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1
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Shen X, Wang X, Lu X, Zhao Y, Guan W. Molecular biology of pancreatic neuroendocrine tumors: From mechanism to translation. Front Oncol 2022; 12:967071. [PMID: 36248960 PMCID: PMC9554633 DOI: 10.3389/fonc.2022.967071] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are a group of heterogeneous tumors originated from progenitor cells. As these tumors are predominantly non-functional, most of them display asymptomatic characteristics, making it difficult to be realized from early onset. Therefore, patients with pNETs are usually diagnosed with metastatic disease or at a late disease stage. The relatively low incidence also limits our understanding of the biological background of pNETs, which largely impair the development of new effective drugs. The fact that up to 10% of pNETs develop in patients with genetic syndromes have promoted researchers to focus on the gene mutations and driver mutations in MEN1, DAXX/ATRX and mTOR signaling pathway genes have been implicated in disease development and progression. Recent advances in sequencing technologies have further enriched our knowledge of the complex molecular landscape of pNETs, pointing out crucial roles of genes in DNA damage pathways, chromosomal and telomere alterations and epigenetic dysregulation. These novel findings may not only benefit early diagnosis of pNETs, but also help to uncover tumor heterogeneity and shape the future of translational medical treatment. In this review, we focus on the current molecular biology of pNETs and decipher how these findings may translate into future development of targeted therapy.
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Affiliation(s)
- Xiaofei Shen
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Xingzhou Wang
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Xiaofeng Lu
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Yang Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- *Correspondence: Wenxian Guan, ; Yang Zhao,
| | - Wenxian Guan
- Department of General Surgery, Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- *Correspondence: Wenxian Guan, ; Yang Zhao,
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2
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Pozas J, Alonso-Gordoa T, Román MS, Santoni M, Thirlwell C, Grande E, Molina-Cerrillo J. Novel therapeutic approaches in GEP-NETs based on genetic and epigenetic alterations. Biochim Biophys Acta Rev Cancer 2022; 1877:188804. [PMID: 36152904 DOI: 10.1016/j.bbcan.2022.188804] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/17/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous malignancies with distinct prognosis based on primary tumor localization, grade, stage and functionality. Surgery remains the only curative option in localized tumors, but systemic therapy is the mainstay of treatment for patients with advanced disease. For decades, the therapeutic landscape of GEP-NETs was limited to chemotherapy regimens with low response rates. The arrival of novel agents such as somatostatin analogues, peptide receptor radionuclide therapy, tyrosine kinase inhibitors or mTOR-targeted drugs, has changed the therapeutic paradigm of GEP-NETs. However, the efficacy of these agents is limited in time and there is scarce knowledge of optimal treatment sequencing. In recent years, massive parallel sequencing techniques have started to unravel the genomic intricacies of these tumors, allowing us to better understand the mechanisms of resistance to current treatments and to develop new targeted agents that will hopefully start an era for personalized treatment in NETs. In this review we aim to summarize the most relevant genomic aberrations and signaling pathways underlying GEP-NET tumorigenesis and potential therapeutic strategies derived from them.
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Affiliation(s)
- Javier Pozas
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain
| | - Maria San Román
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain
| | | | | | - Enrique Grande
- Medical Oncology Ddepartment. MD Anderson Cancer Center Madrid, 28033 Madrid, Spain
| | - Javier Molina-Cerrillo
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Medicine School, Alcalá University, Madrid, Spain.
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3
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Alhussein MM, Mokbel A, Cosman T, Aghel N, Yang EH, Mukherjee SD, Dent S, Ellis PM, Dhesy-Thind S, Leong DP. Pertuzumab Cardiotoxicity in Patients With HER2-Positive Cancer: A Systematic Review and Meta-analysis. CJC Open 2021; 3:1372-1382. [PMID: 34901806 PMCID: PMC8640623 DOI: 10.1016/j.cjco.2021.06.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/18/2021] [Indexed: 01/06/2023] Open
Abstract
Background Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The cardiotoxicity of trastuzumab, a HER2-targeting monoclonal antibody, is well established. However, the cardiotoxic effect of pertuzumab, another HER2-directed therapy, is less well documented. The objective of this systematic review and meta-analysis was to determine the risk of cardiac events in patients with HER2-positive cancer who are receiving pertuzumab. Methods We performed a systematic review of phase 2 and 3 randomized controlled trials in which the addition of pertuzumab to other standard therapies in patients with stage I-IV HER2-positive cancer was evaluated, and cardiac adverse effects reported. We searched MEDLINE (1946-2020), Embase (1974-2020), and CENTRAL. Two independent reviewers assessed the risk of bias and extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and random-effects models. Results Eight randomized controlled trials (8420 patients) were included: 1 was gastro-esophageal; 7 were breast cancer trials. Participants’ median age ranged from 49 to 61.5 years. All participants received trastuzumab and chemotherapy in addition to pertuzumab or placebo. Compared with placebo, pertuzumab increased the risk of clinical heart failure (HF; RR [95% CI]: 1.97 [1.05-3.70]; I2 = 0%). However, pertuzumab had no demonstrable effect on asymptomatic/minimally symptomatic left ventricular systolic dysfunction (RR [95% CI]: 1.19 [0.89-1.61]; I2 = 19%). Conclusions Pertuzumab increases the risk of clinical HF, but not asymptomatic/minimally symptomatic left ventricular systolic dysfunction, in HER2-positive cancer patients. Further research into the mechanisms underlying pertuzumab-related HF is needed to understand its clinical spectrum of cardiotoxicity.
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Affiliation(s)
- Muhammad Mustafa Alhussein
- Department of Medicine, Division of Cardiology, Cardio-Oncology Program, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Abir Mokbel
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Department of Rheumatology, Cairo University, Cairo, Egypt
| | - Tammy Cosman
- Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Nazanin Aghel
- Department of Medicine, Division of Cardiology, Cardio-Oncology Program, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Eric H Yang
- UCLA Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California, Los Angeles, USA
| | - Som D Mukherjee
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Susan Dent
- Department of Medicine, Duke Cancer Institute, Duke University, Durham, North Carolina, USA
| | - Peter M Ellis
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Sukhbinder Dhesy-Thind
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, Ontario, Canada
| | - Darryl P Leong
- Department of Medicine, Division of Cardiology, Cardio-Oncology Program, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,The Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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4
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Simbolo M, Bersani S, Vicentini C, Taormina SV, Ciaparrone C, Bagante F, Rusev B, Centonze G, Montresor M, Brunelli M, Pedron S, Mafficini A, Paolino G, Mattiolo P, Conci S, Milione M, Guglielmi A, Ruzzenente A, Scarpa A, Luchini C. Molecular characterization of extrahepatic cholangiocarcinoma: perihilar and distal tumors display divergent genomic and transcriptomic profiles. Expert Opin Ther Targets 2021; 25:1095-1105. [PMID: 34873971 DOI: 10.1080/14728222.2021.2013801] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 11/30/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Extrahepatic cholangiocarcinoma (ECC) is classified into two subtypes based on anatomic origin: distal extrahepatic (DECC) and perihilar (PHCC) cholangiocarcinoma. This study aimed to shed light on its genomic and transcriptomic profiles. RESEARCH DESIGN AND METHODS The genomic alterations of 99 ECC (47 PHCC and 52 DECC) were investigated by next-generation sequencing of 96 genes. A subgroup of cases, representative of each subtype, was further investigated using transcriptomic analysis. Bioinformatics tools were applied for clustering and pathway analysis and defining the immune composition of the tumor microenvironment. RESULTS PHCC had more frequent KRAS mutations (p = 0.0047), whereas TP53 mutations were more common in DECC (p = 0.006). Potentially actionable alterations included high-tumor mutational burden and/or microsatellite instability (7.1%), PI3KCA mutations (8.1%), and MYC (10.1%) and ERBB2 amplification (5.1%). The transcriptomic profiles showed the presence of three distinct clusters, which followed the anatomic origin and differed in immune microenvironment. DECC appeared to contain two distinct tumor subgroups, one enriched for druggable alterations and one lacking actionable opportunities. CONCLUSIONS This study provides new insights into the molecular landscape and the actionable alterations of ECC. Our findings represent a step toward improved ECC molecular taxonomy and therapeutic strategies for precision oncology.
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Affiliation(s)
- Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Samantha Bersani
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Caterina Vicentini
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Sergio V Taormina
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Chiara Ciaparrone
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Fabio Bagante
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Borislav Rusev
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Giovanni Centonze
- Pathology Unit, Foundation IRCCS, Istituto Nazionale Tumori, Milano, Italy
| | - Marina Montresor
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Serena Pedron
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Mafficini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Simone Conci
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Massimo Milione
- Pathology Unit, Foundation IRCCS, Istituto Nazionale Tumori, Milano, Italy
| | - Alfredo Guglielmi
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Unit of General and Hepatobiliary Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy
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5
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Konukiewitz B, Jesinghaus M, Kasajima A, Klöppel G. Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls. Virchows Arch 2021; 480:247-257. [PMID: 34647171 PMCID: PMC8986719 DOI: 10.1007/s00428-021-03211-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/06/2021] [Accepted: 09/21/2021] [Indexed: 12/29/2022]
Abstract
Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.
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Affiliation(s)
- Björn Konukiewitz
- Institute of Pathology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität zu Kiel, Arnold-Heller-Straße 3/14, 24105, Kiel, Germany.
| | - Moritz Jesinghaus
- Institute of Pathology, Universitätsklinikum Marburg, Baldingerstraße, 35043, Marburg, Germany
| | - Atsuko Kasajima
- Institute of Pathology, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
| | - Günter Klöppel
- Institute of Pathology, Technische Universität München, Trogerstraße 18, 81675, Munich, Germany
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6
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Zhang MY, He D, Zhang S. Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment. World J Gastrointest Oncol 2020; 12:705-718. [PMID: 32864039 PMCID: PMC7428799 DOI: 10.4251/wjgo.v12.i7.705] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/17/2020] [Accepted: 06/17/2020] [Indexed: 02/05/2023] Open
Abstract
In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.
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Affiliation(s)
- Ming-Yi Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Du He
- Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shuang Zhang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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7
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Chatani PD, Agarwal SK, Sadowski SM. Molecular Signatures and Their Clinical Utility in Pancreatic Neuroendocrine Tumors. Front Endocrinol (Lausanne) 2020; 11:575620. [PMID: 33537001 PMCID: PMC7848028 DOI: 10.3389/fendo.2020.575620] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 11/30/2020] [Indexed: 12/23/2022] Open
Abstract
Pancreatic neuroendocrine tumors (PNETs) are classified based on their histologic differentiation and proliferative indices, which have been used extensively to determine prognosis. Advances in next-generation sequencing and other high-throughput techniques have allowed researchers to objectively explore tumor specimens and learn about the genetic alterations associated with malignant transformation in PNETs. As a result, targeted, pathway-specific therapies have been emerging for the treatment of unresectable and metastatic disease. As we continue to trial various pharmaceutical products, evidence from studies using multi-omics approaches indicates that clinical aggressiveness stratifies along other genotypic and phenotypic demarcations, as well. In this review, we explore the clinically relevant and potentially targetable molecular signatures of PNETs, their associated trials, and the overall differences in reported prognoses and responses to existing therapies.
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Affiliation(s)
- Praveen Dilip Chatani
- Endocrine Surgery Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Sunita Kishore Agarwal
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Samira Mercedes Sadowski
- Endocrine Surgery Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Samira Mercedes Sadowski,
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8
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Hirabayashi K, Tajiri T, Bosch DE, Morimachi M, Miyaoka M, Inomoto C, Nakamura N, Yeh MM. Loss of nectin-3 expression as a marker of tumor aggressiveness in pancreatic neuroendocrine tumor. Pathol Int 2019; 70:84-91. [PMID: 31855317 DOI: 10.1111/pin.12881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 11/19/2019] [Indexed: 12/30/2022]
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare, and prediction of aggressive characteristics, such as recurrence and metastasis and prognosis of PanNETs remain difficult. Nectins are cell adhesion molecules that regulate the formation of adherens and tight junctions. In this study, we investigated the clinicopathological significance of nectin-3 expression in patients with PanNETs. Immunohistochemical analysis of nectin-3 expression was performed on 78 cases of PanNET. Low nectin-3 expression in the membrane (positive ratio ≤25%) was observed in 62 cases (79.5%) and was significantly correlated with larger tumor size (>20 mm; P = 0.003), G2/G3 tumors (P = 0.025), higher Ki67 labeling index (≥3%; P = 0.009), lymphatic involvement (P = 0.047), advanced pT-factor (T2-T4; P = 0.003), lymph node metastasis (P = 0.006), advanced Union for International Cancer Control/American Joint Committee on Cancer-stage (Stage II-IV; P = 0.001), advanced ENETS stage (Stage IIa-IV; P = 0.001), nonfunctioning tumors (P = 0.002), and a shorter disease-free survival (P = 0.019). However, there was no significant correlation between nectin-3 expression in the membrane and/or cytoplasm and the clinicopathological parameters. The present results suggest that decreased nectin-3 expression in the membrane is associated with increased tumor aggressiveness of PanNETs. Clinically, immunohistochemical analysis of nectin-3 may help predict tumor aggressiveness for PanNETs.
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Affiliation(s)
- Kenichi Hirabayashi
- Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
| | - Takuma Tajiri
- Department of Pathology, Tokai University Hachioji Hospital, Tokyo, Japan
| | - Dustin E Bosch
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA
| | - Masashi Morimachi
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Kanagawa, Japan
| | - Masashi Miyaoka
- Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
| | - Chie Inomoto
- Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan
| | - Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.,Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
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9
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Young K, Starling N, Sadanandam A. The molecular biology of pancreatic neuroendocrine neoplasms: Challenges and translational opportunities. Semin Cancer Biol 2019; 61:132-138. [PMID: 31577961 DOI: 10.1016/j.semcancer.2019.09.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare, highly heterogeneous tumours. There have been significant recent advances in our knowledge of genomic events underlying their pathogenesis. However, treatment decisions remain largely based on tumour stage and grade which is inadequate, the current classification paradigm failing to capture the significant heterogeneity in tumour biology. There is a well-acknowledged unmet clinical need for novel biomarkers to enable individualised risk-adapted therapeutic strategies for PanNEN patients. Improvements in our understanding of the molecular biology of multiple solid tumours have led to the development of new biomarker assays and gene expression signatures to guide treatment decisions in other cancer types. A similar index for PanNENs, to improve patient prognostication and classification, would be highly clinically relevant and with advances in the field now seems potentially possible. This article will seek to review the molecular biology of PanNENs, the subtypes developed to date and the potential clinical opportunities these advances may afford.
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Affiliation(s)
- Kate Young
- The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Naureen Starling
- The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
| | - Anguraj Sadanandam
- The Royal Marsden NHS Foundation Trust, London, United Kingdom; Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
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10
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Neradil J, Kyr M, Polaskova K, Kren L, Macigova P, Skoda J, Sterba J, Veselska R. Phospho-Protein Arrays as Effective Tools for Screening Possible Targets for Kinase Inhibitors and Their Use in Precision Pediatric Oncology. Front Oncol 2019; 9:930. [PMID: 31616636 PMCID: PMC6763615 DOI: 10.3389/fonc.2019.00930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 09/05/2019] [Indexed: 11/13/2022] Open
Abstract
The specific targeting of signal transduction by low-molecular-weight inhibitors or monoclonal antibodies represents a very promising personalized treatment strategy in pediatric oncology. In this study, we present the successful and clinically relevant use of commercially available phospho-protein arrays for analyses of the phosphorylation profiles of a broad spectrum of receptor tyrosine kinases and their downstream signaling proteins in tumor tissue samples. Although these arrays were made for research purposes on human biological samples, they have already been used by several authors to profile various tumor types. Our study performed a systematic analysis of the advantages and pitfalls of the use of this method for personalized clinical medicine. In certain clinical cases and their series, we demonstrated the important aspects of data processing and evaluation, the use of phospho-protein arrays for single sample and serial sample analyses, and the validation of obtained results by immunohistochemistry, as well as the possibilities of this method for the hierarchical clustering of pediatric solid tumors. Our results clearly show that phospho-protein arrays are apparently useful for the clinical consideration of druggable molecular targets within a specific tumor. Thus, their potential validation for diagnostic purposes may substantially improve the personalized approach in the treatment of relapsed or refractory solid tumors.
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Affiliation(s)
- Jakub Neradil
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia.,Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Michal Kyr
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Kristyna Polaskova
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Leos Kren
- Department of Pathology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Petra Macigova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia.,Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia.,Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Jaroslav Sterba
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia.,Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, Brno, Czechia
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11
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Gao L, Natov NS, Daly KP, Masud F, Chaudhry S, Sterling MJ, Saif MW. An update on the management of pancreatic neuroendocrine tumors. Anticancer Drugs 2019; 29:597-612. [PMID: 29782352 DOI: 10.1097/cad.0000000000000633] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) are a rare and heterogeneous group of neoplasia and differ in their clinical presentation, behavior, and prognosis based on both histological features and cancer stage at the time of diagnosis. Although small-sized tumors can be surgically resected, locally advanced and metastatic tumors confer a poor prognosis. In addition, only limited treatment options are available to the latter group of patients with PNETs, such as hormonal analogs, cytotoxic agents, and targeted therapy. In selected patients, liver-directed therapies are also used. As expected, clinicians taking care of these patients are challenged to develop an effective and comprehensive treatment strategy for their patients amid a wide variety of treatment modalities. Targeted therapy for PNETs is limited to sunitinib and everolimus. Presently, a number of clinical studies are ongoing to assess the efficacy of newer targeted agents alone and in combination with previous agents for the treatment of advanced PNETs. The authors reviewed the current treatment and also discussed the emerging agents and emphasized the need to identify biomarkers.
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Affiliation(s)
- Limin Gao
- Division of Hematology and Oncology, GI Oncology Program and Experimental Therapeutics
| | - Nikola S Natov
- Division of Gastroenterology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | | | | | - Sadia Chaudhry
- Foundation University Medical College, Rawalpindi, Pakistan
| | - Mark J Sterling
- Division of Gastroenterology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Muhammad W Saif
- Division of Hematology and Oncology, GI Oncology Program and Experimental Therapeutics
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12
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Romano D. Relevance of neuroendocrine tumours models assessed by kinomic profiling. ANNALES D'ENDOCRINOLOGIE 2019; 80:144-148. [PMID: 31054767 DOI: 10.1016/j.ando.2019.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Although there is evidence of a significant rise of neuroendocrine tumours (NETs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite many efforts achieved to expose driver oncogene mutations in NETs, the genetic landscape of NETs is characterized by relatively few mutations and chromosomal aberrations per tumour compared with other tumour types. In addition, NETs display few actionable mutations providing compelling rationale for targeted therapies. Recent works aiming at characterizing currently used NETs in vitro models at the genomic level raised concerns on their reliability as bona fide tools to study NETs biology. However, the lack of actionable mutation in NETs implies that sole use of genomic is not sufficient to describe these models and establish appropriate therapeutic strategies. Several kinases and kinase-involving signalling pathways have been demonstrated as abnormally regulated in NETs. Yet, kinases have only been investigated regardless of their involvement in large intracellular signalling networks. In order to assess the validity of in vitro NETs models to study NETs biology, "next-generation" high throughput functional technologies based on "kinome-wide activity" will demonstrate the similarities between signalling pathways in NETs models and patients' samples. These approaches will significantly assist in identifying actionable alterations in NETs signalling pathways and guide patient stratification into early-phase clinical trials based on kinase inhibition targeted therapies.
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Affiliation(s)
- David Romano
- Marseille Medical Genetics, MMG, U1251 Inserm, Aix-Marseille université, Marseille, France.
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13
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Mafficini A, Scarpa A. Genetics and Epigenetics of Gastroenteropancreatic Neuroendocrine Neoplasms. Endocr Rev 2019; 40:506-536. [PMID: 30657883 PMCID: PMC6534496 DOI: 10.1210/er.2018-00160] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
Abstract
Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway-based overview. This provided a summary of the critical alterations sustaining neoplastic cells. It also highlighted similarities and differences across anatomical locations and points that need further investigation. GEP-NENs include well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). NENs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, NECs are G3 by definition. The distinction between NETs and NECs is also linked to their genetic background, as TP53 and RB1 inactivation in NECs set them apart from NETs. A large number of genetic and epigenetic alterations have been reported. Recurrent changes have been traced back to a reduced number of core pathways, including DNA damage repair, cell cycle regulation, and phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling. In pancreatic tumors, chromatin remodeling/histone methylation and telomere alteration are also affected. However, also owing to the paucity of disease models, further research is necessary to fully integrate and functionalize data on deregulated pathways to recapitulate the large heterogeneity of behaviors displayed by these tumors. This is expected to impact diagnostics, prognostic stratification, and planning of personalized therapy.
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Affiliation(s)
- Andrea Mafficini
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.,Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
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Abstract
Pancreatic neuroendocrine tumors are rare tumors of the pancreas originating from the islets of the Langerhans. These tumors comprise 1% to 3% of all newly diagnosed pancreatic cancers every year and have a unique heterogeneity in clinical presentation. Whole-genome sequencing has led to an increased understanding of the molecular biology of these tumors. In this review, we will summarize the current knowledge of the signaling pathways involved in the tumorigenesis of pancreatic neuroendocrine tumors as well as the major studies targeting these pathways at preclinical and clinical levels.
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15
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Simbolo M, Vicentini C, Ruzzenente A, Brunelli M, Conci S, Fassan M, Mafficini A, Rusev B, Corbo V, Capelli P, Bria E, Pedron S, Turri G, Lawlor RT, Tortora G, Bassi C, Guglielmi A, Scarpa A. Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma. Sci Rep 2018; 8:7119. [PMID: 29740198 PMCID: PMC5940669 DOI: 10.1038/s41598-018-25669-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 04/26/2018] [Indexed: 12/11/2022] Open
Abstract
The incidence and mortality rates of intrahepatic cholangiocarcinoma have been rising worldwide. Few patients present an early-stage disease that is amenable to curative surgery and after resection, high recurrence rates persist. To identify new independent marker related to aggressive behaviour, two prognostic groups of patient were selected and divided according to prognostic performance. All patients alive at 36 months were included in good prognostic performers, while all patients died due to disease within 36 months in poor prognostic performers. Using high-coverage target sequencing we analysed principal genetic alterations in two groups and compared results to clinical data. In the 33 cases included in poor prognosis group, TP53 was most mutated gene (p = 0.011) and exclusively present in these cases. Similarly, ARID1A was exclusive of this group (p = 0.024). TP53 and ARID1A are mutually exclusive in this study. Statistical analysis showed mutations in TP53 and ARID1A genes and amplification of MET gene as independent predictors of poor prognosis (TP53, p = 0.0031, ARID1A, p = 0.0007, MET, p = 0.0003 in Cox analysis). LOH in PTEN was also identified as marker of disease recurrence (p = 0.04) in univariate analysis. This work improves our understanding of aggressiveness related to this tumour type and has identified novel prognostic markers of clinical outcome.
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Affiliation(s)
- Michele Simbolo
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Caterina Vicentini
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Simone Conci
- Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy
| | - Matteo Fassan
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy
| | - Andrea Mafficini
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Borislav Rusev
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Vincenzo Corbo
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Emilio Bria
- Medical Oncology, Università Cattolica del Sacro Cuore, Fondazione Policlinico 'A. Gemelli', Roma, Italy.
| | - Serena Pedron
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giona Turri
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Rita T Lawlor
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giampaolo Tortora
- Department of Medicine, U.O.C Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Bassi
- Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy
| | - Alfredo Guglielmi
- Department of Surgery, General and Hepatobiliary Surgery, University Hospital G.B. Rossi, University of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
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Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms. Clin Transl Oncol 2017; 20:561-569. [PMID: 29124519 DOI: 10.1007/s12094-017-1758-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 09/30/2017] [Indexed: 12/20/2022]
Abstract
Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers.
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Di Domenico A, Wiedmer T, Marinoni I, Perren A. Genetic and epigenetic drivers of neuroendocrine tumours (NET). Endocr Relat Cancer 2017; 24:R315-R334. [PMID: 28710117 DOI: 10.1530/erc-17-0012] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 07/14/2017] [Indexed: 12/13/2022]
Abstract
Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.
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Affiliation(s)
- Annunziata Di Domenico
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | - Tabea Wiedmer
- Institute of PathologyUniversity of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical SciencesUniversity of Bern, Bern, Switzerland
| | | | - Aurel Perren
- Institute of PathologyUniversity of Bern, Bern, Switzerland
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18
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Hendifar AE, Liu S, Wolin E. The Role of mTOR Inhibitors in Neuroendocrine Tumors. MTOR INHIBITION FOR CANCER THERAPY: PAST, PRESENT AND FUTURE 2016:93-112. [DOI: 10.1007/978-2-8178-0492-7_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Reg3g Promotes Pancreatic Carcinogenesis in a Murine Model of Chronic Pancreatitis. Dig Dis Sci 2015; 60:3656-68. [PMID: 26182900 DOI: 10.1007/s10620-015-3787-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 06/29/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND Regenerating islet-derived 3 (Reg3) is abnormally expressed in several human digestive system diseases, including chronic pancreatitis (CP) and pancreatic cancer (PC). AIM The purpose of this study was to clarify the mechanism of the enhanced expression of Reg3 in inflammation-induced PC. METHODS C57BL/6 mice were treated with caerulein for 6 weeks to induce CP and then injected with pReg3g--a lentivirus system encoding for murine Reg3g--accompanied by dimethylbenzanthracene to induce PC. We detected pancreatic histopathological characteristics, tumor-related gene expression, inflammation-associated pathway activation, serum biochemical indicators, and immunological cell activities. RESULTS The mice that developed CP after caerulein treatment were marked by pronounced histologic lesions, elevated serum amylase levels, and activation of inflammation-related pathways. Mice given a high dose of pReg3g developed PC by 16 weeks, with recognizable tumors in the pancreas. While, both the low and high doses of pReg3g produced higher transcription of c-fos, k-ras, cytokeratin-19, and proliferating cell nuclear antigen, and a lower expression of caspase-3 compared to pNEG controls. Additionally, the higher dose of pReg3g increased the expressions of pSTAT3, NFκB (p65), and SOCS3 methylation during PC development. In addition, mice treated with pReg3g displayed higher levels of serum IL10 and TGFβ and suppressed T lymphocyte proliferation and DC function. CONCLUSION The comprehensive analysis suggests enhanced Reg3g expression exacerbates PC in inflammation-associated cancer progression. Reg3g appears to promote CP-related PC in mice through multiple mechanisms, involving enhanced transcription of pancreatic tumor markers, repression of anti-tumor immunity, and activation of STAT3/p65 signal transduction pathways.
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Capurso G, Archibugi L, Delle Fave G. Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:594-601. [PMID: 25619712 DOI: 10.1002/jhbp.210] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Accepted: 12/11/2014] [Indexed: 12/11/2022]
Abstract
Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.
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Affiliation(s)
- Gabriele Capurso
- Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Rome, Italy
| | - Livia Archibugi
- Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Rome, Italy
| | - Gianfranco Delle Fave
- Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Rome, Italy
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Tumor-associated macrophages are a useful biomarker to predict recurrence after surgical resection of nonfunctional pancreatic neuroendocrine tumors. Ann Surg 2015; 260:1088-94. [PMID: 25389924 DOI: 10.1097/sla.0000000000000262] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Patients with nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) have poorer survival than those with functional PNETs. Our objective was to identify risk factors for recurrence after resection to better define surveillance parameters to improve long-term outcomes. METHODS A retrospective analysis was performed for NF-PNET patients who underwent resection at the University of Michigan from 1995 to 2012. Immunohistochemical staining of tissues from patients with and without disease recurrence was performed for Ki-67 and the macrophage marker CD68, as tumor-associated macrophages are important for PNET development and progression. Clinicopathological factors and patient outcomes were measured. RESULTS Ninety-seven NF-PNET patients underwent surgical resection. There was a recurrence rate of 14.4% (14/97). The median time to recurrence was 0.61 years, with 10 (71%) patients recurring within the first 2 years. Six of 7 patients (86%) monitored at 6-month surveillance intervals were diagnosed with recurrence on their first computed tomographic scan or during the intervening intervals. By Cox proportional hazards analysis, the most significant independent risk factors for recurrence were higher grade, stage, and intraoperative blood loss. High CD68 score and Ki-67 index correlated with recurrence risk, and Ki-67 index inversely correlated with time to recurrence. In patients who otherwise had few risk factors, a high CD68 score was a significant prognostic factor for recurrence. CONCLUSIONS In patients with NF-PNETs, risk factors associated with recurrence were high EBL, grade, stage, CD68 score, and Ki-67 index. The CD68 score was an important prognostic factor in patients who otherwise had few clinicopathological risk factors; therefore, the CD68 score should be considered when planning surveillance strategies. We recommend that NF-PNET patients at high risk of recurrence undergo initial surveillance every 3 months for 2 years after surgery.
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De Dosso S, Grande E, Barriuso J, Castellano D, Tabernero J, Capdevila J. The targeted therapy revolution in neuroendocrine tumors: in search of biomarkers for patient selection and response evaluation. Cancer Metastasis Rev 2014; 32:465-77. [PMID: 23589060 DOI: 10.1007/s10555-013-9421-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The molecular events of tumorigenesis in neuroendocrine tumors are poorly understood. Understanding of the molecular alterations will lead to the identification of molecular markers, providing new targets for therapeutics. The purpose of this review was to critically analyze the genetic abnormalities in neuroendocrine tumors, with the aim of identifying biomarkers that indicate a response to agents developed against these targets and to serve as an understanding for the combinations of different active compounds. Human epidermal growth factor receptor 1/2 (EGFR and HER2), vascular endothelial growth factor receptors, hepatocyte growth factor receptor (c-Met), platelet-derived growth factor receptor, insulin-like growth factor, phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway, and heat shock proteins are all interesting candidate biomarkers with involvement in carcinogenesis and tumor evolution of several neoplasms, including neuroendocrine tumors. Some of them have already been evaluated both as targets and also as biomarkers in clinical trials conducted in advanced neuroendocrine tumor settings, and others should encourage further investigations into innovative therapeutic opportunities.
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Affiliation(s)
- Sara De Dosso
- Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
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23
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Estrella JS, Broaddus RR, Mathews A, Milton DR, Yao JC, Wang H, Rashid A. Progesterone receptor and PTEN expression predict survival in patients with low- and intermediate-grade pancreatic neuroendocrine tumors. Arch Pathol Lab Med 2014; 138:1027-36. [PMID: 25076292 DOI: 10.5858/arpa.2013-0195-oa] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
CONTEXT The PI3K-AKT-mTOR (phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin) pathway plays a crucial role in a subset of advanced pancreatic neuroendocrine tumors (PanNETs). In breast and endometrial carcinoma, activation of this pathway inhibits progesterone receptor (PR) expression. OBJECTIVE To determine whether combined low expression of PR and phosphatase and tensin homologue (PTEN), a negative regulator of the PI3K-AKT-mTOR pathway, is a prognostic factor. DESIGN A total of 160 resected PanNETs (89 low grade and 71 intermediate grade) were analyzed for PR and PTEN immunohistochemical positivity and staining was correlated with metastasis-free survival (MFS) and overall survival (OS). Progesterone receptor staining was scored as positive by using 1% or greater as cutoff. Weak/faint staining in greater than 90% of tumor cells was considered low PTEN positivity. RESULTS Most PanNETs (110 cases, 69%) were both PR and PTEN positive, 45 (28%) were either PR or PTEN positive, and only 5 (3%) had a PR-negative and PTEN-low profile. Combined PR-PTEN positivity was significantly associated with MFS in patients with stage I and II disease (P <.001) and OS in all patients (P < .001) and remained a significant predictor of survival after adjusting for other factors. Patients with PR-negative-PTEN-low PanNETs had the shortest median MFS and OS, compared to those with tumors that were either PR or PTEN positive and with tumors positive for both PR and PTEN (P ≤ .001). CONCLUSION Combined immunohistochemical assessment of PR and PTEN may help identify a small subset of PanNETs with more aggressive behavior and may aid in risk stratification.
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Affiliation(s)
- Jeannelyn S Estrella
- From the Departments of Pathology (Drs Estrella, Broaddus, Wang, and Rashid), Immunology (Ms Mathews), Biostatistics (Ms Milton), and Gastrointestinal Medical Oncology, (Dr Yao), The University of Texas MD Anderson Cancer Center, Houston, Texas
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Luchini C, Capelli P, Fassan M, Simbolo M, Mafficini A, Pedica F, Ruzzenente A, Guglielmi A, Corbo V, Scarpa A. Next-generation histopathologic diagnosis: a lesson from a hepatic carcinosarcoma. J Clin Oncol 2014; 32:e63-e66. [PMID: 24493719 DOI: 10.1200/jco.2012.47.5855] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Claudio Luchini
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Paola Capelli
- Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Matteo Fassan
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Michele Simbolo
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Andrea Mafficini
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Federica Pedica
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Alfredo Guglielmi
- Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
| | - Vincenzo Corbo
- Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Azienda Ospedaliera Universitaria Integrata di Verona; Miriam Cherubini Centre for Applied Research on Cancer, University of Verona, Verona, Italy
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25
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Simbolo M, Fassan M, Ruzzenente A, Mafficini A, Wood LD, Corbo V, Melisi D, Malleo G, Vicentini C, Malpeli G, Antonello D, Sperandio N, Capelli P, Tomezzoli A, Iacono C, Lawlor RT, Bassi C, Hruban RH, Guglielmi A, Tortora G, de Braud F, Scarpa A. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget 2014; 5:2839-2852. [PMID: 24867389 PMCID: PMC4058049 DOI: 10.18632/oncotarget.1943] [Citation(s) in RCA: 157] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 04/30/2014] [Indexed: 02/06/2023] Open
Abstract
One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing. Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry. At least one mutated gene was observed in 118/153 (77%) cancers. The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%). IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC. Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival. Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases. Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases. Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.
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Affiliation(s)
- Michele Simbolo
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Fassan
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Department of Surgery, General Surgery A, University of Verona, Verona, Italy
| | - Andrea Mafficini
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Laura D. Wood
- Department of Pathology, Johns Hopkins University and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Vincenzo Corbo
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Davide Melisi
- Department of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Giuseppe Malleo
- Department of Surgery, General Surgery B, University of Verona, Verona, Italy
| | - Caterina Vicentini
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Giorgio Malpeli
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Surgery, General Surgery A, University of Verona, Verona, Italy
- Department of Surgery, General Surgery B, University of Verona, Verona, Italy
| | - Davide Antonello
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Surgery, General Surgery A, University of Verona, Verona, Italy
- Department of Surgery, General Surgery B, University of Verona, Verona, Italy
| | - Nicola Sperandio
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Capelli
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Anna Tomezzoli
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Calogero Iacono
- Department of Surgery, General Surgery A, University of Verona, Verona, Italy
| | - Rita T. Lawlor
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Bassi
- Department of Surgery, General Surgery B, University of Verona, Verona, Italy
| | - Ralph H. Hruban
- Department of Pathology, Johns Hopkins University and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Alfredo Guglielmi
- Department of Surgery, General Surgery A, University of Verona, Verona, Italy
| | - Giampaolo Tortora
- Department of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Filippo de Braud
- Medical Oncology Unit 1, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - Aldo Scarpa
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
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26
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Meeker A, Heaphy C. Gastroenteropancreatic endocrine tumors. Mol Cell Endocrinol 2014; 386:101-20. [PMID: 23906538 DOI: 10.1016/j.mce.2013.07.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 07/19/2013] [Accepted: 07/22/2013] [Indexed: 02/06/2023]
Abstract
Gastroenteropancreatic endocrine tumors (GEP-NETs) are relatively uncommon; comprising approximately 0.5% of all human cancers. Although they often exhibit relatively indolent clinical courses, GEP-NETs have the potential for lethal progression. Due to their scarcity and various technical challenges, GEP-NETs have been understudied. As a consequence, we have few diagnostic, prognostic and predictive biomarkers for these tumors. Early detection and surgical removal is currently the only reliable curative treatment for GEP-NET patients; many of whom, unfortunately, present with advanced disease. Here, we review the genetics and epigenetics of GEP-NETs. The last few years have witnessed unprecedented technological advances in these fields, and their application to GEP-NETS has already led to important new information on the molecular abnormalities underlying them. As outlined here, we expect that "omics" studies will provide us with new diagnostic and prognostic biomarkers, inform the development of improved pre-clinical models, and identify novel therapeutic targets for GEP-NET patients.
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Affiliation(s)
- Alan Meeker
- The Johns Hopkins University School of Medicine, Department of Pathology, Bond Street Research Annex Bldg., Room B300, 411 North Caroline Street, Baltimore, MD 21231, United States.
| | - Christopher Heaphy
- The Johns Hopkins University School of Medicine, Department of Pathology, Bond Street Research Annex Bldg., Room B300, 411 North Caroline Street, Baltimore, MD 21231, United States
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27
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Cingarlini S, Bonomi M, Trentin C, Corbo V, Scarpa A, Tortora G. Profiling mTOR Pathway in Neuroendocrine Tumors. MANAGEMENT OF NEUROENDOCRINE TUMORS OF THE PANCREAS AND DIGESTIVE TRACT 2014:9-27. [DOI: 10.1007/978-2-8178-0430-9_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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28
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Raymond E, García-Carbonero R, Wiedenmann B, Grande E, Pavel M. Systemic therapeutic strategies for GEP-NETS: what can we expect in the future? Cancer Metastasis Rev 2013; 33:367-72. [DOI: 10.1007/s10555-013-9467-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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29
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Oberg K, Casanovas O, Castaño JP, Chung D, Delle Fave G, Denèfle P, Harris P, Khan MS, Kulke MH, Scarpa A, Tang LH, Wiedenmann B. Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res 2013; 19:2842-9. [PMID: 23459719 DOI: 10.1158/1078-0432.ccr-12-3458] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The treatment landscape and biologic understanding of neuroendocrine tumors (NET) has shifted dramatically in recent years. Recent studies have shown that somatostatin analogues have the potential not only to control symptoms of hormone hypersecretion but also have the ability to slow tumor growth in patients with advanced carcinoid. The results of clinical trials have further shown that the VEGF pathway inhibitor sunitinib and the mTOR inhibitor everolimus have efficacy in patients with advanced pancreatic NETs. The efficacy of these targeted therapies in NET suggests that the molecular characterization of NETs may provide an avenue to predict both which patients may benefit most from the treatment and to overcome potential drug resistance. Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. These observations offer the potential for new therapeutic and diagnostic advances for patients with NET.
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Affiliation(s)
- Kjell Oberg
- Department of Endocrine Oncology, University Hospital, Uppsala, Sweden.
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30
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Wolin EM. PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors. Cancer Lett 2013; 335:1-8. [PMID: 23419523 DOI: 10.1016/j.canlet.2013.02.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 02/06/2013] [Accepted: 02/08/2013] [Indexed: 02/07/2023]
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is implicated in the pathogenesis of pancreatic neuroendocrine tumors (pNETs). Activation of this pathway is driven by aberrant tyrosine kinase receptor activities. Mutations in the PI3K/Akt/mTOR pathway occur in 15% of pNETs, and expression of genes of the PI3K/Akt/mTOR pathway is altered in the majority of pNETs. The mTOR inhibitor everolimus has been approved by the FDA for the treatment of pNET, but its efficacy may be limited by its inability to prevent mTORC2-mediated activation of Akt. Specific inhibitors of PI3K, Akt, or other pathway nodes, and their concomitant use with mTOR inhibitors, or agents with dual activity, may be more effective. Preclinical studies demonstrate that inhibitors of the PI3K pathway have antitumor activity in pNET cells, either through direct inhibition of individual pathway nodes or indirect inhibition of molecular chaperones such as heat-shock protein 90. Clinical studies are underway evaluating individual node and dual node inhibitors.
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Affiliation(s)
- Edward M Wolin
- Division of Hematology/Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA.
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31
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Capurso G, Fendrich V, Rinzivillo M, Panzuto F, Bartsch DK, Fave GD. Novel molecular targets for the treatment of gastroenteropancreatic endocrine tumors: answers and unsolved problems. Int J Mol Sci 2012; 14:30-45. [PMID: 23344019 PMCID: PMC3565249 DOI: 10.3390/ijms14010030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 12/01/2012] [Accepted: 12/03/2012] [Indexed: 01/17/2023] Open
Abstract
As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents.
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Affiliation(s)
- Gabriele Capurso
- Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy; E-Mails: (G.C.); (M.R.); (F.P.)
| | - Volker Fendrich
- Department of Surgery, Philipps-University, Marburg, Germany; E-Mails: (V.F.); (D.K.B.)
| | - Maria Rinzivillo
- Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy; E-Mails: (G.C.); (M.R.); (F.P.)
| | - Francesco Panzuto
- Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy; E-Mails: (G.C.); (M.R.); (F.P.)
| | - Detlef K. Bartsch
- Department of Surgery, Philipps-University, Marburg, Germany; E-Mails: (V.F.); (D.K.B.)
| | - Gianfranco Delle Fave
- Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy; E-Mails: (G.C.); (M.R.); (F.P.)
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32
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Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One 2012; 7:e43192. [PMID: 23071490 PMCID: PMC3468610 DOI: 10.1371/journal.pone.0043192] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 07/19/2012] [Indexed: 12/24/2022] Open
Abstract
Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.
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Affiliation(s)
- Winnie S. Liang
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - David W. Craig
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - John Carpten
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | | | - Michael J. Demeure
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
| | - Glen J. Weiss
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
| | - Tyler Izatt
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Shripad Sinari
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Alexis Christoforides
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Jessica Aldrich
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Ahmet Kurdoglu
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Michael Barrett
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Lori Phillips
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Hollie Benson
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Waibhav Tembe
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | | | - Jeffrey A. Kiefer
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Christophe Legendre
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Richard Posner
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Galen H. Hostetter
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Angela Baker
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Jan B. Egan
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Mayo Clinic, Scottsdale, Arizona, United States of America
| | - Haiyong Han
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Douglas Lake
- Arizona State University, Tempe, Arizona, United States of America
| | - Edward C. Stites
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Ramesh K. Ramanathan
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
| | - Rafael Fonseca
- Mayo Clinic, Scottsdale, Arizona, United States of America
| | | | - Daniel Von Hoff
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Mayo Clinic, Scottsdale, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
- * E-mail:
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33
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Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One 2012. [PMID: 23071490 DOI: 10.137/journal.pone.0043192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.
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Affiliation(s)
- Winnie S Liang
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
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Shin JU, Lee CH, Lee KT, Lee JK, Lee KH, Kim KM, Kim KM, Park SM, Rhee JC. Prognostic significance of ATM and cyclin B1 in pancreatic neuroendocrine tumor. Tumour Biol 2012; 33:1645-1651. [PMID: 22707287 DOI: 10.1007/s13277-012-0420-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2012] [Accepted: 05/09/2012] [Indexed: 12/11/2022] Open
Abstract
Ataxia telangiectasia mutated kinase (ATM) and cyclin B1 are involved in cell cycle control. The prognostic significance of both molecules has not yet been investigated in pancreatic neuroendocrine tumors. The aim of this study was to evaluate the clinical and prognostic significance of ATM and cyclin B1 in patients with pancreatic neuroendocrine tumors. A total of 107 pancreatic neuroendocrine tumor specimens that were surgically resected were immunohistochemically investigated using the tissue microarray technique. Clinicopathologic results and survival were evaluated retrospectively. High expression of ATM and cyclin B1 was related to well-differentiated endocrine tumors of the World Health Organization (WHO) classification, but not related to TNM stages. The high ATM expression group (ATM ≥ 4) had a significantly smaller tumor size, lower recurrence rate, more number of functioning tumor, and well differentiation of WHO classification. The high cyclin B1 expression group (cyclin B1 ≥ 5) was related to smaller tumor size, less vascular invasion, less recurrence rate, and less death rate. However, cyclin B1 was the only significant factor for survival following multivariate analysis (p = 0.008; OR, 0.54; 95 % CI, 0.35-0.85). The current results suggested that expression of ATM and cyclin B1 may be useful markers to identify patients with poor prognosis who may benefit from close follow-up and aggressive therapy in pancreatic neuroendocrine tumors.
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Affiliation(s)
- Jae Uk Shin
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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35
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Schnerch D, Yalcintepe J, Schmidts A, Becker H, Follo M, Engelhardt M, Wäsch R. Cell cycle control in acute myeloid leukemia. Am J Cancer Res 2012; 2:508-528. [PMID: 22957304 PMCID: PMC3433102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 07/27/2012] [Indexed: 06/01/2023] Open
Abstract
Acute myeloid leukemia (AML) is the result of a multistep transforming process of hematopoietic precursor cells (HPCs) which enables them to proceed through limitless numbers of cell cycles and to become resistant to cell death. Increased proliferation renders these cells vulnerable to acquiring mutations and may favor leukemic transformation. Here, we review how deregulated cell cycle control contributes to increased proliferation in AML and favors genomic instability, a prerequisite to confer selective advantages to particular clones in order to adapt and independently proliferate in the presence of a changing microenvironment. We discuss the connection between differentiation and proliferation with regard to leukemogenesis and outline the impact of specific alterations on response to therapy. Finally, we present examples, how a better understanding of cell cycle regulation and deregulation has already led to new promising therapeutic strategies.
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Affiliation(s)
- Dominik Schnerch
- Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Germany
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36
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Cingarlini S, Bonomi M, Corbo V, Scarpa A, Tortora G. Profiling mTOR pathway in neuroendocrine tumors. Target Oncol 2012; 7:183-8. [PMID: 22890559 DOI: 10.1007/s11523-012-0226-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 07/25/2012] [Indexed: 12/11/2022]
Abstract
The serine/threonine kinase mammalian target of rapamycin (mTOR) plays a central role in regulating critical cellular processes such as growth, proliferation, and protein synthesis. The study of cancer predisposing syndromes within which neuroendocrine tumors (NETs) may arise has furnished clues on the involvement of mTOR pathway in sporadic diseases so far. Recent comprehensive analyses have definitely shown activation of mTOR pathway in both experimental and human sporadic NETs. Upstream regulators of mTOR (PTEN and TSC2) have been found mutated in sporadic pNETs. Activation of mTOR pathways in NETs is already demonstrated by expression profiles analysis that revealed downregulation of TSC2 gene and alterations of TSC2 and PTEN protein expression in the vast majority of well-differentiated tumors. Moreover, a global microRNA expression analysis revealed the overexpression, in highly aggressive tumors, of a microRNA (miR-21) that targets PTEN reducing its expression and therefore leading to mTOR activation as well. Overall, these clues have furnished the rationale for the use of mTOR inhibitors the treatment of pNETs. With the recent approval of Everolimus (mTOR-targeted drug) for the treatment of advanced pNETs, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR pathway involvement in NETs, the clinical evidence supporting the use of mTOR inhibitors in cancer treatment, and the current clinical issues that remain to be elucidated to improve patient management.
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Affiliation(s)
- S Cingarlini
- Section of Medical Oncology, Department of Medicine, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona, Italy.
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Abstract
The serine/threonine kinase mammalian target of rapamycin (mTOR) plays a central role in regulating critical cellular processes such as growth, proliferation, and protein synthesis. The study of cancer predisposing syndromes within which neuroendocrine tumors (NETs) may arise has furnished clues on the involvement of mTOR pathway in sporadic diseases so far. Recent comprehensive analyses have definitely shown activation of mTOR pathway in both experimental and human sporadic NETs. Upstream regulators of mTOR (PTEN and TSC2) have been found mutated in sporadic pNETs. Activation of mTOR pathways in NETs is already demonstrated by expression profiles analysis that revealed downregulation of TSC2 gene and alterations of TSC2 and PTEN protein expression in the vast majority of well-differentiated tumors. Moreover, a global microRNA expression analysis revealed the overexpression, in highly aggressive tumors, of a microRNA (miR-21) that targets PTEN reducing its expression and therefore leading to mTOR activation as well. Overall, these clues have furnished the rationale for the use of mTOR inhibitors the treatment of pNETs. With the recent approval of Everolimus (mTOR-targeted drug) for the treatment of advanced pNETs, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR pathway involvement in NETs, the clinical evidence supporting the use of mTOR inhibitors in cancer treatment, and the current clinical issues that remain to be elucidated to improve patient management.
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Capurso G, Festa S, Valente R, Piciucchi M, Panzuto F, Jensen RT, Delle Fave G. Molecular pathology and genetics of pancreatic endocrine tumours. J Mol Endocrinol 2012; 49:R37-R50. [PMID: 22586144 DOI: 10.1530/jme-12-0069] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.
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Affiliation(s)
- Gabriele Capurso
- Digestive and Liver Disease Unit, Faculty of Medicine and Psychology, S. Andrea Hospital, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy
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Knösel T, Chen Y, Altendorf-Hofmann A, Danielczok C, Freesmeyer M, Settmacher U, Wurst C, Schulz S, Yang LL, Petersen I. High KIT and PDGFRA are associated with shorter patients survival in gastroenteropancreatic neuroendocrine tumors, but mutations are a rare event. J Cancer Res Clin Oncol 2012; 138:397-403. [PMID: 22160160 DOI: 10.1007/s00432-011-1107-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 11/22/2011] [Indexed: 12/19/2022]
Abstract
PURPOSE (1) To test whether in genomewide expression profiling differentially expressed genes were also distinct on the protein level including KIT and PDGFRA (2) to correlate the expression with clinicopathological parameters (3) to identify activating mutations that might be eligible for tyrosine kinase inhibitor therapy by mutational analysis of tumors with high expression. METHODS Gastroenteropancreatic neuroendocrine tumors (GEP NETs) from 119 patients were analyzed for protein expression of ten biomarkers. Mutational analysis of KIT (exon 9, 13, 11 and 17) and PDGFRA (exons 12 and 18) was performed on those samples that showed high protein expression. RESULTS High KIT expression was observed in 13% of all specimens, PDGFRA in 33%, CK19 in 26%, CK7 in 2%, CK20 in 5%, S100 in 6%, CD56 in 25%, Chromogranin in 55%, and Synapthophysin in 80%. High expression of KIT and PDGFRA was significantly correlated with shorter disease-specific survival (P = 0.003, P = 0.018, respectively). In multivariate analysis expression of PDGFRA, radicality of surgical treatment and WHO grading influenced disease-specific 10-year survival independently (P = 0.032, P = 0.001 and P = 0.008, respectively). Mutational analysis of highly expressed specimens (n = 51) reveals a novel mutation of KIT in exon 11 (K558N_V559insP) in a well-differentiated metastatic pancreatic neuroendocrine tumor. CONCLUSIONS High expression of KIT and PDGFRA was significantly correlated with shorter patients survival and could serve as prognostic marker. Mutations of the KIT gene might open new avenues for tyrosine kinase inhibitor therapy in a subset of patients with advanced pancreatic neuroendocrine tumors.
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Affiliation(s)
- Thomas Knösel
- Institute of Pathology, Friedrich-Schiller University, Jena University Hospital, Ziegelmühlenweg 1, 07743 Jena, Germany.
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Mahajan K, Coppola D, Chen YA, Zhu W, Lawrence HR, Lawrence NJ, Mahajan NP. Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 180:1386-93. [PMID: 22322295 DOI: 10.1016/j.ajpath.2011.12.028] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Revised: 12/09/2011] [Accepted: 12/22/2011] [Indexed: 12/31/2022]
Abstract
Pancreatic cancer is a significant cause of cancer mortality worldwide as the disease has advanced significantly in patients before symptoms are evident. The signal transduction pathways that promote this rapid progression are not well understood. Ack1 or TNK2, an ubiquitously expressed oncogenic non-receptor tyrosine kinase, integrates signals from ligand-activated receptor tyrosine kinases to modulate intracellular signaling cascades. In the present study, we investigated the Ack1 activation profile in a pancreatic cancer tumor microarray, and observed that expression levels of activated Ack1 and pTyr284-Ack1 positively correlated with the severity of disease progression and inversely correlated with the survival of patients with pancreatic cancer. To explore the mechanisms by which Ack1 promotes tumor progression, we investigated the role of AKT/PKB, an oncogene and Ack1-interacting protein. Ack1 activates AKT directly in pancreatic and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival. In addition, the Ack1 inhibitor AIM-100 not only inhibited Ack1 activation but also suppressed AKT tyrosine phosphorylation, leading to cell cycle arrest in the G1 phase. This effect resulted in a significant decrease in the proliferation of pancreatic cancer cells and induction of apoptosis. Collectively, our data indicate that activated Ack1 could be a prognostic marker for ascertaining early or advanced pancreatic cancer. Thus, Ack1 inhibitors hold promise for therapeutic intervention to inhibit pancreatic tumor growth.
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Affiliation(s)
- Kiran Mahajan
- Department of Drug Discovery, Moffitt Cancer Center, Tampa, Florida 33612, USA
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Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy M, Gallinger S, Schwartz AG, Syngal S, Cote ML, Axilbund J, Schulick R, Ali SZ, Eshleman JR, Velculescu V, Goggins M, Vogelstein B, Papadopoulous N, Hruban RH, Kinzler KW, Klein AP. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov 2012; 2:41-6. [PMID: 22585167 PMCID: PMC3676748 DOI: 10.1158/2159-8290.cd-11-0194] [Citation(s) in RCA: 378] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
UNLABELLED Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.
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Affiliation(s)
- Nicholas J. Roberts
- Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | - Yuchen Jiao
- Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | - Jun Yu
- Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Levy Kopelovich
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | | | - Melissa Bondy
- Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Steven Gallinger
- Hepatobiliary/pancreatic Surgical Oncology Program, University Health Network, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Ann G. Schwartz
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Sapna Syngal
- Population Sciences Division, Dana-Farber Cancer Institute, and Gastroenterology Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Michele L. Cote
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Jennifer Axilbund
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Richard Schulick
- Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Syed Z. Ali
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - James R. Eshleman
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Victor Velculescu
- Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | - Michael Goggins
- Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Departments of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Bert Vogelstein
- Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | - Nikolas Papadopoulous
- Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | - Ralph H. Hruban
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Departments of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Kenneth W. Kinzler
- Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, USA
| | - Alison P. Klein
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Departments of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA
- Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA
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Malpeli G, Amato E, Dandrea M, Fumagalli C, Debattisti V, Boninsegna L, Pelosi G, Falconi M, Scarpa A. Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1C in pancreatic endocrine tumors. BMC Cancer 2011; 11:351. [PMID: 21838870 PMCID: PMC3170651 DOI: 10.1186/1471-2407-11-351] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 08/12/2011] [Indexed: 12/16/2022] Open
Abstract
Background RASSF1A gene silencing by DNA methylation has been suggested as a major event in pancreatic endocrine tumor (PET) but RASSF1A expression has never been studied. The RASSF1 locus contains two CpG islands (A and C) and generates seven transcripts (RASSF1A-RASSF1G) by differential promoter usage and alternative splicing. Methods We studied 20 primary PETs, their matched normal pancreas and three PET cell lines for the (i) methylation status of the RASSF1 CpG islands using methylation-specific PCR and pyrosequencing and (ii) expression of RASSF1 isoforms by quantitative RT-PCR in 13 cases. CpG island A methylation was evaluated by methylation-specific PCR (MSP) and by quantitative methylation-specific PCR (qMSP); pyrosequencing was applied to quantify the methylation of 51 CpGs also encompassing those explored by MSP and qMSP approaches. Results MSP detected methylation in 16/20 (80%) PETs and 13/20 (65%) normal pancreas. At qMSP, 11/20 PETs (55%) and 9/20 (45%) normals were methylated in at least 20% of RASSF1A alleles. Pyrosequencing showed variable distribution and levels of methylation within and among samples, with PETs having average methylation higher than normals in 15/20 (75%) cases (P = 0.01). The evaluation of mRNA expression of RASSF1 variants showed that: i) RASSF1A was always expressed in PET and normal tissues, but it was, on average, expressed 6.8 times less in PET (P = 0.003); ii) RASSF1A methylation inversely correlated with its expression; iii) RASSF1 isoforms were rarely found, except for RASSF1B that was always expressed and RASSF1C whose expression was 11.4 times higher in PET than in normal tissue (P = 0.001). A correlation between RASSF1A expression and gene methylation was found in two of the three PET cell lines, which also showed a significant increase in RASSF1A expression upon demethylating treatment. Conclusions RASSF1A gene methylation in PET is higher than normal pancreas in no more than 75% of cases and as such it cannot be considered a marker for this neoplasm. RASSF1A is always expressed in PET and normal pancreas and its levels are inversely correlated with gene methylation. Isoform RASSF1C is overexpressed in PET and the recent demonstration of its involvement in the regulation of the Wnt pathway points to a potential pathogenetic role in tumor development.
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Affiliation(s)
- Giorgio Malpeli
- Department of Pathology and Diagnostics, University of Verona, Verona, Italy.
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