.pEgr-1-Smac was able to increase the Smac protein expression induced by hypoxia and radiation, inhibit cell proliferation and promote apoptosis. Therefore, this method of gene-radiotherapy is indicated to be an ideal strategy for the treatment of breast cancer.
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Affiliation(s)
- Wei-Wu Liu
- Key Laboratory of Radiobiology, Ministry of Health, School of Public Health, Jilin University, Changchun, Jilin 130021, P.R. China ; Department of Radiology, Second Hospital, Jilin University, Changchun, Jilin 130041, P.R. China
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Diaz-Miqueli A, Martinez GS. Nimotuzumab as a radiosensitizing agent in the treatment of high grade glioma: challenges and opportunities. Onco Targets Ther 2013; 6:931-42. [PMID: 23926436 PMCID: PMC3729249 DOI: 10.2147/ott.s33532] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Nimotuzumab is a humanized monoclonal antibody that binds specifically to human epidermal growth factor receptor, blocking receptor activation. Evidence of its radiosensitizing capacity has been widely evaluated. This article integrates published research findings regarding the role of nimotuzumab in the treatment of high grade glioma in combination with radiotherapy or radiochemotherapy in adult and pediatric populations. First, the mechanisms of action of nimotuzumab and its current applications in clinical trials containing both radiation and chemoradiation therapies are reviewed. Second, a comprehensive explanation of potential mechanisms driving radiosensitization by nimotuzumab in experimental settings is given. Finally, future directions of epidermal growth factor receptor targeting with nimotuzumab in combination with radiation containing regimens, based on its favorable toxicity profile, are proposed. It is hoped that this review may provide further insight into the rational design of new approaches employing nimotuzumab as a useful alternative for the therapeutic management of high grade glioma.
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Mustafa OH, Hamzeh AR, Ghabreau L, Akil N, Almoustafa AE, Alachkar A. Allele Frequencies of the Epidermal Growth Factor Receptors Polymorphism R521K in Colorectal Cancer Patients and Healthy Subjects Indicate a Risk-Reducing Effect of K521 in Syrian Population. NORTH AMERICAN JOURNAL OF MEDICAL SCIENCES 2013; 5:202-6. [PMID: 23626956 PMCID: PMC3632024 DOI: 10.4103/1947-2714.109189] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background: Colorectal cancer contributes heavily to cancer morbidity and mortality worldwide. Numerous therapies are currently in use, including monoclonal antibodies against cellular components involved in tumorigenesis such as epidermal growth factor receptors (EGFRs). Studies showed the polymorphism [R521K] GàA in the EGFR gene to be involved in both colorectal cancer susceptibility and clinical response to therapeutics (e.g., Cetuximab). Aim: We aimed at uncovering allele frequencies of this polymorphism among Syrian colorectal cancer patients and healthy individuals. Materials and Methods: Forty-seven patients with colorectal cancer were included in a case-control study along with 48 healthy subjects, all native Syrians. Individuals were genotyped using PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) and results were statistically analyzed to elucidate significant differences between the two groups. Results: Allele frequencies were 40.4% (G/G), 57.4% (G/A) and 2.1% (A/A) in colorectal cancer patients and 41.6% (G/G), 43.7% (G/A) and 14.5% (A/A) in healthy subjects. The A/A genotype was significantly lower in colorectal cancer patients than in the control group. Conclusions: Homozygosity for the A allele is linked to reducing the risk of developing colorectal cancer in Syrian patients. The lower prevalence of (A/A) locally may predict sub-optimal rates of clinical response to Cetuximab compared with populations with higher frequencies of the A allele. Larger scale investigations are needed for a stronger conclusion.
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Affiliation(s)
- Ola Haj Mustafa
- Department of Pharmacology, University of Aleppo, Aleppo, Syria
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Cante D, La Porta MR, Franco P, Sciacero P, Girelli GF, Marra A, Numico G, Denaro N, Russi EG, Ricardi U. Management of In-Field' Skin Toxicity in Head and Neck Cancer Patients Treated with Combined Cetuximab and Radiotherapy. Oncology 2013; 85:257-61. [DOI: 10.1159/000355579] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Accepted: 09/04/2013] [Indexed: 11/19/2022]
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Ingargiola M, Dittfeld C, Runge R, Zenker M, Heldt JM, Steinbach J, Cordes N, Baumann M, Kotzerke J, Kunz-Schughart LA. Flow cytometric cell-based assay to preselect antibody constructs for radionuclide conjugation. Cytometry A 2012; 81:865-73. [DOI: 10.1002/cyto.a.22110] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 06/28/2012] [Accepted: 07/01/2012] [Indexed: 01/14/2023]
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Clémenson C, Jouannot E, Merino-Trigo A, Rubin-Carrez C, Deutsch E. The vascular disrupting agent ombrabulin (AVE8062) enhances the efficacy of standard therapies in head and neck squamous cell carcinoma xenograft models. Invest New Drugs 2012; 31:273-84. [PMID: 22810221 DOI: 10.1007/s10637-012-9852-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 06/28/2012] [Indexed: 11/25/2022]
Abstract
Targeting tumor vasculature is an emerging strategy in cancer treatment. Promising results have been shown in preclinical studies when vascular disrupting agents (VDAs) are used in combination with other anticancer therapies. Because radiation therapy with concurrent cisplatin or cetuximab has become standard treatment for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), we investigated whether the VDA ombrabulin (AVE8062) could improve the antitumor activity of radiation plus cisplatin and radiation plus cetuximab combinations. HNSCC HEP2 or FaDu tumor bearing mice were treated with ombrabulin, cisplatin, cetuximab, local radiation therapy or combinations of these treatments. Ombrabulin attenuated tumor growth of HEP2 and FaDu xenografts compared to control tumors. A more pronounced tumor growth delay and tumor regression were induced when ombrabulin was added to local irradiation, cisplatin or cetuximab in FaDu tumors compared to single agent treatments. Finally, triple agent therapies combining ombrabulin, irradiation, and either cisplatin or cetuximab were more effective than double combination treatment regimens and increased tumor growth delay in both HEP2 and FaDu tumor models. Of note, complete tumor regression was achieved in FaDu tumor model for the triple combination including platinum. Immunohistochemistry on FaDu tumors demonstrated a specificity of ombrabulin towards intratumoral vessels, in contrast to peritumoral vasculature. Our results provide a rationale for the use of ombrabulin in combination with two standard treatment regimens that are concurrent cisplatin-based chemoradiation and cetuximab plus ionizing radiation therapies, for the treatment of HNSCC.
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Affiliation(s)
- Céline Clémenson
- INSERM U1030, Radiothérapie moléculaire, Université Paris XI, LABEX LERMIT, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif Cedex, France
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Liu J, Guo W, Xu B, Ran F, Chu M, Fu H, Cui J. Angiogenesis inhibition and cell cycle arrest induced by treatment with Pseudolarix acid B alone or combined with 5-fluorouracil. Acta Biochim Biophys Sin (Shanghai) 2012; 44:490-502. [PMID: 22551583 DOI: 10.1093/abbs/gms029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Angiogenesis inhibitors combined with chemotherapeutic drugs have significant efficacy in the treatment of a variety of cancers. Pseudolarix acid B (PAB) is a traditional pregnancy-terminating agent, which has previously been shown to reduce tumor growth and angiogenesis. In this study, we used the high content screening assay to examine the effects of PAB on human umbilical vein endothelial cells (HUVECs). Two hepatocarcinoma 22-transplanted mouse models were used to determine PAB efficacy in combination with 5-fluorouracil (5-Fu). Our results suggested that PAB (0.156-1.250 μM) inhibited HUVECs motility in a concentration-dependent manner without obvious cytotoxicity in vitro. In vivo, PAB (25 mg/kg/day) promoted the anti-tumor efficacy of 5-Fu (5 mg/kg/2 days) in combination therapy, resulting in significantly higher tumor inhibition rates, lower microvessel density values, and prolonged survival times. It was also demonstrated that PAB acted by blocking the cell cycle at both the G(1)/S boundary and M phase, down-regulation of vascular endothelial growth factor, hypoxia-inducible factor 1α and cyclin E expression, and up-regulation of cdc2 expression. These observations provide the first evidence that PAB in combination with 5-Fu may be useful in cancer treatment.
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Affiliation(s)
- Jingtao Liu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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Patel AN, Mehnert JM, Kim S. Treatment of recurrent metastatic head and neck cancer: focus on cetuximab. CLINICAL MEDICINE INSIGHTS. EAR, NOSE AND THROAT 2012; 5:1-16. [PMID: 24179404 PMCID: PMC3791949 DOI: 10.4137/cment.s5129] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
EGFR belongs to the ErbB family of receptor tyrosine kinases and is associated with worse prognosis in head and neck squamous cell carcinoma (HNSCC). Cetuximab is a monoclonal antibody to the extracellular domain of EGFR and inhibits its downstream actions via multiple mechanisms. Besides its proven efficacy in locally advanced and incurable HNSCC, cetuximab has the distinct advantage of having a relatively tolerable side effect profile and not potentiating radiation toxicity. Though therapies for advanced HNSCC are evolving, locoregional recurrence and/or distant metastases occur in a large percentage of patients. Though some patients can be salvaged with surgery or radiation therapy, the majority are incurable, and are treated palliatively with systemic therapy. In the setting of first line therapy for recurrent/metastatic HNSCC, the EXTREME trial provided level 1 evidence that cetuximab improves overall survival when combined with cisplatinum and 5 FU. Following progression on first line chemotherapy, several phase II trials suggest that cetuximab monotherapy is a reasonable choice in this setting. Future studies should concentrate on clinical and molecular markers that may allow more personalized approaches to treating HNSCC, and combining EGFR inhibitors with other agents in a synergistic approach.
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Affiliation(s)
- Akshar N Patel
- Department of Radiation Oncology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ
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Ferreira MBA, Lima JPSN, Cohen EEW. Novel targeted therapies in head and neck cancer. Expert Opin Investig Drugs 2012; 21:281-95. [PMID: 22239178 DOI: 10.1517/13543784.2012.651455] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
INTRODUCTION Molecularly targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. AREAS COVERED Targeted agents for HNSCC expected to improve the effectiveness of current therapy including HER family, Src-family kinase, cell cycle, MET, AKT, HDAC, PARP, COX inhibitors and antiangiogenesis. EXPERT OPINION Epidermal growth factor receptor inhibitors are established in HNSCC and the need now is to find biomarkers for sensitivity to better select patients. Moreover, other pathway inhibitors hold significant promise and are being tested in clinical trials. Angiogenesis inhibition is likely to yield only modest efficacy alone but may augment existing standards. Lastly, one clinical arena where targeted therapies may find secure purchase is in the adjuvant or prevention setting where minimal or preneoplastic disease can be affected by inhibition of a single or few targets.
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Mehra R, Serebriiskii IG, Dunbrack RL, Robinson MK, Burtness B, Golemis EA. Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer. Drug Resist Updat 2011; 14:260-79. [PMID: 21920801 PMCID: PMC3195944 DOI: 10.1016/j.drup.2011.08.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2011] [Revised: 08/16/2011] [Accepted: 08/17/2011] [Indexed: 02/07/2023]
Abstract
Agents targeting EGFR and related ErbB family proteins are valuable therapies for the treatment of many cancers. For some tumor types, including squamous cell carcinomas of the head and neck (SCCHN), antibodies targeting EGFR were the first protein-directed agents to show clinical benefit, and remain a standard component of clinical strategies for management of the disease. Nevertheless, many patients display either intrinsic or acquired resistance to these drugs; hence, major research goals are to better understand the underlying causes of resistance, and to develop new therapeutic strategies that boost the impact of EGFR/ErbB inhibitors. In this review, we first summarize current standard use of EGFR inhibitors in the context of SCCHN, and described new agents targeting EGFR currently moving through pre-clinical and clinical development. We then discuss how changes in other transmembrane receptors, including IGF1R, c-Met, and TGF-β, can confer resistance to EGFR-targeted inhibitors, and discuss new agents targeting these proteins. Moving downstream, we discuss critical EGFR-dependent effectors, including PLC-γ; PI3K and PTEN; SHC, GRB2, and RAS and the STAT proteins, as factors in resistance to EGFR-directed inhibitors and as alternative targets of therapeutic inhibition. We summarize alternative sources of resistance among cellular changes that target EGFR itself, through regulation of ligand availability, post-translational modification of EGFR, availability of EGFR partners for hetero-dimerization and control of EGFR intracellular trafficking for recycling versus degradation. Finally, we discuss new strategies to identify effective therapeutic combinations involving EGFR-targeted inhibitors, in the context of new system level data becoming available for analysis of individual tumors.
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Affiliation(s)
- Ranee Mehra
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Ilya G. Serebriiskii
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Roland L. Dunbrack
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Matthew K. Robinson
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Barbara Burtness
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111
- Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Erica A. Golemis
- Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111
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Russi EG, Merlano MC, Numico G, Corvò R, Benasso M, Vigna-Taglianti R, Melano A, Denaro N, Pergolizzi S, Colantonio I, Lucio F, Brizio R, Ricardi U. The effects on pain and activity of daily living caused by crusted exudation in patients with head and neck cancer treated with cetuximab and radiotherapy. Support Care Cancer 2011; 20:2141-7. [DOI: 10.1007/s00520-011-1324-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Accepted: 11/01/2011] [Indexed: 11/30/2022]
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Bernier J, Russi E, Homey B, Merlano M, Mesía R, Peyrade F, Budach W. Management of radiation dermatitis in patients receiving cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: proposals for a revised grading system and consensus management guidelines. Ann Oncol 2011; 22:2191-200. [DOI: 10.1093/annonc/mdr139] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Argiris A, Duffy AG, Kummar S, Simone NL, Arai Y, Kim SW, Rudy SF, Kannabiran VR, Yang X, Jang M, Chen Z, Suksta N, Cooley-Zgela T, Ramanand SG, Ahsan A, Nyati MK, Wright JJ, Van Waes C. Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer. Clin Cancer Res 2011; 17:5755-64. [PMID: 21750205 PMCID: PMC3368806 DOI: 10.1158/1078-0432.ccr-11-0861] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. EXPERIMENTAL DESIGN Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m²) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1. RESULTS Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m², without dose-limiting toxicities; one patient treated at 1.3 mg/m² was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. CONCLUSIONS Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination.
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MESH Headings
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal, Humanized
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Apoptosis
- Biomarkers, Tumor/analysis
- Boronic Acids/administration & dosage
- Boronic Acids/adverse effects
- Bortezomib
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/radiotherapy
- Cell Line, Tumor
- Cetuximab
- Combined Modality Therapy/adverse effects
- Cytokines/biosynthesis
- Cytokines/blood
- Disease Progression
- ErbB Receptors/metabolism
- Female
- Head and Neck Neoplasms/drug therapy
- Head and Neck Neoplasms/metabolism
- Head and Neck Neoplasms/radiotherapy
- Humans
- Male
- Middle Aged
- Protease Inhibitors/administration & dosage
- Protease Inhibitors/adverse effects
- Pyrazines/administration & dosage
- Pyrazines/adverse effects
- Radiotherapy, Intensity-Modulated/adverse effects
- Signal Transduction
- Squamous Cell Carcinoma of Head and Neck
- Transcription Factors/biosynthesis
- Treatment Outcome
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Affiliation(s)
- Athanassios Argiris
- Hematology-Oncology and Head and Neck Cancer Program, University of Pittsburgh
| | - Austin G. Duffy
- Early Clinical Trials Development, Division of Cancer Treatment and Diagnosis
| | - Shivaani Kummar
- Early Clinical Trials Development, Division of Cancer Treatment and Diagnosis
| | | | - Yoshio Arai
- Radiation Oncology, University of Pittsburgh
| | - Seungwon W. Kim
- Hematology-Oncology and Head and Neck Cancer Program, University of Pittsburgh
| | - Susan. F. Rudy
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
| | - Vishnu. R. Kannabiran
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
| | - Xinping Yang
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
| | - Minyoung Jang
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
| | - Zhong Chen
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
| | - Nanette Suksta
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
| | | | | | - Aarif Ahsan
- Department of Radiation Oncology, University of Michigan
| | | | - John J. Wright
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD
| | - Carter Van Waes
- Radiation Oncology Branch, National Cancer Institute
- Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders
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