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1
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Abd El-Mawgoud HK, AboulMagd AM, Nemr MTM, Hemdan MM, Hassaballah AI, Farag PS. Design, synthesis and cytotoxic evaluation of new thieno[2,3-d]pyrimidine analogues as VEGFR-2/AKT dual inhibitors, apoptosis and autophagy inducers. Bioorg Chem 2024; 150:107622. [PMID: 38996545 DOI: 10.1016/j.bioorg.2024.107622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/22/2024] [Accepted: 07/08/2024] [Indexed: 07/14/2024]
Abstract
Novel thieno[2,3-d]pyrimidine analogues were designed, synthesized and evaluated for anti-proliferative activity against HepG-2, PC-3 and MCF-7 cancer cell lines. In addition, WI-38 normal cell line was used to explore the safety of all the tested compounds. Compounds 2 (IC50 = 4.29 µM HePG-2, 10.84 µM MCF-7), 6 (IC50 = 14.86 μM HePG-2, 8.04 μM PC-3 and 12.90 μM MCF-7) and 17 (IC50 = 9.98 μM HePG-2, 33.66 μM PC-3 and 14.62 μM MCF-7) were the most promising candidates on the tested cancer cells with high selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where compound 2 inhibited VEGFR-2 and AKT at IC50 = 0.161 and 1.06 μM, respectively, Furthermore, derivative 6 inhibited VEGFR-2 and AKT at IC50 = 0.487 and 0.364 μM, respectively, while compound 17 showed IC50 = 0.164 and 0.452 μM, respectively. Moreover, compounds 2, 6 resulted in G1 phase cell cycle arrest while candidate 17 arrest cell cycle at G2/M phase. Similar to the apoptosis results, compound 17 showed the highest autophagic induction among the evaluated derivatives. Finally, docking studies were conducted to assess the binding patterns of these active derivatives. The results showed that the binding patterns inside the active sites of both the VEGFR-2 and AKT-1 (allosteric pocket) crystal structures were identical to the reference ligands.
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Affiliation(s)
- Heba K Abd El-Mawgoud
- Chemistry Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Heliopolis, 11767 Cairo, Egypt.
| | - Asmaa M AboulMagd
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef, Egypt.
| | - Mohamed T M Nemr
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini Street 11562, Cairo, Egypt
| | - Magdy M Hemdan
- Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, 11566 Cairo, Egypt
| | - Aya I Hassaballah
- Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, 11566 Cairo, Egypt
| | - Paula S Farag
- Chemistry Department, Faculty of Science, Ain Shams University, Abbasia, 11566 Cairo, Egypt
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2
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Gu Y, Wang Z, Wang Y. Bispecific antibody drug conjugates: Making 1+1>2. Acta Pharm Sin B 2024; 14:1965-1986. [PMID: 38799638 PMCID: PMC11119582 DOI: 10.1016/j.apsb.2024.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 01/12/2024] [Accepted: 01/17/2024] [Indexed: 05/29/2024] Open
Abstract
Bispecific antibody‒drug conjugates (BsADCs) represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates (ADCs) and bispecific antibodies (BsAbs). Positioned as the next-generation ADC approach, BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs, particularly pertaining to issues such as poor internalization, off-target toxicity, and drug resistance. Presently, ten BsADCs are undergoing clinical trials, and initial findings underscore the imperative for ongoing refinement. This review initially delves into specific design considerations for BsADCs, encompassing target selection, antibody formats, and the linker-payload complex. Subsequent sections delineate the extant progress and challenges encountered by BsADCs, illustrated through pertinent case studies. The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs. Nevertheless, the symbiotic interplay among BsAb, linker, and payload necessitates further optimizations and coordination beyond a simplistic "1 + 1" to effectively surmount the extant challenges facing the BsADC domain.
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Affiliation(s)
- Yilin Gu
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhijia Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuxi Wang
- Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China
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3
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Sachdeva A, Dhawan D, Jain GK, Yerer MB, Collignon TE, Tewari D, Bishayee A. Novel Strategies for the Bioavailability Augmentation and Efficacy Improvement of Natural Products in Oral Cancer. Cancers (Basel) 2022; 15:cancers15010268. [PMID: 36612264 PMCID: PMC9818473 DOI: 10.3390/cancers15010268] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 12/21/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation.
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Affiliation(s)
- Alisha Sachdeva
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Dimple Dhawan
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Gaurav K. Jain
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
- Center for Advanced Formulation Development, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
| | - Mükerrem Betül Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey
| | - Taylor E. Collignon
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Devesh Tewari
- Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110 017, India
- Correspondence: or (D.T.); or (A.B.)
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
- Correspondence: or (D.T.); or (A.B.)
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4
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Munjal M, Kaur R, Kaur R, Munjal S, Chopra P, Verma H, Chopra H. Therapeutic Modalities in Head-Neck Neoplasia and Prognostication: A Review. Indian J Otolaryngol Head Neck Surg 2022; 74:2445-2457. [PMID: 36452817 PMCID: PMC9702289 DOI: 10.1007/s12070-020-02200-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 10/03/2020] [Indexed: 10/23/2022] Open
Abstract
Neoplasia of the head and the neck necessitates intervention, surgical or otherwise, as the site and stage of the pathology may dictate. The various therapeutic modalities employed and prognosis has been reviewed.
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Affiliation(s)
- Manish Munjal
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
| | - Ramanpreet Kaur
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
| | - Raminderjit Kaur
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
| | - Shubham Munjal
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
| | - Parth Chopra
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
| | - Hitesh Verma
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
| | - Hemant Chopra
- Oto-Rhino-Laryngologology and Head Neck Services, Dayanand Medical College and Hospital, Ludhiana, Punjab India
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5
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Elmongy EI, Attallah NGM, Altwaijry N, AlKahtani MM, Henidi HA. Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction. Molecules 2021; 27:molecules27010123. [PMID: 35011354 PMCID: PMC8746632 DOI: 10.3390/molecules27010123] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/15/2021] [Accepted: 12/23/2021] [Indexed: 11/16/2022] Open
Abstract
This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.
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Affiliation(s)
- Elshaymaa I. Elmongy
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia; (N.G.M.A.); (N.A.)
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo P.O. Box 11795, Egypt
- Correspondence: or
| | - Nashwah G. M. Attallah
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia; (N.G.M.A.); (N.A.)
- Egyptian Drug Authority (EDA) (Previously NODCAR), Giza 8655, Egypt
| | - Najla Altwaijry
- Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia; (N.G.M.A.); (N.A.)
| | - Manal Mubarak AlKahtani
- Research Department, Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia; (M.M.A.); (H.A.H.)
| | - Hanan Ali Henidi
- Research Department, Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia; (M.M.A.); (H.A.H.)
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6
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Bavetta M, Silvaggio D, Campione E, Sollena P, Formica V, Coletta D, Graziani G, Romano MCP, Roselli M, Peris K, Bianchi L. The Effects of Association of Topical Polydatin Improves the Preemptive Systemic Treatment on EGFR Inhibitors Cutaneous Adverse Reactions. J Clin Med 2021; 10:jcm10030466. [PMID: 33530427 PMCID: PMC7866016 DOI: 10.3390/jcm10030466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 12/20/2022] Open
Abstract
Epidermal Growth Factor Receptor inhibitors (EGFRi) are approved as therapeutic options in several solid tumors. Cutaneous papulopustular eruption is the most frequent cutaneous adverse-event (AE), usually treated with emollient or corticosteroids according to toxicity grade. Our study evaluated the efficacy and safety of a topical product containing polydatin, a glycosylated polyphenol, natural precursor of resveratrol showing anti-inflammatory and anti-oxidative activities, for the prevention and treatment of skin papulopustular rash in EGFRi-treated patients. Forty oncologic patients treated with EGFRi were enrolled in two groups: group-A, 20 patients with papulopustular AE, and group-B, 20 patients without cutaneous manifestations. The study consisted of twice-daily application of polydatin cream 1.5% (group-A) and 0.8% (group-B) for 6 months. In group-A patients, we observed at week 4 a remarkable improvement of skin manifestation and quality of life evaluated with National-Cancer-Institute-Common-Terminology-Criteria for Adverse-Events (NCI-CTCAE), Dermatology-Life-Quality-Index (DLQI) score and Visual-Analogue-Scale (VAS) pruritus, with a statistical significance of p < 0.05. None of the patients of group-B developed skin AEs to EGFRi. No cutaneous AEs related to the polydatin product were reported in both groups. Polydatin can be a good topical aid for the prevention and management of papulopustular rash in cancer patients receiving EGFRi, also capable of improving cancer patients’ quality of life.
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Affiliation(s)
- Mauro Bavetta
- Dermatology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (E.C.); (L.B.)
- Correspondence: (M.B.); (D.S.)
| | - Dionisio Silvaggio
- Dermatology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (E.C.); (L.B.)
- Correspondence: (M.B.); (D.S.)
| | - Elena Campione
- Dermatology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (E.C.); (L.B.)
| | - Pietro Sollena
- Dermatology Unit, Department of Medical and Surgical Sciences, Fondazione Agostino Gemelli University Hospital IRCCS, 00168 Rome, Italy; (P.S.); (K.P.)
| | - Vincenzo Formica
- Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (V.F.); (D.C.); (M.R.)
| | - Deborah Coletta
- Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (V.F.); (D.C.); (M.R.)
| | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | | | - Mario Roselli
- Oncology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (V.F.); (D.C.); (M.R.)
| | - Ketty Peris
- Dermatology Unit, Department of Medical and Surgical Sciences, Fondazione Agostino Gemelli University Hospital IRCCS, 00168 Rome, Italy; (P.S.); (K.P.)
- Institute of Dermatology, Cattolica del Sacro Cuore University, 00168 Rome, Italy
| | - Luca Bianchi
- Dermatology Unit, Department of Systems Medicine, Tor Vergata University Hospital Foundation, 00133 Rome, Italy; (E.C.); (L.B.)
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7
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A network pharmacology-integrated metabolomics strategy for clarifying the action mechanisms of Schisandrae Chinensis Fructus for treating drug-induced liver injury by acetaminophen. Bioorg Med Chem 2021; 31:115992. [PMID: 33421914 DOI: 10.1016/j.bmc.2020.115992] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/27/2020] [Accepted: 12/30/2020] [Indexed: 12/21/2022]
Abstract
Schisandrae Chinensis Fructus (SCF) was a Traditional Chinese Medicine (TCM) for protecting liver. However, underlying therapeutic mechanisms of SCF for drug-induced liver injury (DILI) by acetaminophen (APAP) are still unclear. This study aims to discover the potential regulation mechanisms of SCF in the treatment of DILI by APAP using the integrated network pharmacology, plasma metabolomics profiling with UPLC-Q-TOF-MS approach. The key targets in the shared pathways of network pharmacology and metabolomics were screened and experimentally validated by Quantitative Real-time PCR analysis. The results showed that SCF could exert excellent effects on DILI by APAP probably through regulating ErbB signaling pathway and Arachidonic acid metabolism pathway, which was reflected by the reduced gene expression of TNF-α, IL-6, IL-1β, COX-2 and EGFR, as well as the increased gene expression of Nrf2, HO-1, MDM2, MAPK8, SRC, PLD1, CYP2E1, CYP1A2, CYP3A1. This study systematically explored the pharmacological mechanisms of SCF in the treatment of DILI, meanwhile, metabolomics combine with network pharmacology approach might be a useful strategy for early diagnosis of DILI by APAP.
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8
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Liao C, An J, Tan Z, Xu F, Liu J, Wang Q. Changes in Protein Glycosylation in Head and Neck Squamous Cell Carcinoma. J Cancer 2021; 12:1455-1466. [PMID: 33531990 PMCID: PMC7847636 DOI: 10.7150/jca.51604] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022] Open
Abstract
Glycosylation is an important posttranslational modification of proteins, and it has a profound influence on diverse life processes. An abnormal polysaccharide structure and mutation of the glycosylation pathway are closely correlated with human cancer progression. Glycoproteins such as EGFR, E-cadherin, CD44, PD-1/PD-L1, B7-H3 and Muc1 play important roles in the progression of head and neck squamous cell carcinoma (HNSCC), and their levels of glycosylation and changes in glycosyl structure are closely linked to HNSCC progression and malignant transformation. The regulation of protein glycosylation in HNSCC provides potential strategies to control cancer stem cell (CSC) subgroup expansion, epithelial-mesenchymal transition (EMT), tumor-related immunity escape and autophagy. Glycoproteins with altered glycosylation can be used as biomarkers for the early diagnosis, monitoring and prognostication of HNSCC. However, the glycobiology of cancer is still a new field that needs to be deeply studied, especially in HNSCC.
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Affiliation(s)
- Chengcheng Liao
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Jiaxing An
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - Zhangxue Tan
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Fangping Xu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Jianguo Liu
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China
| | - Qian Wang
- Oral Disease Research Key Laboratory of Guizhou Tertiary Institution, School of Stomatology, Zunyi Medical University, Zunyi 563006, China.,Microbial Resources and Drug Development Key Laboratory of Guizhou Tertiary Institution, Life Sciences Institute, Zunyi Medical University, Zunyi 563006, China
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9
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Ghorab MM, Abdel-Kader MS, Alqahtani AS, Soliman AM. Synthesis of some quinazolinones inspired from the natural alkaloid L -norephedrine as EGFR inhibitors and radiosensitizers. J Enzyme Inhib Med Chem 2020; 36:218-237. [PMID: 33357002 PMCID: PMC7781899 DOI: 10.1080/14756366.2020.1854243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.
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Affiliation(s)
- Mostafa M Ghorab
- Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
| | - Maged S Abdel-Kader
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.,Department of Pharmacognosy, College of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Ali S Alqahtani
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.,Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Aiten M Soliman
- Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt
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10
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Elmongy EI. Thieno[2,3‐
d
]pyrimidine derivatives: Synthetic approaches and their FLT3 kinase inhibition. J Heterocycl Chem 2020. [DOI: 10.1002/jhet.3934] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Elshaymaa I. Elmongy
- Department of Pharmaceutical Chemistry, Faculty of PharmacyHelwan University Cairo Egypt
- Department of Pharmaceutical Sciences, Faculty of PharmacyPrincess Nourah bint Abdulrahman University Riyadh Saudi Arabia
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11
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Hsu PJ, Yan K, Shi H, Izumchenko E, Agrawal N. Molecular biology of oral cavity squamous cell carcinoma. Oral Oncol 2020; 102:104552. [PMID: 31918173 DOI: 10.1016/j.oraloncology.2019.104552] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 07/30/2019] [Accepted: 12/21/2019] [Indexed: 12/23/2022]
Abstract
Oral cavity squamous cell carcinoma (OCSCC) is a heterogeneous and complex disease that arises due to dysfunction of multiple molecular signaling pathways. Recent advances in high-throughput genetic sequencing technologies coupled with innovative analytical techniques have begun to characterize the molecular determinants driving OCSCC. An understanding of the key molecular signaling networks underlying the initiation and progression of is essential for informing treatment of the disease. In this chapter, we discuss recent findings of key genes altered in OCSCC and potential treatments targeting these genes.
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Affiliation(s)
- Phillip J Hsu
- Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA
| | - Kenneth Yan
- Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Hailing Shi
- Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA
| | - Evgeny Izumchenko
- Section of Hematology Oncology, Department of Medicine, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Nishant Agrawal
- Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA.
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12
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Basheeth N, Patil N. Biomarkers in Head and Neck Cancer an Update. Indian J Otolaryngol Head Neck Surg 2019; 71:1002-1011. [PMID: 31742110 PMCID: PMC6848420 DOI: 10.1007/s12070-019-01683-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 06/04/2019] [Indexed: 12/30/2022] Open
Abstract
The study is aimed at establishing the purpose of tumour markers, their application, classification, diagnostic and therapeutic roles in the management of head and neck cancer. A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane central register of controlled trials for articles published between 1993 and 2016 on tumour markers and their role in head and neck cancer was performed. A broader search of prognostic markers in head and neck cancer was also carried out to avoid missing other pertinent markers. Natural history, tumour biology, stage and prognostic factors influence the outcome of management in patients with Head and Neck Squamous cell carcinoma (HNSCC). Evaluation of the cellular lineage and histogenic origin of diverse neoplasms can be done using tumour biomarkers. Identifying predictive tumour markers can lead to improvement in preventive management of HNSCC. There has been remarkable advancement in molecular technology with gene expression and proteomic profiling. Integration of specific tumour markers into routine clinical practice requires substantiation through well designed clinical trials. The investigation of tumour markers is imperative as they influence the prognosis of HNSCC and provide the potential to improve outcomes of treatment through targeted therapy. We have outlined recent tumour biomarkers in this review which have significant role in diagnosis, screening and prognostication in HNSCC. Recent advancement in clinical applications, therapeutic strategies of tumour markers has been highlighted.
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Affiliation(s)
- Naveed Basheeth
- Otolaryngology and Head and Neck Surgery, Royal College of Surgeons in Ireland, 123 St.Stephens Green, Dublin-2, Ireland
| | - Naishadh Patil
- Otolaryngology and Head and Neck Surgery, Sligo University Hospital, Sligo, Ireland
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13
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Koustas E, Papavassiliou AG, Karamouzis MV. The role of autophagy in the treatment of BRAF mutant colorectal carcinomas differs based on microsatellite instability status. PLoS One 2018; 13:e0207227. [PMID: 30427914 PMCID: PMC6241137 DOI: 10.1371/journal.pone.0207227] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 10/27/2018] [Indexed: 02/05/2023] Open
Abstract
Autophagy has been identified as a catabolic mechanism in cells but its' role in cancer remains controversial. Autophagy has been characterized either as tumor suppressor or inducer mechanism in many tumor types. Monoclonal antibodies against EGFR (cetuximab and panitumumab) represent a major step in the treatment of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy which reveals a potential resistance mechanism to these agents. The last years immunotherapy appears to be a novel promising strategy for the treatment of patients with solid tumors, including colorectal cancer. Checkpoint inhibitors, such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab) antibodies have already been developed and applied in mCRC patients with MSI-H phenotype. The association between mtBRAF and autophagy or MSI status has already been characterized. In our study, we identify the autophagy initiation through anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma cell lines according to microsatellite status. The combination of autophagy inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors appears to be the best treatment approach for microsatellite instability high and stable colorectal cancer cell lines, respectively. Both combinatorial approaches reduce cell viability through the induction of apoptotic cell death. The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype.
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Affiliation(s)
- Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Internal Medicine, ‘Laiko’ General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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14
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Skin toxicity with anti-EGFR monoclonal antibody in cancer patients: a meta-analysis of 65 randomized controlled trials. Cancer Chemother Pharmacol 2018; 82:571-583. [PMID: 30006755 DOI: 10.1007/s00280-018-3644-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 07/04/2018] [Indexed: 12/30/2022]
Abstract
We performed a meta-analysis to fully investigate the skin toxicities of anti-EGFR monoclonal antibody (EGFR-MoAbs) in cancer patients. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with EGFR-MoAbs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till November 2017. The relevant RCTs in cancer patients treated with EGFR-MoAbs were retrieved and the systematic evaluation was conducted. 65 RCTs and 25994 patients were included. The current meta-analysis suggests that the use of EGFR-MoAbs significantly increases the risk of developing all-grade and high-grade skin toxicity, such as rash, hand-foot syndrome, dry skin and oral mucositis. Rash was the most common skin toxicity. Patients receiving nimotuzumab were associated with the least risk of skin toxicity. The risk of high-grade skin toxicity tended to be higher in the study in which the EGFR-MoAbs treatment duration was longer. The available data suggested that the use of EGFR-MoAbs significantly increases the risk of developing skin toxicity. Physicians should be aware of skin toxicity and should monitor cancer patients when receiving EGFR-MoAbs.
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15
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Karamouzis MV, Papavassiliou AG. Combination of checkpoint inhibitors with other agents as a strategy to improve anti-cancer effect - a glimpse to the future. Expert Opin Investig Drugs 2018; 27:569-572. [PMID: 29958097 DOI: 10.1080/13543784.2018.1494724] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In the last years, a remarkable progress has been made in the clinical application of novel immunotherapy agents, the so called 'checkpoint inhibitors,' that has revolutionized the treatment of many malignant tumors. Their design has been based on the immune-mediated mechanisms of antitumor activity circle, such as antigen release and presentation, activation and trafficking of T-cells into tumors, depletion of immunosuppression, and immunogenic cell death. Various combinations of checkpoint inhibitors are being designed and/or tested, such as double checkpoint blockade, combination with chemotherapy, radiotherapy, molecularly targeted agents, and other immune-directed strategies.
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Affiliation(s)
- Michalis V Karamouzis
- a Molecular Oncology Unit, Department of Biological Chemistry , Medical School, National and Kapodistrian University of Athens , Athens , Greece
| | - Athanasios G Papavassiliou
- a Molecular Oncology Unit, Department of Biological Chemistry , Medical School, National and Kapodistrian University of Athens , Athens , Greece
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16
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Moriwaki K, Ayani Y, Kuwabara H, Terada T, Kawata R, Asahi M. TRKB tyrosine kinase receptor is a potential therapeutic target for poorly differentiated oral squamous cell carcinoma. Oncotarget 2018; 9:25225-25243. [PMID: 29861866 PMCID: PMC5982746 DOI: 10.18632/oncotarget.25396] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 04/26/2018] [Indexed: 12/20/2022] Open
Abstract
It has been reported that one of the neurotrophin receptors, tropomyosin receptor kinase B (TRKB), is frequently overexpressed in various tumor tissues including oral squamous cell carcinoma (OSCC), and that its upregulation promotes tumor progression in human cancers. However, the correlation between TRKB overexpression and clinicopathological characteristics is not fully elucidated. Here, we present the correlation between the expression levels of TRKB and/or its secreted ligand, brain-derived neurotrophic factor (BDNF), and clinicopathological characteristics, especially regarding tumor differentiation, tissue invasion, and disease-free survival in patients with OSCC. The results obtained through immunohistochemical analysis of human OSCC tumor specimens showed that the expression levels of TRKB and/or BDNF, were significantly higher in moderately and poorly differentiated OSCC (MD/PD-OSCC) tumor cells than in well differentiated cells (WD-OSCC). Moreover, the OSCC tumors highly expressing TRKB and/or BDNF exhibited promotion in tissue invasion and reduction in disease-free survival in the patients. In an orthotopic transplantation mouse model of human OSCC cell lines, administration of a TRKB-specific inhibitor significantly suppressed the tumor growth and invasion in PD-OSCC-derived tumor cells, but not in WD-OSCC-derived tumor cells. Moreover, the TRKB inhibitor selectively blocked BDNF-induced tumor cell proliferation and migration accompanied with the suppression of TRKB phosphorylation in PD-OSCC but not in WD-OSCC in vitro. Taken together, these data suggest that the BDNF/TRKB signaling pathway may regulate tumor progression in poorly differentiated OSCC. Expression levels of signal molecules may be an accurate prognosis marker for tumor aggressiveness, and the molecules may be an attractive target for new OSCC therapies.
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Affiliation(s)
- Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Yusuke Ayani
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Hiroko Kuwabara
- Department of Pathology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Tetsuya Terada
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Ryo Kawata
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Michio Asahi
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
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17
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Deng C, Xiong J, Gu X, Chen X, Wu S, Wang Z, Wang D, Tu J, Xie J. Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiency in vitro. Oncotarget 2018; 8:38568-38580. [PMID: 28445134 PMCID: PMC5503554 DOI: 10.18632/oncotarget.16930] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 03/24/2017] [Indexed: 11/25/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) overexpression is related to the increased aggressiveness, metastases, and poor prognosis in various cancers. In this study, we successfully constructed a new EGFR nanobody-based immunotoxin rE/CUS containing cucurmosin (CUS), The immunotoxin was expressed by prokaryotic system and we obtained a yield of 5 mg protein per liter expression medium. The percentage of it's binding ability totumor cell lines A549, HepG2, SW116, which highly expressed EGFR was 55.6%, 79.6% and 97.1%, respectively, but SW620 was only 4.45%. rE/CUS has the ability to bind A549, HepG2, SW116 cells specifically, and the antigen binding capability was not affected because of extra part of CUS component. The rE/CUS significantly inhibited the cell viability against EGFR over expression tumor cell lines in a dose-and time-dependent manner. Moreover, rE/CUS also induced apoptosis of HepG2 and A549 mightily. Our results demonstrate that rE/CUS is a potential therapeutic strategy for treating EGFR-positive solid tumors.
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Affiliation(s)
- Cuimin Deng
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian, China
| | - Jiani Xiong
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Xiaofan Gu
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiaoying Chen
- Department of Experimental Teaching Center of Basic Medical Science, Fujian Medical University, Fuzhou, Fujian, China
| | - Shuifa Wu
- Department of Pharmacology, The 180th Hospital of PLA, Quanzhou, Fujian, China
| | - Zhe Wang
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian, China
| | - Duanduan Wang
- Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Jinjin Tu
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian, China
| | - Jieming Xie
- Department of Pharmacology, Fujian Medical University, Fuzhou, Fujian, China
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18
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Zhang XF, Pan K, Weng DS, Chen CL, Wang QJ, Zhao JJ, Pan QZ, Liu Q, Jiang SS, Li YQ, Zhang HX, Xia JC. Cytotoxic T lymphocyte antigen-4 expression in esophageal carcinoma: implications for prognosis. Oncotarget 2018; 7:26670-9. [PMID: 27050369 PMCID: PMC5042006 DOI: 10.18632/oncotarget.8476] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 03/02/2016] [Indexed: 02/07/2023] Open
Abstract
To examine the relationship between cytotoxic T lymphocyte antigen-4 (CTLA-4) expression and esophageal carcinoma prognosis, CTLA-4 expression was immunohistochemically detected in paraffin-embedded primary tumor specimens from 158 patients with esophageal cancer. CTLA-4 was detected in the cytoplasm and cell membranes of esophageal cancer cells and in interstitial lymphocytes. In univariate analyses (log-rank), higher interstitial CTLA-4+ lymphocyte density and higher tumor CTLA-4 expression were associated with shorter overall survival (OS). After controlling for age and clinical stage, multivariate analysis (Cox) found that tumor CTLA-4 expression was an independent predictor of shorter OS (HR 2.016, P = 0.004). These results indicate that CTLA-4 expression in the tumor environment (both lymphocytes and tumor cells) is associated with poorer prognosis. In addition, CTLA-4 profiles may be useful for predicting the benefits and toxicity of CTLA-4 blockade in patients with esophageal carcinoma.
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Affiliation(s)
- Xiao-Fei Zhang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Ke Pan
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - De-Sheng Weng
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Chang-Long Chen
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qi-Jing Wang
- Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Jing-Jing Zhao
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qiu-Zhong Pan
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Qing Liu
- Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Shan-Shan Jiang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Yong-Qiang Li
- Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Hong-Xia Zhang
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
| | - Jian-Chuan Xia
- State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China.,Department of Biotherapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People's Republic of China
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19
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Ghith A, Ismail NS, Youssef K, Abouzid KA. Medicinal Attributes of Thienopyrimidine Based Scaffold Targeting Tyrosine Kinases and Their Potential Anticancer Activities. Arch Pharm (Weinheim) 2017; 350. [DOI: 10.1002/ardp.201700242] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 08/14/2017] [Accepted: 09/05/2017] [Indexed: 01/02/2023]
Affiliation(s)
- Amna Ghith
- Faculty of Pharmaceutical Sciences and Pharmaceutical Industries; Department of Pharmaceutical Chemistry; Future University in Egypt; Cairo Egypt
| | - Nasser S.M. Ismail
- Faculty of Pharmaceutical Sciences and Pharmaceutical Industries; Department of Pharmaceutical Chemistry; Future University in Egypt; Cairo Egypt
| | - Khairia Youssef
- Faculty of Pharmaceutical Sciences and Pharmaceutical Industries; Department of Pharmaceutical Chemistry; Future University in Egypt; Cairo Egypt
| | - Khaled A.M. Abouzid
- Faculty of Pharmacy; Department of Pharmaceutical Chemistry; Ain Shams University; Abbassia, Cairo Egypt
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20
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Jiffar T, Yilmaz T, Lee J, Miller Y, Feng L, El-Naggar A, Kupferman ME. Brain derived neutrophic factor (BDNF) coordinates lympho-vascular metastasis through a fibroblast-governed paracrine axis in the tumor microenvironment. ACTA ACUST UNITED AC 2017; 4. [PMID: 28966935 PMCID: PMC5617346 DOI: 10.14800/ccm.1566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
It has long been known that the tumor microenvironment contributes to the proliferation and survival of neoplasms through the constant interaction with the stromal and immune compartments. In this investigation, we explored the role of cancer-associated fibroblasts (CAFs) in the regulation of the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC) though a complex intercellular BDNF-TrkB signaling system. Our studies show that conditioned media derived from patient-derived CAFs promoted HNSCC cell proliferation, in vitro cell migration, cell invasion and chemotherapy resistance, compared to normal fibroblasts. Furthermore, examination of the in vivo impact of CAF pathophysiology in the tumor microenvironment in animal xenograft models revealed that HNSCC cell lines in combination with CAFs promoted tumor growth and increased incidence of lymphovascular metastasis as compared to injection of tumor cells or CAF cells alone. Using pharmacological and genetic alterations, we mechanistically demonstrate the critical importance of BDNF-TrkB signaling in the tumor microenvironment. These investigations further support the rationale for BDNF/TRKB targeted therapy against in the treatment of HNSCC.
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Affiliation(s)
- Tilahun Jiffar
- Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston TX 77030, USA
| | - Turker Yilmaz
- Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston TX 77030, USA
| | - Junegoo Lee
- Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston TX 77030, USA
| | - Yair Miller
- Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston TX 77030, USA
| | - Lei Feng
- Department of Biostatistics, MD Anderson Cancer Center, Houston TX 77030, USA
| | - Adel El-Naggar
- Department of Pathology, MD Anderson Cancer Center, Houston TX 77030, USA
| | - Michael E Kupferman
- Department of Head and Neck Surgery, MD Anderson Cancer Center, Houston TX 77030, USA
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21
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Koustas E, Karamouzis MV, Mihailidou C, Schizas D, Papavassiliou AG. Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer. Cancer Lett 2017; 396:94-102. [PMID: 28323034 DOI: 10.1016/j.canlet.2017.03.023] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 03/10/2017] [Accepted: 03/13/2017] [Indexed: 02/07/2023]
Abstract
The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways. Recent data also suggest that acquired-resistance to anti-EGFR MoAbs is accompanied by inhibition of EGFR internalization, ubiqutinization, degradation and prolonged downregulation. It is well established that autophagy, a self-cannibalization process, is considered to be associated with resistance to the anti-EGFR MoAbs therapy. Additionally, autophagy induced by anti-EGFR MoAbs acts as a protective response in cancer cells. Thus, inhibition of autophagy after treatment with EGFR MoAbs can result in autophagic cell death. A combination therapy comprising of anti-EGFR MoAbs and autophagy inhibitors would represent a multi-pronged approach that could be evolved into an active therapeutic strategy in mCRC patients.
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Affiliation(s)
- Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Chrysovalantou Mihailidou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Schizas
- First Department of Surgery, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios G Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
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22
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Shagufta, Ahmad I. An insight into the therapeutic potential of quinazoline derivatives as anticancer agents. MEDCHEMCOMM 2017; 8:871-885. [PMID: 30108803 PMCID: PMC6072504 DOI: 10.1039/c7md00097a] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 04/05/2017] [Indexed: 12/20/2022]
Abstract
Cancer is one of the major causes of worldwide human mortality. A wide range of cytotoxic drugs are available on the market, and several compounds are in different phases of clinical trials. Many studies suggest that these cytotoxic molecules are also associated with different types of adverse side effects; therefore researchers around the globe are involved in the development of more efficient and safer anticancer drugs. In recent years, quinazoline and its derivatives have been considered as a novel class of cancer chemotherapeutic agents that show promising activity against different tumors. The aim of this article is to comprehensively review and highlight the recent developments concerning the anticancer activity of quinazoline derivatives as well as offer perspectives on the development of novel quinazoline derivatives as anticancer agents in the near future.
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Affiliation(s)
- Shagufta
- Department of Mathematics and Natural Sciences , School of Arts and Sciences , American University of Ras Al Khaimah , Ras Al Khaimah , United Arab Emirates . ;
| | - Irshad Ahmad
- Department of Mathematics and Natural Sciences , School of Arts and Sciences , American University of Ras Al Khaimah , Ras Al Khaimah , United Arab Emirates . ;
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23
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HER-3 targeting alters the dimerization pattern of ErbB protein family members in breast carcinomas. Oncotarget 2016; 7:5576-97. [PMID: 26716646 PMCID: PMC4868707 DOI: 10.18632/oncotarget.6762] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 12/22/2015] [Indexed: 01/06/2023] Open
Abstract
Breast carcinogenesis is a multi-step process in which membrane receptor tyrosine kinases are crucial participants. Lots of research has been done on epidermal growth factor receptor (EGFR) and HER-2 with important clinical results. However, breast cancer patients present intrinsic or acquired resistance to available HER-2-directed therapies, mainly due to HER-3. Using new techniques, such as proximity ligation assay, herein we evaluate the dimerization pattern of HER-3 and the importance of context-dependent dimer formation between HER-3 and other HER protein family members. Additionally, we show that the efficacy of novel HER-3 targeting agents can be better predicted in certain breast cancer patient sub-groups based on the dimerization pattern of HER protein family members. Moreover, this model was also evaluated and reproduced in human paraffin-embedded breast cancer tissues.
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24
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RANKL Signaling and ErbB Receptors in Breast Carcinogenesis. Trends Mol Med 2016; 22:839-850. [DOI: 10.1016/j.molmed.2016.07.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 07/26/2016] [Accepted: 07/29/2016] [Indexed: 02/07/2023]
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25
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Ismail RS, Ismail NS, Abuserii S, Abou El Ella DA. Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents. FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES 2016. [DOI: 10.1016/j.fjps.2016.02.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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26
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Engström W, Darbre P, Eriksson S, Gulliver L, Hultman T, Karamouzis MV, Klaunig JE, Mehta R, Moorwood K, Sanderson T, Sone H, Vadgama P, Wagemaker G, Ward A, Singh N, Al-Mulla F, Al-Temaimi R, Amedei A, Colacci AM, Vaccari M, Mondello C, Scovassi AI, Raju J, Hamid RA, Memeo L, Forte S, Roy R, Woodrick J, Salem HK, Ryan EP, Brown DG, Bisson WH. The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. Carcinogenesis 2015; 36 Suppl 1:S38-60. [PMID: 26106143 DOI: 10.1093/carcin/bgv030] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
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Affiliation(s)
- Wilhelm Engström
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden,
| | - Philippa Darbre
- School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6UB, UK
| | - Staffan Eriksson
- Department of Biochemistry, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, Box 575, 75123 Uppsala, Sweden
| | - Linda Gulliver
- Faculty of Medicine, University of Otago, PO Box 913, Dunedin 9050, New Zealand
| | - Tove Hultman
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden, School of Biological Sciences, University of Reading, Whiteknights, Reading RG6 6UB, UK
| | - Michalis V Karamouzis
- Department of Biological Chemistry Medical School, Institute of Molecular Medicine and Biomedical Research, University of Athens, Marasli 3, Kolonaki, Athens 10676, Greece
| | - James E Klaunig
- Department of Environmental Health, School of Public Health, Indiana University Bloomington , 1025 E. 7th Street, Suite 111, Bloomington, IN 47405, USA
| | - Rekha Mehta
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, 251 Sir F.G. Banting Driveway, AL # 2202C, Tunney's Pasture, Ottawa, Ontario K1A 0K9, Canada
| | - Kim Moorwood
- Department of Biochemistry and Biology, University of Bath , Claverton Down, Bath BA2 7AY, UK
| | - Thomas Sanderson
- INRS-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, Quebec H7V 1B7, Canada
| | - Hideko Sone
- Environmental Exposure Research Section, Center for Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan
| | - Pankaj Vadgama
- IRC in Biomedical Materials, School of Engineering & Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, UK
| | - Gerard Wagemaker
- Center for Stem Cell Research and Development, Hacettepe University, Ankara 06100, Turkey
| | - Andrew Ward
- Department of Biochemistry and Biology, University of Bath , Claverton Down, Bath BA2 7AY, UK
| | - Neetu Singh
- Centre for Advanced Research, King George's Medical University, Chowk, Lucknow, Uttar Pradesh 226003, India
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze 50134, Italy
| | - Anna Maria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - A Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Jayadev Raju
- Regulatoty Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, HPFB, Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Roslida A Hamid
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Lorenzo Memeo
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Stefano Forte
- Mediterranean Institute of Oncology, Viagrande 95029, Italy
| | - Rabindra Roy
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Jordan Woodrick
- Molecular Oncology Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Hosni K Salem
- Urology Dept. kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Elizabeth P Ryan
- Department of Environmental and Radiological Sciences, Colorado State University//Colorado School of Public Health, Fort Collins CO 80523-1680, USA and
| | - Dustin G Brown
- Department of Environmental and Radiological Sciences, Colorado State University//Colorado School of Public Health, Fort Collins CO 80523-1680, USA and
| | - William H Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
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Collart-Dutilleul PY, Chaubron F, Vos JD, Cuisinier FJ. Allogenic banking of dental pulp stem cells for innovative therapeutics. World J Stem Cells 2015; 7:1010-1021. [PMID: 26328017 PMCID: PMC4550625 DOI: 10.4252/wjsc.v7.i7.1010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 04/10/2015] [Accepted: 06/19/2015] [Indexed: 02/06/2023] Open
Abstract
Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat.
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Ernani V, Saba NF. Oral Cavity Cancer: Risk Factors, Pathology, and Management. Oncology 2015; 89:187-95. [PMID: 26088938 DOI: 10.1159/000398801] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 04/07/2015] [Indexed: 11/19/2022]
Abstract
Oral cavity cancers are predominantly squamous cell carcinomas, which arise from premalignant lesions through a multistep carcinogenesis process. Tobacco and alcohol are the major etiologic factors, although human papillomavirus has also recently been implicated as a causative agent. The possibility of a second primary malignancy should be considered during the diagnostic evaluation of head and neck cancers, as well as during the posttreatment surveillance phase. The goals of treatment are not only to improve survival outcomes but also to preserve organ function. These cancers are generally treated with a combination of surgery, radiation therapy, and chemotherapy. A multidisciplinary approach, involving surgeons, medical oncologists, and radiation oncologists, as well as dentists, dietitians, and rehabilitation therapists, is generally required for optimal treatment planning and management of patients with head and neck cancer.
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Affiliation(s)
- Vinicius Ernani
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Ga., USA
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Chibaudel B, Lacave R, Lefevre M, Soussan P, Antoine M, Périé S, Belloc JB, Banal A, Albert S, Chabolle F, Céruse P, Baril P, Gatineau M, Housset M, Moukoko R, Benetkiewicz M, de Gramont A, Bonnetain F, Lacau St Guily J. Induction therapy with cetuximab plus docetaxel, cisplatin, and 5-fluorouracil (ETPF) in patients with resectable nonmetastatic stage III or IV squamous cell carcinoma of the oropharynx. A GERCOR phase II ECHO-07 study. Cancer Med 2015; 4:721-31. [PMID: 25684313 PMCID: PMC4430265 DOI: 10.1002/cam4.408] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/19/2014] [Accepted: 12/10/2014] [Indexed: 01/22/2023] Open
Abstract
Induction TPF regimen is a standard treatment option for squamous cell carcinoma (SCC) of the oropharynx. The efficacy and safety of adding cetuximab to induction TPF (ETPF) therapy was evaluated. Patients with nonmetastatic resectable stage III/IV SCC of the oropharynx were treated with weekly cetuximab followed the same day by docetaxel and cisplatin and by a continuous infusion of 5-fluorouracil on days 1-5 (every 3 weeks, 3 cycles). The primary endpoint was clinical and radiological complete response (crCR) of primary tumor at 3 onths. Secondary endpoints were crCR rates, overall response, pathological CR, progression-free survival, overall survival, and safety. Forty-two patients were enrolled, and 41 received ETPF. The all nine planned cetuximab doses and the full three doses of planned chemotherapy were completed in 31 (76%) and 36 (88%) patients, respectively. Twelve (29%) patients required dose reduction. The crCR of primary tumor at the completion of therapy was observed in nine (22%) patients. ETPF was associated with a tumor objective response rate (ORR) of 58%. The most frequent grade 3-4 toxicities were as follows: nonfebrile neutropenia (39%), febrile neutropenia (19%), diarrhea (10%), and stomatitis (12%). Eighteen (44%) patients experienced acne-like skin reactions of any grade. One toxic death occurred secondary to chemotherapy-induced colitis with colonic perforation. This phase II study reports an interesting response rate for ETPF in patients with moderately advanced SCC of the oropharynx. The schedule of ETPF evaluated in this study cannot be recommended at this dosage.
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Affiliation(s)
- Benoist Chibaudel
- Division of Medical Oncology, Franco-British Hospital InstituteLevallois-Perret, France
- GERCOR (Cooperator Multidisciplinary Oncology Group)Paris, France
- GERCOR-IRC (GERCOR-Innovative Research Consortium)Paris, France
| | - Roger Lacave
- Department of Histology and Tumor Biology, Hospital TenonParis, France
- ER2 Division, University Pierre et Marie CurieParis, France
- Clinical Research Group (GRC), Hospital TenonParis, France
| | - Marine Lefevre
- Division of Anatomic Pathology, Hospital TenonParis, France
| | | | | | - Sophie Périé
- Department of Otorhinolaryngology-Cervicofacial Surgery, Hospital TenonParis, France
| | - Jean-Baptiste Belloc
- Department of Otorhinolaryngology-Maxillofacial Surgery, Hospital Simone VeilMontmorency, France
| | - Alain Banal
- Department of Otorhinolaryngology-Head and Neck Surgery, Centre René HugueninSaint-Cloud, France
| | - Sébastien Albert
- Department of Otorhinolaryngology-Head and Neck Surgery, Hospital Bichat-Claude BernardParis, France
| | - Frédéric Chabolle
- Department of Otolaryngology and Cervicofacial Surgery, Hospital FochSuresnes, France
| | - Philippe Céruse
- Department of Otorhinolaryngology-Cervicofacial Surgery, Hospital center Lyon-SudLyon, France
| | - Philippe Baril
- Department of Otorhinolaryngology-Head and Neck Surgery, Hospital DelafontaineSaint-Denis, France
| | - Michel Gatineau
- Medical Oncology Service, Groupe Hospitalier Saint JosephParis, France
| | - Martin Housset
- Department of Radiation Oncology, Georges Pompidou European HospitalParis, France
| | - Rachel Moukoko
- GERCOR (Cooperator Multidisciplinary Oncology Group)Paris, France
| | | | - Aimery de Gramont
- Division of Medical Oncology, Franco-British Hospital InstituteLevallois-Perret, France
- GERCOR (Cooperator Multidisciplinary Oncology Group)Paris, France
- GERCOR-IRC (GERCOR-Innovative Research Consortium)Paris, France
| | - Franck Bonnetain
- Methodological and Quality of Life in Oncology Unit (EA3181) & Quality of Life and Cancer Clinical Research Platform, Besançon University HospitalBesançon, France
| | - Jean Lacau St Guily
- ER2 Division, University Pierre et Marie CurieParis, France
- Clinical Research Group (GRC), Hospital TenonParis, France
- Department of Otorhinolaryngology-Cervicofacial Surgery, Hospital TenonParis, France
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Abstract
Cancers of the stomach and esophagus are among the most challenging cancers of the GI tract to treat, associated with poor median survivals for metastatic disease and significant, sometimes prolonged, deteriorations in patient performance status as the diseases progress. However, in the past decade, we have begun to better understand disease biology and carcinogenesis, leading to the identification of subtypes of these diseases. There is also an increasing awareness of the global heterogeneity of disease and its impact on drug development. Our improved understanding of the molecular underpinnings of gastric and esophageal cancers has been accompanied with the development of novel therapeutic strategies. Recent actively investigated targets in this disease include human epidermal growth factor receptor 2, angiogenesis, MET, and immune checkpoint inhibition, with approvals of two new targeted agents, trastuzumab and ramucirumab. Improvements in our ability to deliver cytotoxic therapy, which is better tolerated and allows patients an opportunity to benefit from second- and more advanced lines of therapy, have also been observed. In this review, the current state-of-the-art management of advanced and metastatic gastric and esophageal adenocarcinomas, specifically highlighting the development of targeted therapies in these diseases, is described.
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Affiliation(s)
- Manish A Shah
- From Weill Cornell Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY.
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Ku GY, Ilson DH. Emerging mAbs for the treatment of esophagogastric cancer. Expert Opin Emerg Drugs 2014; 20:63-74. [DOI: 10.1517/14728214.2015.983072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Wu X, Bhayani MK, Dodge CT, Nicoloso MS, Chen Y, Yan X, Adachi M, Thomas L, Galer CE, Jiffar T, Pickering CR, Kupferman ME, Myers JN, Calin GA, Lai SY. Coordinated targeting of the EGFR signaling axis by microRNA-27a*. Oncotarget 2014; 4:1388-98. [PMID: 23963114 PMCID: PMC3824521 DOI: 10.18632/oncotarget.1239] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) has been characterized as a critical factor in the development and progression of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC). However, monotherapy with EGFR-specific agents has not been as dramatic as preclinical studies have suggested. Since complex regulation of the EGFR signaling axis might confound current attempts to inhibit EGFR directly, we searched for microRNAs (miRNAs) that may target the EGFR signaling axis. We identified miR-27a (miR-27a-3p) and its complementary or star (*) strand, miR-27a* (miR-27a-5p), as novel miRNAs targeting EGFR, which were significantly downregulated in multiple HNSCC cell lines. Analysis of human specimens demonstrated that miR-27a* is significantly underexpressed in HNSCC as compared to normal mucosa. Increased expression of miR-27a* in HNSCC produced a profound cytotoxic effect not seen with miR-27a. Analysis for potential targets of miR-27a* led to the identification of AKT1 (protein kinase B) and mTOR (mammalian target of rapamycin) within the EGFR signaling axis. Treatment with miR-27a* led to coordinated downregulation of EGFR, AKT1 and mTOR. Overexpression of EGFR signaling pathway components decreased the overall effect of miR-27a* on HNSCC cell viability. Constitutive and inducible expression of miR-27a* in a murine orthotopic xenograft model of oral cavity cancer led to decreased tumor growth. Direct intratumoral injection of miR-27a* inhibited tumor growth in vivo. These findings identify miR-27a* as a functional star sequence that exhibits novel coordinated regulation of the EGFR pathway in solid tumors and potentially represents a novel therapeutic option.
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Affiliation(s)
- Xiaoli Wu
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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Cui R, Chu L, Liu ZQ, Xiao YY, Zhu XL, Chen YJ, Xu Q. Hematologic toxicity assessment in solid tumor patients treated with cetuximab: a pooled analysis of 18 randomized controlled trials. Int J Cancer 2014; 136:936-44. [PMID: 24975040 DOI: 10.1002/ijc.29045] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 06/07/2014] [Accepted: 06/11/2014] [Indexed: 12/21/2022]
Abstract
The role of cetuximab in treatment-related hematologic toxicity is not clear. We performed a meta-analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as abstracts presented at American Society of Clinical Oncology conferences and ClinicalTrials.gov were searched to identify relevant studies. Eligible studies included RCTs in which cetuximab in combination with chemotherapy or chemoradiotherapy was compared with chemotherapy or chemoradiotherapy alone. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed- or random-effects models. A total of 11,234 patients with a variety of advanced solid tumors from 18 RCTs were included in the meta-analysis. Compared with chemotherapy alone, the addition of cetuximab was associated with increased risks of ≥grade 3 leucopenia/neutropenia and anemia events in colorectal cancer, with RRs of 1.16 (95% CI 1.05-1.27, p=0.002; incidence, 21.0 vs. 18.0%) and 2.67 (95% CI 1.53-4.65, p=0.01; incidence, 4.0 vs. 2.0%), respectively. Cetuximab was also associated with an increased risk of leucopenia/neutropenia in nonsmall cell lung cancer (NSCLC) (RR: 1.15; 95% CI 1.08-1.22, p<0.01). Additionally, K-ras wild type in the case of colorectal cancer patients was more vulnerable to ≥grade 3 leucopenia or neutropenia events in cetuximab group (RR: 1.31; 95% CI 1.11-1.54, p=0.001). With present evidence, cetuximab in conjunction with chemotherapy or chemoradiotherapy, compared with chemotherapy or chemoradiotherapy alone, was associated with increased slight risk of ≥grade 3 HTEs, especially in colorectal cancer and NSCLC.
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Affiliation(s)
- Ran Cui
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, No. 301 Middle Yanchang Road, Zhabei District, Shanghai, 200072, China
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Zheng DJ, Yu GH, Gao JF, Gu JD. Concomitant EGFR inhibitors combined with radiation for treatment of non-small cell lung carcinoma. Asian Pac J Cancer Prev 2014; 14:4485-94. [PMID: 24083690 DOI: 10.7314/apjcp.2013.14.8.4485] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) is considered to be one of the key driver genes in non-small cell lung cancer (NSCLC). Several clinical trials have shown great promise of EGFR tyrosine kinase inhibitors (TKIs) in the first-line treatment of NSCLC. Many advances have been made in the understanding of EGFR signal transduction network and the interaction between EGFR and tumor microenvironment in mediating cancer survival and development. The concomitant targeted therapy and radiation is a new strategy in the treatment of NSCLC. A number of preclinical studies have demonstrated synergistic anti-tumor activity in the combination of EGFR inhibitors and radiotherapy in vitro and in vivo. In the present review, we discuss the rationale of the combination of EGFR inhibitors and radiotherapy in the treatment of NSCLC.
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Affiliation(s)
- De-Jie Zheng
- Department of Clinical Oncology, Weifang People's Hospital, Weifang, China E-mail :
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36
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Sarris EG, Harrington KJ, Saif MW, Syrigos KN. Multimodal treatment strategies for elderly patients with head and neck cancer. Cancer Treat Rev 2014; 40:465-75. [DOI: 10.1016/j.ctrv.2013.10.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2013] [Revised: 10/06/2013] [Accepted: 10/18/2013] [Indexed: 12/15/2022]
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Ku GY, Ilson DH. Emerging tyrosine kinase inhibitors for esophageal cancer. Expert Opin Emerg Drugs 2013; 18:219-30. [PMID: 23725567 DOI: 10.1517/14728214.2013.805203] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Because of the poor prognosis for patients with esophagogastric cancers (EGCs), increasing attention has focused on targeted agents. AREAS COVERED Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), and MET. We briefly discuss preclinical data and the rationale for targeting these pathways and summarize the results of clinical trials of tyrosine kinase inhibitors (TKIs) against these targets. EXPERT OPINION While anti-EGFR therapy has been extensively investigated, completed Phase III trials suggest that this is not a promising target. A Phase III trial of an anti-VEGF antibody failed to show improvement in the primary endpoint of overall survival but response rates and progression-free survival were improved; a Phase III trial of an anti-VEGF receptor 2 antibody in second-line therapy did show improved survival. As such, Phase II and III evaluations of anti-VEGF TKIs are ongoing. The only Food and Drug Administration-approved targeted therapy in EGC is trastuzumab, an anti-Her2 antibody, and the results of a Phase III evaluation of lapatinib, an anti-Her2 TKI, are awaited. Phase III evaluation of an mTOR inhibitor has been negative. Finally, MET inhibition appears to have significant clinical potential and early testing of MET TKIs is underway.
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Affiliation(s)
- Geoffrey Y Ku
- Memorial Sloan-Kettering Cancer Center, Department of Medicine, Gastrointestinal Oncology Service, 300 East 66th Street, New York, NY 10065, USA
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Cellular immunotherapy for carcinoma using genetically modified EGFR-specific T lymphocytes. Neoplasia 2013; 15:544-53. [PMID: 23633926 DOI: 10.1593/neo.13168] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2013] [Revised: 02/28/2013] [Accepted: 03/04/2013] [Indexed: 02/05/2023]
Abstract
Epidermal growth factor receptor (EGFR) is overexpressed in a variety of human malignancies, including pancreatic cancer, breast cancer, colon cancer, and non-small cell lung cancer. Overexpression of EGFR is a predictive marker of therapeutic response and several lines of evidence suggest that EGFR is an excellent target for tumor therapy. However, the effective antitumor capacity of EGFR-specific T cells against EGFR-overexpressing tumor cells has not been fully elucidated. In our previous study, we identified an anti-EGFR single-chain variable fragment (scFv) with specific and high affinity after screening by ribosome display. In this study, the anticancer potential of anti-EGFR scFv was investigated on the basis of cell-targeted therapy. A chimeric antigen receptor (CAR) targeting EGFR was constructed and expressed on the cell membrane of T lymphocytes. These CAR-modified T cells demonstrated antitumor efficacy both in vitro and in vivo. In addition, the safety evaluation showed that CAR-modified lymphocytes have no or very minimal acute systemic toxicity. Taken together, our study provided the experimental basis for clinical application of genetically engineered lymphocytes; moreover, we also evaluate a new and interesting cell therapy protocol.
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Karamouzis MV, Papavassiliou AG. Tackling the cancer signal transduction “Labyrinth”: A combinatorial use of biochemical tools with mathematical models will enhance the identification of optimal targets for each molecular defect. Cancer 2013; 120:316-22. [DOI: 10.1002/cncr.28424] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 09/16/2013] [Indexed: 12/19/2022]
Affiliation(s)
- Michalis V. Karamouzis
- Molecular Oncology Unit; Department of Biological Chemistry; University of Athens Medical School; Athens Greece
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit; Department of Biological Chemistry; University of Athens Medical School; Athens Greece
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Basu D, Bewley AF, Sperry SM, Montone KT, Gimotty PA, Rasanen K, Facompre ND, Weinstein GS, Nakagawa H, Diehl JA, Rustgi AK, Herlyn M. EGFR inhibition promotes an aggressive invasion pattern mediated by mesenchymal-like tumor cells within squamous cell carcinomas. Mol Cancer Ther 2013; 12:2176-86. [PMID: 23939378 PMCID: PMC3796003 DOI: 10.1158/1535-7163.mct-12-1210] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Squamous cell carcinomas (SCC) with an infiltrative invasion pattern carry a higher risk of treatment failure. Such infiltrative invasion may be mediated by a mesenchymal-like subpopulation of malignant cells that we have previously shown to arise from epithelial-mesenchymal transition (EMT) and resist epidermal growth factor receptor (EGFR) targeting. Here, we show that SCCs with infiltrative, high-risk invasion patterns contain abundant mesenchymal-like cells, which are rare in tumors with low-risk patterns. This cellular heterogeneity was modeled accurately in three-dimensional culture using collagen-embedded SCC spheroids, which revealed distinct invasive fronts created by collective migration of E-cadherin-positive cells versus infiltrative migration of individual mesenchymal-like cells. Because EGFR expression by mesenchymal-like cells was diminished in the spheroid model and in human SCCs, we hypothesized that SCCs shift toward infiltrative invasion mediated by this subpopulation during anti-EGFR therapy. Anti-EGFR treatment of spheroids using erlotinib or cetuximab enhanced infiltrative invasion by targeting collective migration by E-cadherin-positive cells while sparing mesenchymal-like cells; by contrast, spheroid invasion in absence of mesenchymal-like cells was abrogated by erlotinib. Similarly, cetuximab treatment of xenografts containing mesenchymal-like cells created an infiltrative invasive front composed of this subpopulation, whereas no such shift was observed upon treating xenografts lacking these cells. These results implicate mesenchymal-like SCC cells as key mediators of the infiltrative invasion seen in tumors with locally aggressive behavior. They further show that EGFR inhibition can promote an infiltrative invasion front composed of mesenchymal-like cells preferentially in tumors where they are abundant before therapy.
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Affiliation(s)
- Devraj Basu
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA
- The Wistar Institute, Philadelphia, PA
- VA Medical Center, Philadelphia, PA
| | - Arnaud F. Bewley
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA
| | - Steven M. Sperry
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA
| | - Kathleen T. Montone
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
| | - Phyllis A. Gimotty
- Department of Epidemiology and Biostatistics, Center for Clinical Epidemiology and Biostatistics, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | | | - Nicole D. Facompre
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA
- The Wistar Institute, Philadelphia, PA
| | - Gregory S. Weinstein
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA
| | - Hiroshi Nakagawa
- Department of Medicine and Genetics, Division of Gastroenterology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - J. Alan Diehl
- Department of Cancer Biology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - Anil K. Rustgi
- Department of Medicine and Genetics, Division of Gastroenterology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
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Wang YP, Liu IJ, Chiang CP, Wu HC. Astrocyte elevated gene-1 is associated with metastasis in head and neck squamous cell carcinoma through p65 phosphorylation and upregulation of MMP1. Mol Cancer 2013; 12:109. [PMID: 24063540 PMCID: PMC3856534 DOI: 10.1186/1476-4598-12-109] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 09/17/2013] [Indexed: 12/21/2022] Open
Abstract
Background The survival rate of head and neck squamous cell carcinoma (HNSCC) at advanced stage is poor, despite contemporary advances in treatment modalities. Recent studies have indicated that astrocyte elevated gene-1 (AEG-1), a single transmembrane protein without any known functional domains, is overexpressed in various malignancies and is implicated in both distant metastasis and poor survival. Results High expression of AEG-1 in HNSCC was positively correlated with regional lymph node metastasis and a poor 5-year survival rate. Knockdown of AEG-1 in HNSCC cell lines reduced their capacity for colony formation, migration and invasion. Furthermore, decreased tumor volume and metastatic foci were observed after knockdown of AEG-1 in subcutaneous xenografts and pulmonary metastasis assays in vivo, respectively. We also demonstrated that AEG-1 increased phosphorylation of the p65 subunit of NF-κB, and regulated the expression of MMP1 in HNSCC cells. Moreover, compromised phosphorylation of the p65 (RelA) subunit of NF-κB at serine 536 was observed upon silencing of AEG-1 in both HNSCC cell lines and clinical specimens. Conclusion High expression of AEG-1 is associated with lymph node metastasis and its potentially associated mechanism is investigated.
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Affiliation(s)
- Yi-Ping Wang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
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Hong L, Han Y, Brain L. Epidermal growth factor receptor: an important target in esophageal cancer. Expert Opin Ther Targets 2013; 17:1179-85. [PMID: 23855932 DOI: 10.1517/14728222.2013.820709] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Even after complete tumor removal by surgery, the clinical outcomes remain poor in patients with advanced esophageal cancer, justifying the need for new treatment options. Epidermal growth factor receptor (EGFR) is a molecular target for antibody-based therapy in various cancer types, and it may play important roles in the development of esophageal cancer. AREAS COVERED This review evaluates the expression, function, and mechanism of EGFR in esophageal cancer and analyzes its value for the prognosis and therapy of esophageal cancer. Future developments toward the clinical applications of EGFR to cancer treatment are also envisaged. EXPERT OPINION EGFR may function as an ideal therapeutic target for esophageal cancer. Further investigation of epidermal growth-factor-receptor-mediated pathways will push insight into the novel strategies of target therapy for esophageal cancer. More clinical trials should be performed to promote the success of therapeutic-clinical use of EGFR and its targets in esophageal cancer.
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Affiliation(s)
- Liu Hong
- Fourth Military Medical University, Xijing Hospital, Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology , Xi'an, 710032, Shaanxi Province , China +86 29 84773974 ; +86 29 82539041 ;
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Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck. Strahlenther Onkol 2013; 189:625-31. [DOI: 10.1007/s00066-013-0378-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2013] [Accepted: 05/06/2013] [Indexed: 10/26/2022]
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Olivatto LO, Vieira FM, Pereira BV, Victorino AP, Bezerra M, Araujo CM, Erlich F, Faroni L, Castro L, Lusis EC, Marins A, Ferreira CG. Phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma. Cancer 2013; 119:2973-80. [PMID: 23674135 DOI: 10.1002/cncr.28045] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Revised: 02/15/2013] [Accepted: 02/19/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS Cetuximab was administered on days 1, 8, 15, 29, 36, 43, and 50 (400 mg/m(2) initial dose, then 250 mg/m(2) /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP = 800/60 mg/m(2) /day and up to dose level (+2) 5-FU/CP = 1000/80 mg/m(2) /day. RESULTS Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (+2). The RP2D was 5-FU/CP = 800/80 mg/m(2) /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in ≥ 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued.
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Affiliation(s)
- Luis O Olivatto
- Division of Clinical Oncology, Hospital do Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
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45
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Pallis A, Syrigos K. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC. Lung Cancer 2013; 80:120-30. [DOI: 10.1016/j.lungcan.2012.12.025] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 12/08/2012] [Accepted: 12/16/2012] [Indexed: 01/16/2023]
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46
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Expression and purification of chimeric peptide comprising EGFR B-cell epitope and measles virus fusion protein T-cell epitope in Escherichia coli. Protein Expr Purif 2013; 88:7-12. [DOI: 10.1016/j.pep.2012.11.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 11/02/2012] [Accepted: 11/16/2012] [Indexed: 01/31/2023]
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Vashist YK, Trump F, Gebauer F, Kutup A, Güngör C, Kalinin V, Muddasar R, Vettorazzi E, Yekebas EF, Brandt B, Pantel K, Izbicki JR. EGFR intron-1 CA repeat polymorphism is a predictor of relapse and survival in complete resected only surgically treated esophageal cancer. Target Oncol 2013; 9:43-52. [PMID: 23377570 DOI: 10.1007/s11523-013-0260-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 01/14/2013] [Indexed: 12/31/2022]
Abstract
Basal transcription regulation of the epidermal growth factor receptor is dependent upon a CA simple sequence repeat polymorphism in the intron-1 (CA-SSR-1). Here, we evaluate the role of CA-SSR-1 in complete resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Genomic DNA was extracted from peripheral blood leukocytes of 241 patients. To determine the number of the CA repeats in the CA-SSR-1, DNA was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters and clinical outcome. Three genotypes were defined based on cut-off points for short allele (S) with ≤18 and long allele (L) >18 CA repeats. A steadily increasing risk was evident between LL, SL, and SS genotype for larger tumor size, presence of lymph node metastases, and disseminated tumor cells in bone marrow as well as tumor recurrence (P < 0.001, chi-square test). A gradual decrease in disease-free and overall survival (OS) was present among LL, SL, and SS patients (P < 0.001, log-rank test). The different outcomes were also evident in nodal status and histological type adjusted subgroup analyses. CA-SSR-1 was identified as the strongest independent prognosticator of tumor recurrence and OS (P < 0.001, Cox regression analysis). CA-SSR-1 is a strong predictive factor for tumor recurrence and overall survival in patients with complete resected esophageal cancer without neoadjuvant or adjuvant therapy.
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Affiliation(s)
- Yogesh K Vashist
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martini Strasse 52, 20246, Hamburg, Germany,
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Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, Gyanchandani R, Blumenschein GR, Chen HX, Grandis JR, Harari PM, Kies MS, Kim S. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 2012; 24:220-5. [PMID: 22898037 DOI: 10.1093/annonc/mds245] [Citation(s) in RCA: 111] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND We evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS The combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed. RESULTS Cetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3-4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy. CONCLUSIONS Cetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.
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Affiliation(s)
- A Argiris
- Department of Medicine, Division of Hematology/Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
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Perisanidis C, Savarese-Brenner B, Würger T, Wrba F, Huynh A, Schopper C, Kornek G, Selzer E, Ewers R, Psyrri A, Krainer M, Filipits M. HCRP1 expression status is a significant prognostic marker in oral and oropharyngeal cancer. Oral Dis 2012; 19:206-11. [PMID: 22891969 DOI: 10.1111/j.1601-0825.2012.01972.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 06/18/2012] [Accepted: 07/03/2012] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The hepatocellular carcinoma-related protein 1 (HCRP1) is a key factor in the degradation of the epidermal growth factor receptor. In this study, we assessed the prognostic significance of HCRP1 expression in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS HCRP1 expression was determined by immunohistochemistry on tissue biopsy sections of 111 patients with locally advanced OOSCC undergoing neoadjuvant chemoradiotherapy followed by surgery. The Kaplan-Meier method and Cox regression models were used for survival analyses. RESULTS Low HCRP1 expression was associated with poor recurrence-free survival (P = 0.046) and overall survival (P = 0.03). Multivariate analysis revealed that low HCRP1 expression remained an independent risk factor for relapse (HR 2.98, 95% CI 1.19-7.49, P = 0.02) and death (HR 3.04, 95% CI 1.19-7.79, P = 0.02). CONCLUSION Low HCRP1 expression was found to be of adverse prognostic significance in patients with OOSCC who received preoperative chemoradiotherapy.
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Affiliation(s)
- C Perisanidis
- Departments of Cranio-, Maxillofacial and Oral Surgery, Medical University of Vienna, Vienna, Austria
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Zhou X, Qiu J, Wang Z, Huang N, Li X, Li Q, Zhang Y, Zhao C, Luo C, Zhang N, Teng X, Chen Z, Liu X, Yu X, Wu W, Wei YQ, Li J. In vitro and in vivo anti-tumor activities of anti-EGFR single-chain variable fragment fused with recombinant gelonin toxin. J Cancer Res Clin Oncol 2012; 138:1081-90. [PMID: 22392077 DOI: 10.1007/s00432-012-1181-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 02/15/2012] [Indexed: 02/05/2023]
Abstract
PURPOSE Epidermal growth factor receptor (EGFR) plays an important role in the growth and metastasis of many solid tumors. Strategies that target EGFR hold promising therapeutic potential for the treatment for non-small cell lung cancer (NSCLC), as EGFR is normally overexpressed in these tumors. This study was designed to determine whether an anti-EGFR immunotoxin has anti-tumor activity against NSCLC, and if so, to further investigate the possible mechanisms of cytotoxicity. METHODS A fusion protein of anti-EGFR single-chain variable fragment (anti-EGFR scFv) and the plant toxin gelonin (rGel) was constructed, expressed in bacteria, and purified to homogeneity. Cytotoxicity of anti-EGFR scFv/rGel (E/rG) immunotoxin was assessed on A549, HCC827, and H1975 cells (EGFR-overexpressing NSCLC-derived cell lines) and A549 xenografts in nude mice. RESULTS Cytotoxicity experiments using E/rG on A549, HCC827, and H1975 cells demonstrated that E/rG can specifically inhibit proliferation of these cells, whereas it did not affect the proliferation of Raji cells that do not express EGFR. Treatment for A549 xenografts in nude mice with E/rG resulted in significant suppression of tumor growth compared to controls. Immunofluorescence in frozen tissue sections confirmed that E/rG could specifically bind to tumor tissues in nude mice bearing A549 tumor xenografts, while rGel alone showed no binding activity. Furthermore, E/rG inhibited the growth of A549 cells by cytotoxic effects that blocked tumor proliferation, and the immunotoxin-induced cell death may be mediated by autophagy. CONCLUSIONS These results showed that E/rG might have significant potential as a novel clinical therapeutic agent against human NSCLC.
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Affiliation(s)
- Xikun Zhou
- State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 1 Keyuan Road 4th, Chengdu, Sichuan 610041, People's Republic of China
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