1
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Ünal Ç, Sağlam S. Metronomic Temozolomide (mTMZ) and Bevacizumab-The Safe and Effective Frontier for Treating Metastatic Neuroendocrine Tumors (NETs): A Single-Center Experience. Cancers (Basel) 2023; 15:5688. [PMID: 38067391 PMCID: PMC10705735 DOI: 10.3390/cancers15235688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/18/2023] [Accepted: 11/29/2023] [Indexed: 10/16/2024] Open
Abstract
Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment's efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide-capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials.
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Affiliation(s)
- Çağlar Ünal
- Division of Medical Oncology, Department of Internal Medicine, Kartal Dr. Lütfi Kırdar City Hospital, İstanbul 34870, Turkey
| | - Sezer Sağlam
- Division of Medical Oncology, Department of Internal Medicine, Demiroglu Bilim University, İstanbul 34870, Turkey;
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2
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Mohamed A, Wu S, Hamid M, Mahipal A, Cjakrabarti S, Bajor D, Selfridge JE, Asa SL. Management of Appendix Neuroendocrine Neoplasms: Insights on the Current Guidelines. Cancers (Basel) 2022; 15:295. [PMID: 36612291 PMCID: PMC9818268 DOI: 10.3390/cancers15010295] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/19/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5-1% of intestinal neoplasms; they are found in 0.3-0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.
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Affiliation(s)
- Amr Mohamed
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sulin Wu
- Department of Internal Medicine, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
- Department of Medical Genetics, Center for Human Genetics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Mohamed Hamid
- Department of Stem Cell Biology and Regenerative Medicine, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - Amit Mahipal
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sakti Cjakrabarti
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - David Bajor
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - J. Eva Selfridge
- Division of Hematology and Medical Oncology, UH Seidman Cancer Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Sylvia L. Asa
- Department of Pathology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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3
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Guo Y, Jiang Y, Rose JB, Nagaraju GP, Jaskula-Sztul R, Hjelmeland AB, Beck AW, Chen H, Ren B. Protein Kinase D1 Signaling in Cancer Stem Cells with Epithelial-Mesenchymal Plasticity. Cells 2022; 11:3885. [PMID: 36497140 PMCID: PMC9739736 DOI: 10.3390/cells11233885] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/20/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are extremely diverse and highly vascularized neoplasms that arise from endocrine cells in the pancreas. The pNETs harbor a subpopulation of stem cell-like malignant cells, known as cancer stem cells (CSCs), which contribute to intratumoral heterogeneity and promote tumor maintenance and recurrence. In this study, we demonstrate that CSCs in human pNETs co-express protein kinase PKD1 and CD44. We further identify PKD1 signaling as a critical pathway in the control of CSC maintenance in pNET cells. PKD1 signaling regulates the expression of a CSC- and EMT-related gene signature and promotes CSC self-renewal, likely leading to the preservation of a subpopulation of CSCs at an intermediate EMT state. This suggests that the PKD1 signaling pathway may be required for the development of a unique CSC phenotype with plasticity and partial EMT. Given that the signaling networks connected with CSC maintenance and EMT are complex, and extend through multiple levels of regulation, this study provides insight into signaling regulation of CSC plasticity and partial EMT in determining the fate of CSCs. Inhibition of the PKD1 pathway may facilitate the elimination of specific CSC subsets, thereby curbing tumor progression and metastasis.
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Affiliation(s)
- Yichen Guo
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yinan Jiang
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - J. Bart Rose
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Ganji Purnachandra Nagaraju
- Department of Medicine, Division of Hematology and Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Renata Jaskula-Sztul
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Anita B. Hjelmeland
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Cell Developmental and Integrative Biology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adam W. Beck
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Herbert Chen
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Bin Ren
- Department of Surgery, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- O’Neal Comprehensive Cancer Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- GBS Biomedical Engineering Program, Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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4
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Mohindroo C, McAllister F, De Jesus-Acosta A. Genetics of Pancreatic Neuroendocrine Tumors. Hematol Oncol Clin North Am 2022; 36:1033-1051. [PMID: 36154786 DOI: 10.1016/j.hoc.2022.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) represent a relatively rare disease; however, the incidence has been increasing during the last 2 decades. Next generation sequencing has greatly increased our understanding of driver mutations in pNETs. Sporadic pNETs have consistently presented with mutations in MEN1, DAXX/ATRX, and genes related to the mammalian target of rapamycin pathway. Inherited pNETs have traditionally been associated with multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1, and tuberous sclerosis complex. The current review expands on the existing knowledge and the relevant updates on the genetics of pNETs.
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Affiliation(s)
- Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Internal Medicine, Sinai Hospital of Baltimore, 2435 W. Belvedere Ave, Ste 56, Baltimore, MD 21215, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ana De Jesus-Acosta
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, CRB1, 1650 Orleans Street, CRB1 Rm 409, Baltimore, MD 21287.
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Badescu MC, Badulescu OV, Scripcariu DV, Butnariu LI, Bararu-Bojan I, Popescu D, Ciocoiu M, Gorduza EV, Costache II, Rezus E, Rezus C. Myocardial Ischemia Related to Common Cancer Therapy-Prevention Insights. LIFE (BASEL, SWITZERLAND) 2022; 12:life12071034. [PMID: 35888122 PMCID: PMC9325217 DOI: 10.3390/life12071034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/08/2022] [Accepted: 07/10/2022] [Indexed: 12/18/2022]
Abstract
Modern antineoplastic therapy improves survival and quality of life in cancer patients, but its indisputable benefits are accompanied by multiple and major side effects, such as cardiovascular ones. Endothelial dysfunction, arterial spasm, intravascular thrombosis, and accelerated atherosclerosis affect the coronary arteries, leading to acute and chronic coronary syndromes that negatively interfere with the oncologic treatment. The cardiac toxicity of antineoplastic agents may be mitigated by using adequate prophylactic measures. In the absence of dedicated guidelines, our work provides the most comprehensive, systematized, structured, and up-to-date analyses of the available literature focusing on measures aiming to protect the coronary arteries from the toxicity of cancer therapy. Our work facilitates the implementation of these measures in daily practice. The ultimate goal is to offer clinicians the necessary data for a personalized therapeutic approach for cancer patients receiving evidence-based oncology treatments with potential cardiovascular toxicity.
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Affiliation(s)
- Minerva Codruta Badescu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (M.C.B.); (D.P.); (I.I.C.); (C.R.)
- III Internal Medicine Clinic, “St. Spiridon” County Emergency Clinical Hospital, 1 Independence Boulevard, 700111 Iasi, Romania
| | - Oana Viola Badulescu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.B.-B.); (M.C.)
- Hematology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 1 Independence Boulevard, 700111 Iasi, Romania
- Correspondence: (O.V.B.); (D.V.S.); (L.I.B.)
| | - Dragos Viorel Scripcariu
- Surgery Department, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
- 1st Surgical Oncology Unit, Regional Institute of Oncology, 2-4 General Henri Mathias Berthelot Street, 700483 Iasi, Romania
- Correspondence: (O.V.B.); (D.V.S.); (L.I.B.)
| | - Lăcrămioara Ionela Butnariu
- Department of Mother and Child Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Correspondence: (O.V.B.); (D.V.S.); (L.I.B.)
| | - Iris Bararu-Bojan
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.B.-B.); (M.C.)
| | - Diana Popescu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (M.C.B.); (D.P.); (I.I.C.); (C.R.)
| | - Manuela Ciocoiu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.B.-B.); (M.C.)
| | - Eusebiu Vlad Gorduza
- Department of Mother and Child Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Irina Iuliana Costache
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (M.C.B.); (D.P.); (I.I.C.); (C.R.)
- Cardiology Clinic, “St. Spiridon” County Emergency Clinical Hospital, 700111 Iasi, Romania
| | - Elena Rezus
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania;
- I Rheumatology Clinic, Clinical Rehabilitation Hospital, 14 Pantelimon Halipa Street, 700661 Iasi, Romania
| | - Ciprian Rezus
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (M.C.B.); (D.P.); (I.I.C.); (C.R.)
- III Internal Medicine Clinic, “St. Spiridon” County Emergency Clinical Hospital, 1 Independence Boulevard, 700111 Iasi, Romania
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Dai M, Mullins CS, Lu L, Alsfasser G, Linnebacher M. Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022; 14:383-396. [PMID: 35734622 PMCID: PMC9160679 DOI: 10.4240/wjgs.v14.i5.383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/17/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare group of tumors originating from neuroendocrine cells of the digestive system. Their incidence has increased over the last decades. The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed. Unfunctional GEP-NENs are usually asymptomatic; some grow slowly and thus impede early diagnosis, which ultimately results in a high rate of misdiagnosis. Therefore, many GEP-NEN patients present with later staged tumors. Motivated hereby, research attention for diagnosis and treatment for GEP-NENs increased in recent years. The result of which is great progress in clinical diagnosis and treatment. According to the most recent clinical guidelines, improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas (NECs), which are subclassified into large and small cell NECs. Combining different functional imaging methods facilitates precise diagnosis. The expression of somatostatin receptors helps to predict prognosis. Genetic analyses of mutations affecting death domain associated protein (DAXX), multiple endocrine neoplasia type 1 (MEN 1), alpha thalassemia/intellectual disability syndrome X-linked (ATRX), retinoblastoma transcriptional corepressor 1 (RB 1), and mothers against decapentaplegic homolog 4 (SMAD 4) help distinguishing grade 3 NENs from poorly differentiated NECs. The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.
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Affiliation(s)
- Meng Dai
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Christina S Mullins
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Lili Lu
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Guido Alsfasser
- Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Michael Linnebacher
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
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Anticancer Effect of Heparin-Taurocholate Conjugate on Orthotopically Induced Exocrine and Endocrine Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13225775. [PMID: 34830928 PMCID: PMC8616444 DOI: 10.3390/cancers13225775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/10/2021] [Accepted: 11/15/2021] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Pancreatic cancer has a less than 9% 5-year survival rate among patients because it is very difficult to detect and diagnose early. Combinatorial chemotherapy with surgery or radiotherapy is a potential remedy to treat pancreatic cancer. However, these strategies still have side effects such as hair loss, skin soreness and fatigue. To overcome these side effects, angiogenesis inhibitors such as sunitinib are used to deliver targeted blood vessels around tumor tissues, including pancreatic cancer tumors. It is still controversial whether antiangiogenesis therapy is sufficient to treat pancreatic cancer. So far, many scientists have not been focused on the tumor types of pancreatic cancer when they have developed antipancreatic cancer medication. Here, we used heparin–taurocholate (LHT) as an anticancer drug to treat pancreatic cancer through inhibition of angiogenic growth factors. In this study, we examined the anticancer efficacy of LHT on various types of pancreatic cancer in an orthotopic model. Abstract Pancreatic cancers are classified based on where they occur, and are grouped into those derived from exocrine and those derived from neuroendocrine tumors, thereby experiencing different anticancer effects under medication. Therefore, it is necessary to develop anticancer drugs that can inhibit both types. To this end, we developed a heparin–taurocholate conjugate, i.e., LHT, to suppress tumor growth via its antiangiogenic activity. Here, we conducted a study to determine the anticancer efficacy of LHT on pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET), in an orthotopic animal model. LHT reduced not only proliferation of cancer cells, but also attenuated the production of VEGF through ERK dephosphorylation. LHT effectively reduced the migration, invasion and tube formation of endothelial cells via dephosphorylation of VEGFR, ERK1/2, and FAK protein. Especially, these effects of LHT were much stronger on PNET (RINm cells) than PDAC (PANC1 and MIA PaCa-2 cells). Eventually, LHT reduced ~50% of the tumor weights and tumor volumes of all three cancer cells in the orthotopic model, via antiproliferation of cancer cells and antiangiogenesis of endothelial cells. Interestingly, LHT had a more dominant effect in the PNET-induced tumor model than in PDAC in vivo. Collectively, these findings demonstrated that LHT could be a potential antipancreatic cancer medication, regardless of pancreatic cancer types.
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Pinato DJ, Vallipuram A, Evans JS, Wong C, Zhang H, Brown M, Dina RE, Trivedi P, Akarca AU, Marafioti T, Mauri FA, Sharma R. Programmed Cell Death Ligand Expression Drives Immune Tolerogenesis across the Diverse Subtypes of Neuroendocrine Tumours. Neuroendocrinology 2021; 111:465-474. [PMID: 32097935 DOI: 10.1159/000506745] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/21/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION A comprehensive characterization of the tumour microenvironment is lacking in neuroendocrine tumours (NETs), where programmed cell death-1 receptor-ligand (PD-1/PD-L1) inhibitors are undergoing efficacy testing. OBJECTIVE We investigated drivers of cancer-related immunosuppression across NETs of various sites and grades using multi-parameter immunohistochemistry and targeted transcriptomic profiling. METHODS Tissue microarrays (n = 102) were stained for PD-L1 and 2 and indoleamine deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumour-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis. PD-L1 expression was tested in circulating tumour cells (CTCs, n = 12) to evaluate its relationship with metastatic dissemination. RESULTS PD-L1 expression was highest in lung NETs (n = 30, p = 0.007), whereas PD-L2 was highest in pancreatic NETs (n = 53, p < 0.001) with no correlation with grade or hypoxia/angiogenesis. PD-L1+ NETs (n = 26, 25%) had greater CD4+/FOXP3+ and CD8+/PD1+ TILs (p < 0.001) and necrosis (p = 0.02). CD4+/FOXP3+ infiltrate had the highest PD-L1/IDO-1 co-expressing tumours (p = 0.006). Grade 3 well-differentiated NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TIL density (p < 0.001), and NanoString immune profiling revealed enrichment of macrophage-related transcripts in cases with poorer prognosis. We identified PD-L1(+) CTC subpopulations in 75% of evaluated patients (n = 12). CONCLUSIONS PD-L1 expression correlates with T-cell exhaustion independent of tumour hypoxia and is enhanced in a subpopulation of CTCs, suggesting its relevance to the progression of NETs. These findings support a potential therapeutic role for PD-L1 inhibitors in a subset of NETs.
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Affiliation(s)
- David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom,
| | - Anu Vallipuram
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Joanne S Evans
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Clement Wong
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Hua Zhang
- Department of Medical Oncology, LC-4112, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Matthew Brown
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Roberto E Dina
- Department of Histopathology, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Pritesh Trivedi
- Department of Histopathology, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Ayse U Akarca
- Department of Histopathology, Rockefeller Building, University College London Hospital, London, United Kingdom
| | - Teresa Marafioti
- Department of Histopathology, Rockefeller Building, University College London Hospital, London, United Kingdom
| | - Francesco A Mauri
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
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9
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Shaurova T, Zhang L, Goodrich DW, Hershberger PA. Understanding Lineage Plasticity as a Path to Targeted Therapy Failure in EGFR-Mutant Non-small Cell Lung Cancer. Front Genet 2020; 11:281. [PMID: 32292420 PMCID: PMC7121227 DOI: 10.3389/fgene.2020.00281] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 03/09/2020] [Indexed: 12/19/2022] Open
Abstract
Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called “bypass activation”). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.
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Affiliation(s)
- Tatiana Shaurova
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Letian Zhang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - David W Goodrich
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Pamela A Hershberger
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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10
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Wang Z, Zhao Y, An Z, Li W. Molecular Links Between Angiogenesis and Neuroendocrine Phenotypes in Prostate Cancer Progression. Front Oncol 2020; 9:1491. [PMID: 32039001 PMCID: PMC6985539 DOI: 10.3389/fonc.2019.01491] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 12/11/2019] [Indexed: 12/11/2022] Open
Abstract
As a common therapy for prostate cancer, androgen deprivation therapy (ADT) is effective for the majority of patients. However, prolonged ADT promotes drug resistance and progression to an aggressive variant with reduced androgen receptor signaling, so called neuroendocrine prostate cancer (NEPC). Until present, NEPC is still poorly understood, and lethal with no effective treatments. Elevated expression of neuroendocrine related markers and increased angiogenesis are two prominent phenotypes of NEPC, and both of them are positively associated with cancers progression. However, direct molecular links between the two phenotypes in NEPC and their mechanisms remain largely unclear. Their elucidation should substantially expand our knowledge in NEPC. This knowledge, in turn, would facilitate the development of effective NEPC treatments. We recently showed that a single critical pathway regulates both ADT-enhanced angiogenesis and elevated expression of neuroendocrine markers. This pathway consists of CREB1, EZH2, and TSP1. Here, we seek new insights to identify molecules common to pathways promoting angiogenesis and neuroendocrine phenotypes in prostate cancer. To this end, our focus is to summarize the literature on proteins reported to regulate both neuroendocrine marker expression and angiogenesis as potential molecular links. These proteins, often described in separate biological contexts or diseases, include AURKA and AURKB, CHGA, CREB1, EZH2, FOXA2, GRK3, HIF1, IL-6, MYCN, ONECUT2, p53, RET, and RB1. We also present the current efforts in prostate cancer or other diseases to target some of these proteins, which warrants testing for NEPC, given the urgent unmet need in treating this aggressive variant of prostate cancer.
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Affiliation(s)
- Zheng Wang
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
| | - Yicheng Zhao
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
| | - Zhiqiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (GSBS), Houston, TX, United States
| | - Wenliang Li
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
- MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (GSBS), Houston, TX, United States
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Ren B, Rose JB, Liu Y, Jaskular-Sztul R, Contreras C, Beck A, Chen H. Heterogeneity of Vascular Endothelial Cells, De Novo Arteriogenesis and Therapeutic Implications in Pancreatic Neuroendocrine Tumors. J Clin Med 2019; 8:jcm8111980. [PMID: 31739580 PMCID: PMC6912347 DOI: 10.3390/jcm8111980] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023] Open
Abstract
Arteriogenesis supplies oxygen and nutrients in the tumor microenvironment (TME), which may play an important role in tumor growth and metastasis. Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic malignancy and are frequently metastatic on presentation. Nearly a third of pNETs secrete bioactive substances causing debilitating symptoms. Current treatment options for metastatic pNETs are limited. Importantly, these tumors are highly vascularized and heterogeneous neoplasms, in which the heterogeneity of vascular endothelial cells (ECs) and de novo arteriogenesis may be critical for their progression. Current anti-angiogenetic targeted treatments have not shown substantial clinical benefits, and they are poorly tolerated. This review article describes EC heterogeneity and heterogeneous tumor-associated ECs (TAECs) in the TME and emphasizes the concept of de novo arteriogenesis in the TME. The authors also emphasize the challenges of current antiangiogenic therapy in pNETs and discuss the potential of tumor arteriogenesis as a novel therapeutic target. Finally, the authors prospect the clinical potential of targeting the FoxO1-CD36-Notch pathway that is associated with both pNET progression and arteriogenesis and provide insights into the clinical implications of targeting plasticity of cancer stem cells (CSCs) and vascular niche, particularly the arteriolar niche within the TME in pNETs, which will also provide insights into other types of cancer, including breast cancer, lung cancer, and malignant melanoma.
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Affiliation(s)
- Bin Ren
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Nutrition & Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Diabetes Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Graduate Biomedical Science Program of the Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence:
| | - J. Bart Rose
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yehe Liu
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Renata Jaskular-Sztul
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Carlo Contreras
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Adam Beck
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
| | - Herbert Chen
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA; (J.B.R.); (R.J.-S.); (C.C.); (A.B.); (H.C.)
- O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Graduate Biomedical Science Program of the Graduate School, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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12
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Ferrari SM, Centanni M, Virili C, Miccoli M, Ferrari P, Ruffilli I, Ragusa F, Antonelli A, Fallahi P. Sunitinib in the Treatment of Thyroid Cancer. Curr Med Chem 2019; 26:963-972. [PMID: 28990511 DOI: 10.2174/0929867324666171006165942] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 07/17/2017] [Accepted: 08/09/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND Sunitinib (SU11248) is an oral multi-target tyrosine kinase inhibitor (TKI) with low molecular weight, that inhibits platelet-derived growth factor receptors (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs), c-KIT, fms-related tyrosine kinase 3 (FLT3) and RET. The concurrent inhibition of these pathways reduces tumor vascularization and causes cancer cell apoptosis, inducing a tumor shrinkage. Sunitinib is approved for the treatment of imatinib-resistant gastrointestinal stromal tumor (GIST), renal carcinoma, and pancreatic neuroendocrine tumors. METHODS We searched the literature on PubMed library. RESULTS In vitro studies showed that sunitinib targeted the cytosolic MEK/ERK and SAPK/JNK pathways in the RET/PTC1 cell inhibiting cell proliferation and causing stimulation of sodium/iodide symporter (NIS) gene expression in RET/PTC1 cells. Furthermore sunitinib is active in vitro and in vivo against anaplastic thyroid cancer (ATC) cells. Most of the clinical studies report that sunitinib is effective as first- and second-line TKI therapy in patients with advanced dedifferentiated thyroid cancer (DeTC), or medullary thyroid cancer (MTC). Sunitinib 37.5 mg/day is well tolerated, and effective. The most common adverse events include: reduction in blood cell counts (in particular leukocytes), hand-foot skin reaction, diarrhea, fatigue, nausea, hypertension, and musculoskeletal pain. CONCLUSION Even if sunitinib is promising in the therapy of differentiated thyroid carcinoma (DTC), until now no phase III studies have been published, and additional prospective researches are necessary in order to evaluate the real efficacy of sunitinib in aggressive thyroid cancer.
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Affiliation(s)
- Silvia Martina Ferrari
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy
| | - Marco Centanni
- Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Latina, Italy
| | - Camilla Virili
- Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Latina, Italy
| | - Mario Miccoli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy
| | - Paola Ferrari
- Department of Oncology, University of Pisa, Pisa, Italy
| | - Ilaria Ruffilli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy
| | - Francesca Ragusa
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy
| | - Poupak Fallahi
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy
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Capozzi M, De Divitiis C, Ottaiano A, von Arx C, Scala S, Tatangelo F, Delrio P, Tafuto S. Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment. Cancer Manag Res 2019; 11:3847-3860. [PMID: 31118801 PMCID: PMC6502442 DOI: 10.2147/cmar.s188316] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 02/28/2019] [Indexed: 12/13/2022] Open
Abstract
Lenvatinib is an emerging multi-kinase inhibitor with a preferential anti-angiogenic activity, which has shown efficacy in the treatment of renal cell carcinoma, differentiated thyroid cancer and hepatocellular carcinoma. It inhibits vascular endothelial growth factor receptor family (VEGFR1–3), fibroblast growth factor receptor family (FGFR1–4), platelet-derived growth factor receptor–alpha (PDGFRα), tyrosine-kinase receptor (KIT) and rearranged during transfection receptor (RET). In this review we have evaluated the development from bench to bedside of lenvatinib. PubMed, MEDLINE and clinicaltrials.gov are the sources of data. Furthermore, the preclinical in vitro and in vivo data, as well as efficacy and toxicity results of lenvatinib in the clinic, are presented and discussed. Treatment with lenvatinib causes side effects (hypertension, proteinuria, fatigue and diarrhea), which are predominantly related to the inhibition of angiogenesis. For these reasons, the identification of biomarkers of efficacy and resistance to lenvatinib is a key challenge in order to select responsive patients. This review provides an overview on lenvatinib's clinical use, perspectives and indications for future development.
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Affiliation(s)
- Monica Capozzi
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS - Fondazione "G. Pascale", Napoli, Italia
| | - Chiara De Divitiis
- UOSD Oncology- AOU "San Giovanni di Dio e Ruggi D'Aragona", Salerno, Italia
| | - Alessandro Ottaiano
- SSD Innovative Therapies for Abdominal Metastases - Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS - Fondazione "G. Pascale", Napoli, Italia
| | - Claudia von Arx
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Stefania Scala
- Molecular Immunology and Immunoregulation, Istituto Nazionale Tumori, IRCCS - Fondazione "G. Pascale", Napoli, Italia
| | - Fabiana Tatangelo
- Department of Pathology, Istituto Nazionale Tumori, IRCCS - Fondazione "G. Pascale", Napoli, Italia
| | - Paolo Delrio
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS - Fondazione "G. Pascale", Napoli, Italia
| | - Salvatore Tafuto
- Department of Abdominal Oncology, Istituto Nazionale Tumori, IRCCS - Fondazione "G. Pascale", Napoli, Italia
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14
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Angiogenesis in Pancreatic Cancer: Pre-Clinical and Clinical Studies. Cancers (Basel) 2019; 11:cancers11030381. [PMID: 30889903 PMCID: PMC6468440 DOI: 10.3390/cancers11030381] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/11/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis is a crucial event in tumor development and progression, occurring by different mechanisms and it is driven by pro- and anti-angiogenic molecules. Pancreatic cancer vascularization is characterized by a high microvascular density, impaired microvessel integrity and poor perfused vessels with heterogeneous distribution. In this review article, after a brief introduction on pancreatic cancer classification and on angiogenesis mechanisms involved in its progression, the pre-clinical and clinical trials conducted in pancreatic cancer treatment using anti-angiogenic inhibitors will be described. Finally, we will discuss the anti-angiogenic therapy paradox between the advantage to abolish vessel supply to block tumor growth and the disadvantage due to reduction of drug delivery at the same time. The purpose is to identify new anti-angiogenic molecules that may enhance treatment regimen.
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15
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Beyens M, Vandamme T, Peeters M, Van Camp G, Op de Beeck K. Resistance to targeted treatment of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer 2019; 26:R109-R130. [PMID: 32022503 DOI: 10.1530/erc-18-0420] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The mammalian target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling. The PI3K/Akt/mTOR pathway has a pivotal role in the oncogenesis of neuroendocrine tumors (NETs). In addition, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) drive angiogenesis in NETs and therefore contributes to neuroendocrine tumor development. Hence, mTOR and angiogenesis inhibitors have been developed. Everolimus, a first-generation mTOR inhibitor, has shown significant survival benefit in advanced gastroenteropancreatic NETs. Sunitinib, a pan-tyrosine kinase inhibitor that targets the VEGF receptor, has proven to increase progression-free survival in advanced pancreatic NETs. Nevertheless, primary and acquired resistance to rapalogs and sunitinib has limited the clinical benefit for NET patients. Despite the identification of multiple molecular mechanisms of resistance, no predictive biomarker has made it to the clinic. This review is focused on the mTOR signaling and angiogenesis in NET, the molecular mechanisms of primary and acquired resistance to everolimus and sunitinib and how to overcome this resistance by alternative drug compounds.
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Affiliation(s)
- Matthias Beyens
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
- Center for Oncological Research, University of Antwerp, Antwerp, Belgium
| | - Timon Vandamme
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
- Center for Oncological Research, University of Antwerp, Antwerp, Belgium
- Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Marc Peeters
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Guy Van Camp
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
- Center for Oncological Research, University of Antwerp, Antwerp, Belgium
| | - Ken Op de Beeck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
- Center for Oncological Research, University of Antwerp, Antwerp, Belgium
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16
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Wu S, Zhou J, Guo J, Hua Z, Li J, Wang Z. Apatinib inhibits tumor growth and angiogenesis in PNET models. Endocr Connect 2019; 8:8-19. [PMID: 30557852 PMCID: PMC6330719 DOI: 10.1530/ec-18-0397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022]
Abstract
Angiogenesis has a pivotal role in the growth and metastasis of pancreatic neuroendocrine tumors (PNETs). Apatinib inhibits angiogenesis as a highly selective KDR inhibitor and has been used to treat advanced gastric cancer and malignancies in clinical settings. However, the efficacy of apatinib in PNETs remains unclear. The aim of this study was to compare the antitumor efficacy of apatinib with that of the standard PNET drug sunitinib in our subcutaneous and liver metastasis models of insulinoma and non-functional PNET. Our results revealed that apatinib had a generally comparable or even superior antitumor effect to that of sunitinib on primary PNET, and it inhibited angiogenesis without directly causing tumor cell cytotoxicity. Apatinib inhibited the tumor in a dose-dependent manner, and the high dose was well tolerated in mice. We also found that the apatinib efficacy in liver metastasis models was cell-type (disease) selective. Although apatinib efficiently inhibited INR1G9-represented non-functional PNET liver metastasis, it led to the emergence of a hypoxic area in the INS-1-represented insulinoma and promoted liver metastasis. Our study demonstrated that apatinib has promise for clinical applications in certain malignant PNETs, and the application of anti-angiogenesis drugs to benign insulinomas may require careful consideration.
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Affiliation(s)
- Shan Wu
- College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, People’s Republic of China
- Research Center for Translational Medicine, Cancer Stem Cell Institute, East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Jianjun Zhou
- Research Center for Translational Medicine, Cancer Stem Cell Institute, East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Jing Guo
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China
| | - Zhan Hua
- Department of General Surgery, China-Japan Friendship Hospital, Beijing, People’s Republic of China
- Correspondence should be addressed to Z Hua, J Li or Z Wang: , or
| | - Jianchen Li
- College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, People’s Republic of China
- Correspondence should be addressed to Z Hua, J Li or Z Wang: , or
| | - Zai Wang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China
- Correspondence should be addressed to Z Hua, J Li or Z Wang: , or
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17
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Li S, Xu HX, Wu CT, Wang WQ, Jin W, Gao HL, Li H, Zhang SR, Xu JZ, Qi ZH, Ni QX, Yu XJ, Liu L. Angiogenesis in pancreatic cancer: current research status and clinical implications. Angiogenesis 2018; 22:15-36. [PMID: 30168025 DOI: 10.1007/s10456-018-9645-2] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 08/20/2018] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is one of the most lethal malignancies worldwide. Although the standard of care in pancreatic cancer has improved, prognoses for patients remain poor with a 5-year survival rate of < 5%. Angiogenesis, namely, the formation of new blood vessels from pre-existing vessels, is an important event in tumor growth and hematogenous metastasis. It is a dynamic and complex process involving multiple mechanisms and is regulated by various molecules. Inhibition of angiogenesis has been an established therapeutic strategy for many solid tumors. However, clinical outcomes are far from satisfying for pancreatic cancer patients receiving anti-angiogenic therapies. In this review, we summarize the current status of angiogenesis in pancreatic cancer research and explore the reasons for the poor efficacy of anti-angiogenic therapies, aiming to identify some potential therapeutic targets that may enhance the effectiveness of anti-angiogenic treatments.
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Affiliation(s)
- Shuo Li
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Hua-Xiang Xu
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Chun-Tao Wu
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Wen-Quan Wang
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Wei Jin
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - He-Li Gao
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Hao Li
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Shi-Rong Zhang
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Jin-Zhi Xu
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Zi-Hao Qi
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Quan-Xing Ni
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xian-Jun Yu
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Liang Liu
- Department of Pancreatic & Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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18
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Uri I, Grozinsky-Glasberg S. Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Clin Diabetes Endocrinol 2018; 4:16. [PMID: 30009041 PMCID: PMC6042326 DOI: 10.1186/s40842-018-0066-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022] Open
Abstract
Background Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP NETs). The only treatment that offers a cure is surgery, however most patients are diagnosed with metastatic disease, and curative surgery is usually not an option.Since the majority of patients are not candidate for curative surgery, they can be offered long-term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence based treatment options include somatostatin analogues, everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), peptide receptor radionuclide therapy (PRRT), chemotherapy, etc., alone or combined with cytoreductive procedures (surgery or liver directed procedures). However, there is an increasing need for novel therapies. Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. Following first line therapy with somatostatin analogues, there is no clear information to date indicating a preferred treatment sequence, and therefore the treatment approach should be individualized based on each NET patient characteristics. Conclusions NET patients are increasingly diagnosed throughout the world, usually with metastatic disease and requiring systemic therapy. We believe that each patient should be therefore thoroughly evaluated and individually discussed by a multidisciplinary and dedicated NET-expert team, updated with all treatment options including ongoing clinical trials, and before selecting the proper treatment sequence.
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Affiliation(s)
- Inbal Uri
- Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120 Jerusalem, Israel
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120 Jerusalem, Israel
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19
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Wei YL, Bai JA, He N, Tang QY. Tumor microenvironment of gastroenteropancreatic neuroendocrine neoplasms. Shijie Huaren Xiaohua Zazhi 2017; 25:2896-2905. [DOI: 10.11569/wcjd.v25.i32.2896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironment provides a unique environment for tumor development, where the biology behavior of tumor cells is regulated not only by their genetics but also by the surrounding environment. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) originating from the neuroendocrine cells of the gastroenteropancreatic system are characterized by a propensity to secrete a variety of peptide hormones and biogenic amines. The symptoms of GEP-NENs at early stages are often atypical, thus delaying the diagnosis. A further understanding of the pathobiology of GEP-NENs on the basis of studies on GEP-NENs tumor microenvironment can provide new evidence for clinical diagnosis and treatment. This review aims to introduce different cell types, several proteins involved in extracellular matrix remodeling, some growth factors, and chromogranin A (CgA) in the tumor microenvironment of GEP-NENs, in order to highlight their indispensable roles in GEP-NENs progression.
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Affiliation(s)
- Ya-Ling Wei
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Jian-An Bai
- Department of Gastroenterology, the Third Affiliated Hospital of Nanjing Medical University, Nanjing 211100, Jiangsu Province, China
| | - Na He
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Qi-Yun Tang
- Department of General Practice, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
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Uri I, Avniel-Polak S, Gross DJ, Grozinsky-Glasberg S. Update in the Therapy of Advanced Neuroendocrine Tumors. Curr Treat Options Oncol 2017; 18:72. [PMID: 29143892 DOI: 10.1007/s11864-017-0514-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OPINION STATEMENT Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP-NETs). The only treatment that offers a cure is surgery; however, most patients are diagnosed with metastatic disease, and curative surgery is usually not an option. These patients can be offered long-term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence-based treatment options include somatostatin analogs, everolimus (a mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), and peptide receptor radionuclide therapy, alone or combined with cytoreductive procedures (surgery or liver-directed procedures). Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. We believe that each patient should be thoroughly evaluated and their case discussed by a multidisciplinary team that is up-to-date with all treatment modalities including ongoing clinical trials, before selecting the proper treatment option.
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Affiliation(s)
- Inbal Uri
- Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120, Jerusalem, Israel
| | - Shani Avniel-Polak
- Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120, Jerusalem, Israel
| | - David J Gross
- Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120, Jerusalem, Israel
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, Endocrinology and Metabolism Department, Division of Medicine, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120, Jerusalem, Israel.
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21
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Segarra I, Modamio P, Fernández C, Mariño EL. Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees. Front Pharmacol 2017; 8:488. [PMID: 28785221 PMCID: PMC5519571 DOI: 10.3389/fphar.2017.00488] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 07/10/2017] [Indexed: 12/22/2022] Open
Abstract
The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug–drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies.
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Affiliation(s)
- Ignacio Segarra
- Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of BarcelonaBarcelona, Spain
| | - Pilar Modamio
- Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of BarcelonaBarcelona, Spain
| | - Cecilia Fernández
- Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of BarcelonaBarcelona, Spain
| | - Eduardo L Mariño
- Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of BarcelonaBarcelona, Spain
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Neuzillet C, de Mestier L, Rousseau B, Mir O, Hebbar M, Kocher HM, Ruszniewski P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours. Pharmacol Ther 2017; 181:49-75. [PMID: 28723416 DOI: 10.1016/j.pharmthera.2017.07.006] [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] [Indexed: 12/14/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom.
| | - Louis de Mestier
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Gastroenterology and Pancreatology, Beaujon University Hospital (AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Institut Mondor de Recherche Biomédicale, INSERM UMR955 Team 18, Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Olivier Mir
- Department of Cancer Medicine - Sarcoma Group, Department of Early Drug Development (DITEP) - Phase 1 Unit, Gustave Roussy Cancer Campus, University of Paris Sud, 114, Rue Edouard Vaillant, 94800 Villejuif, France
| | - Mohamed Hebbar
- Department of Medical Oncology, Lille University Hospital, 1, Rue Polonovski, 59037 Lille, France
| | - Hemant M Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom
| | - Philippe Ruszniewski
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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23
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A novel synthetic small molecule YF-452 inhibits tumor growth through antiangiogenesis by suppressing VEGF receptor 2 signaling. SCIENCE CHINA-LIFE SCIENCES 2017; 60:202-214. [PMID: 28194552 DOI: 10.1007/s11427-016-0369-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 12/26/2016] [Indexed: 12/18/2022]
Abstract
Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1,3,4,9-tetrahydro-β-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation of microvascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.
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Abstract
Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors including well differentiated pancreatic neuroendocrine tumors (pNETs) and neuroendocrine carcinomas (pNECs). The incidence of pNENs has increased over the past few decades. Although, the understanding and interest for this tumor have also increased significantly, the debate about classification and diagnosis continues. Although the primary treatment for pNENs is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pNENs. Although many therapeutic methods have proven effective, the choice of treatment and specific programs are still unclear. Our article presents an overview of pNENs, with a focus on their diagnostic work-up, clinical presentation and treatment options.
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Affiliation(s)
- Jian Sun
- Department of Hepatobiliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Address correspondence to: Dr. Jian Sun, Department of Biliopancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiangxi Road, Guangzhou 510120, China. E-mail:
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