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Chen X, Habib S, Alexandru M, Chauhan J, Evan T, Troka JM, Rahimi A, Esapa B, Tull TJ, Ng WZ, Fitzpatrick A, Wu Y, Geh JLC, Lloyd-Hughes H, Palhares LCGF, Adams R, Bax HJ, Whittaker S, Jacków-Malinowska J, Karagiannis SN. Chondroitin Sulfate Proteoglycan 4 (CSPG4) as an Emerging Target for Immunotherapy to Treat Melanoma. Cancers (Basel) 2024; 16:3260. [PMID: 39409881 PMCID: PMC11476251 DOI: 10.3390/cancers16193260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody-drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape.
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Affiliation(s)
- Xinyi Chen
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Shabana Habib
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Madalina Alexandru
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Jitesh Chauhan
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Theodore Evan
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Joanna M. Troka
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Avigail Rahimi
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Benjamina Esapa
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Thomas J. Tull
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Wen Zhe Ng
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Amanda Fitzpatrick
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
- Oncology Department, Guy’s and St Thomas’ Hospitals, London SE1 9RT, UK
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Innovation Hub, Guy’s Hospital, London SE1 9RT, UK
| | - Yin Wu
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Innovation Hub, Guy’s Hospital, London SE1 9RT, UK
- Peter Gorer Department of Immunobiology, Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King’s College London, London SE1 9RT, UK
| | - Jenny L. C. Geh
- St John’s Institute of Dermatology, Guy’s, King’s and St. Thomas’ Hospitals NHS Foundation Trust, London SE1 9RT, UK
- Department of Plastic Surgery, Guy’s, King’s and St. Thomas’ Hospitals, London SE1 9RT, UK
| | - Hawys Lloyd-Hughes
- Department of Plastic Surgery, Guy’s, King’s and St. Thomas’ Hospitals, London SE1 9RT, UK
| | - Lais C. G. F. Palhares
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Rebecca Adams
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Heather J. Bax
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Sean Whittaker
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Joanna Jacków-Malinowska
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
| | - Sophia N. Karagiannis
- St. John’s Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King’s College London, London SE1 9RT, UK (J.M.T.); (A.R.); (H.J.B.)
- Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King’s College London, Innovation Hub, Guy’s Hospital, London SE1 9RT, UK
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Bignucolo A, Scarabel L, Toffoli G, Cecchin E, De Mattia E. Predicting drug response and toxicity in metastatic colorectal cancer: the role of germline markers. Expert Rev Clin Pharmacol 2022; 15:689-713. [PMID: 35829762 DOI: 10.1080/17512433.2022.2101447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Despite the introduction of targeted agents leading to therapeutic advances, clinical management of patients with metastatic colorectal cancer (mCRC) is still challenged by significant interindividual variability in treatment outcomes, both in terms of toxicity and therapy efficacy. The study of germline genetic variants could help to personalize and optimize therapeutic approaches in mCRC. AREAS COVERED A systematic review of pharmacogenetic studies in mCRC patients published on PubMed between 2011 and 2021, evaluating the role of germline variants as predictive markers of toxicity and efficacy of drugs currently approved for treatment of mCRC, was perfomed. EXPERT OPINION Despite the large amount of pharmacogenetic data published to date, only a few genetic markers (i.e., DPYD and UGT1A1 variants) reached the clinical practice, mainly to prevent the toxic effects of chemotherapy. The large heterogeneity of available studies represents the major limitation in comparing results and identifying potential markers for clinical use, the role of which remains exploratory in most cases. However, the available published findings are an important starting point for future investigations. They highlighted new promising pharmacogenetic markers within the network of inflammatory and immune response signaling. In addition, the emerging role of previously overlooked rare variants has been pointed out.
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Affiliation(s)
- Alessia Bignucolo
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Lucia Scarabel
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Erika Cecchin
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
| | - Elena De Mattia
- Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, 33081 Aviano (PN), Italy
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Fixing the GAP: the role of RhoGAPs in cancer. Eur J Cell Biol 2022; 101:151209. [DOI: 10.1016/j.ejcb.2022.151209] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/29/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
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Majidpoor J, Mortezaee K. Angiogenesis as a hallmark of solid tumors - clinical perspectives. Cell Oncol (Dordr) 2021; 44:715-737. [PMID: 33835425 DOI: 10.1007/s13402-021-00602-3] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/04/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Angiogenesis is a key and early step in tumorigenesis, and is known as a hallmark of solid tumors and a key promoter of tumor recurrence. Unlike normal tissue vessels, the architecture of the tumor vasculature is abnormal, being leaky, tortuous, fragile and blind-ended. Perivascular cells are either detached or absent, causing reduction of vascular integrity, an increase in vessel immaturity, incoherent perfusion, defective functionality and enhanced tumor dissemination and metastasis. The abnormal tumor vasculature along with the defective tumor vessel functionality finally causes bouts of hypoxia and acidity in the tumor microenvironment (TME), further reinvigorating tumor aggression. Interstitial hypertension or high interstitial fluid pressure (IFP) is an outcome of tumor hyper-permeability. High IFP can be a barrier for either effective delivery of anti-cancer drugs toward the TME or accumulation of drugs within the tumor area, thus promoting tumor resistance to therapy. Some tumors do, however, not undergo angiogenesis but instead undergo vessel co-option or vascular mimicry, thereby adding another layer of complexity to cancer development and therapy. CONCLUSIONS Combination of anti-angiogenesis therapy with chemotherapy and particularly with immune checkpoint inhibitors (ICIs) is a promising strategy for a number of advanced cancers. Among the various approaches for targeting tumor angiogenesis, vascular normalization is considered as the most desired method, which allows effective penetration of chemotherapeutics into the tumor area, thus being an appropriate adjuvant to other cancer modalities.
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Affiliation(s)
- Jamal Majidpoor
- Department of Anatomy, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Keywan Mortezaee
- Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Tumor Microenvironment in Metastatic Colorectal Cancer: The Arbitrator in Patients' Outcome. Cancers (Basel) 2021; 13:cancers13051130. [PMID: 33800796 PMCID: PMC7961499 DOI: 10.3390/cancers13051130] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Colorectal cancer accounts for approximately 10% of all annually diagnosed cancers worldwide being liver metastasis, the most common cause of death in patients with colorectal cancer. The interplay between tumor and stromal cells in the primary tumor microenvironment and at distant metastases are rising in importance as potential mechanisms of the tumor progression. In this review we discuss the new biomarkers derived from tumor microenvironment and liquid biopsy as emerging prognostic and treatments response markers for metastatic colorectal cancer. We also review the developing new clinical strategies based on tumor microenvironmental cells to tackle metastatic disease in metastatic colorectal cancer patients. Abstract Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits.
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Fridman WH, Miller I, Sautès-Fridman C, Byrne AT. Therapeutic Targeting of the Colorectal Tumor Stroma. Gastroenterology 2020; 158:303-321. [PMID: 31622621 DOI: 10.1053/j.gastro.2019.09.045] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 09/05/2019] [Accepted: 09/08/2019] [Indexed: 02/07/2023]
Abstract
Colorectal tumors have been classified based on histologic factors, genetic factors, and consensus molecular subtypes, all of which affect the tumor microenvironment. Elements of the tumor microenvironment serve as therapeutic targets and might be used as prognostic factors. For example, immune checkpoint inhibitors are used to treat tumors with microsatellite instability, and anti-angiogenic agents may be used in combination with other drugs to slow or inhibit tumor growth. We review the features of the colorectal tumor stroma that are associated with patient outcomes and discuss potential therapeutic agents that target these features.
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Affiliation(s)
- Wolf H Fridman
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Inflammation, Complement and Cancer Team, Paris, France.
| | - Ian Miller
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Catherine Sautès-Fridman
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Inflammation, Complement and Cancer Team, Paris, France
| | - Annette T Byrne
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
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Džunić M, Pejčić B, Andjelković-Apostolović M, Vrbić S, Pejčić I, Petković I. PREDICTORS OF THERAPY RESPONSE AND EARLY RECURRENCE IN PATIENTS WITH POTENTIALLY RESECTABLE COLORECTAL LIVER METASTASES TREATED WITH BEVACIZUMAB AND FOLFOX4 AS A CONVERSION THERAPY. ACTA MEDICA MEDIANAE 2019. [DOI: 10.5633/amm.2019.0310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Zhuo YJ, Shi Y, Wu T. NRP-1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer. Oncol Lett 2019; 18:4629-4638. [PMID: 31611971 PMCID: PMC6781724 DOI: 10.3892/ol.2019.10842] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 08/01/2019] [Indexed: 12/24/2022] Open
Abstract
Neuropilin-1 (NRP-1), a member of the NRP-family, has been reported to be vital for tumor angiogenesis, growth and metastasis. As a co-receptor of vascular endothelial growth factor (VEGF), NRP-1 can bind to VEGF and meditate vascular development through the VEGF-VEGF receptor 2 (VEGFR2) signaling pathway. Furthermore, NRP-1 is capable of binding with platelet-derived growth factor (PDGF) to regulate the PDGF-PDGF receptor (PDGR) signaling pathway in tumor angiogenesis. In the present study, The DNA was obtained from the paraffin-embedded tissues of patients with advanced gastric cancer (AGC), amplified using PCR and subsequently sequenced to determine the polymorphisms within NRP-1, VEGFR2 [kinase insert domain receptor (KDR)] and PDGF. The effect of the functional polymorphism of the aforementioned genes on the overall survival (OS) and progression-free survival (PFS) of 81 patients with advanced gastric cancer was examined. Three single nucleotide polymorphisms (SNPs) of KDR were significantly associated with clinical outcomes. The rs1870377 TT genotype was positively associated with longer OS and PFS times compared with the AA+AT genotype (PFS, P=0.012; OS, P=0.038), the rs7692791 wild-type TT genotype was positively associated with longer PFS time and the rs2034965 AA+GA genotype was associated with shorter OS time (P=0.034). With regards to the SNPs of NRP-1, the rs2065364 AA genotype was significantly associated with improved OS and PFS times (PFS, P=0.023; OS, P=0.045). Following multivariate analysis using Cox proportional hazards regression models, patients with the KDR rs7692791 TT genotype experienced a longer PFS time compared with those with the CT genotype (P=0.016), and patients with the NRP-1 rs2065364 variant-type AA genotype still experienced a longer PFS time compared with those patients with the AG+GG genotypes (P=0.006). Regarding OS, the results demonstrated that the KDR rs2034965 AG+GG genotypes presented with a significant reduction in OS time (P=0.029), and that the KDR rs1870377 AT+AA genotypes had worse OS times compared with the wild-type TT genotype (P=0.021). In addition, increased mortality risk and AGC progression were significantly associated with the number of adverse alleles for combinations of NRP-1 rs2065364 and KDR rs1870377. In conclusion, the data from the present study demonstrated that the selected KDR and NRP-1 gene polymorphisms may be potential prognostic biomarkers in AGC.
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Affiliation(s)
- Yue-Jian Zhuo
- Department of Medical Oncology, The Second Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116000, P.R. China
| | - Yu Shi
- Department of Medical Oncology, The Second Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116000, P.R. China
| | - Tao Wu
- Department of Medical Oncology, The Second Hospital Affiliated to Dalian Medical University, Dalian, Liaoning 116000, P.R. China
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Sun J, Xu H, Qi M, Zhang C, Shi J. Identification of key genes in osteosarcoma by meta‑analysis of gene expression microarray. Mol Med Rep 2019; 20:3075-3084. [PMID: 31432118 PMCID: PMC6755242 DOI: 10.3892/mmr.2019.10543] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 06/17/2019] [Indexed: 12/17/2022] Open
Abstract
Osteosarcoma (OS) is one of the most malignant tumors in children and young adults. To better understand the underlying mechanism, five related datasets deposited in the Gene Expression Omnibus were included in the present study. The Bioconductor ‘limma’ package was used to identify differentially expressed genes (DEGs) and the ‘Weighted Gene Co-expression Network Analysis’ package was used to construct a weighted gene co-expression network to identify key modules and hub genes, associated with OS. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes overrepresentation analyses were used for functional annotation. The results indicated that 1,405 genes were dysregulated in OS, including 927 upregulated and 478 downregulated genes, when the cut off value was set at a ≥2 fold-change and an adjusted P-value of P<0.01 was used. Functional annotation of DEGs indicated that these genes were involved in the extracellular matrix (ECM) and that they function in several processes, including biological adhesion, ECM organization, cell migration and leukocyte migration. These findings suggested that dysregulation of the ECM shaped the tumor microenvironment and modulated the OS hallmark. Genes assigned to the yellow module were positively associated with OS and could contribute to the development of OS. In conclusion, the present study has identified several key genes that are potentially druggable genes or therapeutics targets in OS. Functional annotations revealed that the dysregulation of the ECM may contribute to OS development and, therefore, provided new insights to improve our understanding of the mechanisms underlying OS.
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Affiliation(s)
- Junkui Sun
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hongen Xu
- Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Muge Qi
- Henan Center for Disease Control and Prevention, Zhengzhou, Henan 450016, P.R. China
| | - Chi Zhang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jianxiang Shi
- Precision Medicine Center, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Cengiz C, Bulut S, Boyacioglu AS, Kuzu MA. Nerve/Glial Antigen 2: A Novel Target for Anti-Tumor Therapy in Colorectal Cancer. Digestion 2018; 96:60-66. [PMID: 28715802 DOI: 10.1159/000478853] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 06/19/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS To identify cell surface markers selectively expressed by tumor cells and tumor vasculature is the current goal for tumor therapy. One such marker is nerve/glial antigen 2 (NG2), which is a transmembrane glycoprotein. We aimed to investigate the expression of NG2 in colorectal cancer (CRC) and its association with clinicopathological parameters. METHODS Immunohistochemical staining of NG2, vascular endothelial growth factor, and CD34 in 65 patients diagnosed with CRC over a 5-year period was performed. NG2 expression in both tumor cells and tumor vasculature was scored according to the German Reactive Scoring System. The association between NG2 and patient and tumor characteristics was analyzed. RESULTS NG2 was expressed by tumor cells in 56.9%, tumor vasculature in 43%, and simultaneously by both in 27.6% of the cases. Tumor cell NG2 was more common in elderly patients (p = 0.023) and vascular NG2 was associated with better tumor differentiation (p = 0.035). Notably, vascular NG2 was expressed in half of the patients with left colon cancer, although it was not expressed in a majority of those with right colon cancer (50.9 vs. 17.7%, p = 0.041). CONCLUSION Both tumor cell and vascular NG2 expression were shown to be present in a significant number of patients with CRC and this makes NG2 a double target for anti-tumor therapies. Such therapies might be more effective for elderly patients with well-differentiated left colon cancer.
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Affiliation(s)
- Cem Cengiz
- Department of Gastroenterology, TOBB University of Economics and Technology, Ankara, Turkey
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Ma S, Pradeep S, Hu W, Zhang D, Coleman R, Sood A. The role of tumor microenvironment in resistance to anti-angiogenic therapy. F1000Res 2018; 7:326. [PMID: 29560266 PMCID: PMC5854986 DOI: 10.12688/f1000research.11771.1] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/08/2018] [Indexed: 12/11/2022] Open
Abstract
Anti-angiogenic therapy has been demonstrated to increase progression-free survival in patients with many different solid cancers. Unfortunately, the benefit in overall survival is modest and the rapid emergence of drug resistance is a significant clinical problem. Over the last decade, several mechanisms have been identified to decipher the emergence of resistance. There is a multitude of changes within the tumor microenvironment (TME) in response to anti-angiogenic therapy that offers new therapeutic opportunities. In this review, we compile results from contemporary studies related to adaptive changes in the TME in the development of resistance to anti-angiogenic therapy. These include preclinical models of emerging resistance, dynamic changes in hypoxia signaling and stromal cells during treatment, and novel strategies to overcome resistance by targeting the TME.
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Affiliation(s)
- Shaolin Ma
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Reproductive Medicine Research Center, Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong province, China
| | - Sunila Pradeep
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei Hu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dikai Zhang
- Reproductive Medicine Research Center, Department of Gynecology and Obstetrics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong province, China
| | - Robert Coleman
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anil Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Noonan SA, Morrissey ME, Martin P, Biniecka M, Ó'Meachair S, Maguire A, Tosetto M, Nolan B, Hyland J, Sheahan K, O'Donoghue D, Mulcahy H, Fennelly D, O'Sullivan J. Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment. Oncotarget 2018. [PMID: 29535825 PMCID: PMC5828217 DOI: 10.18632/oncotarget.24276] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort. Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA. This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS). In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.
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Affiliation(s)
- Sinead A Noonan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Maria E Morrissey
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
| | - Petra Martin
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Monika Biniecka
- Education and Research Centre, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Shane Ó'Meachair
- Centre for Health Decision Science (CHeDS), School of Computer Science and Statistics, Trinity College Dublin, Dublin, Ireland
| | - Aoife Maguire
- Department of Histopathology, St. James's Hospital, Dublin, Ireland
| | - Miriam Tosetto
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Blathnaid Nolan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - John Hyland
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Kieran Sheahan
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Diarmuid O'Donoghue
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Hugh Mulcahy
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - David Fennelly
- Centre for Colorectal Disease, St. Vincent's University Hospital, University College Dublin, Dublin, Ireland
| | - Jacintha O'Sullivan
- Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James's Hospital, Dublin, Ireland
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13
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Ilieva KM, Cheung A, Mele S, Chiaruttini G, Crescioli S, Griffin M, Nakamura M, Spicer JF, Tsoka S, Lacy KE, Tutt ANJ, Karagiannis SN. Chondroitin Sulfate Proteoglycan 4 and Its Potential As an Antibody Immunotherapy Target across Different Tumor Types. Front Immunol 2018; 8:1911. [PMID: 29375561 PMCID: PMC5767725 DOI: 10.3389/fimmu.2017.01911] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 12/14/2017] [Indexed: 12/18/2022] Open
Abstract
Overexpression of the chondroitin sulfate proteoglycan 4 (CSPG4) has been associated with the pathology of multiple types of such as melanoma, breast cancer, squamous cell carcinoma, mesothelioma, neuroblastoma, adult and pediatric sarcomas, and some hematological cancers. CSPG4 has been reported to exhibit a role in the growth and survival as well as in the spreading and metastasis of tumor cells. CSPG4 is overexpressed in several malignant diseases, while it is thought to have restricted and low expression in normal tissues. Thus, CSPG4 has become the target of numerous anticancer treatment approaches, including monoclonal antibody-based therapies. This study reviews key potential anti-CSPG4 antibody and immune-based therapies and examines their direct antiproliferative/metastatic and immune activating mechanisms of action.
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Affiliation(s)
- Kristina M Ilieva
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
| | - Anthony Cheung
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
| | - Silvia Mele
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom
| | - Giulia Chiaruttini
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom
| | - Silvia Crescioli
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom
| | - Merope Griffin
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom
| | - Mano Nakamura
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom.,Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom
| | - James F Spicer
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
| | - Sophia Tsoka
- Department of Informatics, Faculty of Natural and Mathematical Sciences, King's College London, London, United Kingdom
| | - Katie E Lacy
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom
| | - Andrew N J Tutt
- Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom.,Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, London, United Kingdom
| | - Sophia N Karagiannis
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Guy's Hospital, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
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14
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González-Vacarezza N, Alonso I, Arroyo G, Martínez J, De Andrés F, LLerena A, Estévez-Carrizo F. Predictive biomarkers candidates for patients with metastatic colorectal cancer treated with bevacizumab-containing regimen. Drug Metab Pers Ther 2017; 31:83-90. [PMID: 26974145 DOI: 10.1515/dmpt-2015-0027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 01/12/2016] [Indexed: 01/28/2023]
Abstract
Bevacizumab was the first molecular-targeted antiangiogenic therapy approved for the treatment of metastatic colorectal cancer. Until now, there are no predictive biomarkers available to decide the prescription of bevacizumab in patients with colorectal cancer. The purposes of this review were to provide a critical appraisal of the evidence and to identify possible predictive genetic biomarkers. A literature search was performed to identify studies that determine different levels of treatment response between patients stratified according to defined biomarkers. Interesting findings were reported between patients stratified according to rs3025039 and rs833061 polymorphisms of the gene VEGFA, with statistically and clinically significant differences for progression-free survival and overall survival. However, another study conducted in a larger sample does not confirm these previous findings, suggesting that well-designed prospective studies are still needed to achieve conclusive results. FLT1 (or VEGFR1) rs9513070 seems to be an interesting candidate as a predictive biomarker, with differences of more than 10 months in OS between different patients groups. In our opinion, possible interesting biomarker candidates for future research could be the polymorphisms rs833061 and rs3025039 of VEGF-A, rs9513070 or haplotype analysis of FLT1, rs2661280 of RGS5, rs444903 and rs6220 of EGF and Ang-2 or LDH plasma levels.
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15
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Aoyama T, Kashiwabara K, Oba K, Honda M, Sadahiro S, Hamada C, Maeda H, Mayanagi S, Kanda M, Sakamoto J, Saji S, Yoshikawa T. Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials. Cancer Med 2017; 6:2523-2530. [PMID: 28948714 PMCID: PMC5673952 DOI: 10.1002/cam4.1208] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/24/2017] [Accepted: 08/29/2017] [Indexed: 12/25/2022] Open
Abstract
The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020-1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.
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Affiliation(s)
- Toru Aoyama
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | | | - Koji Oba
- Department of Biostatistics, The University of Tokyo, Tokyo, Japan
| | - Michitaka Honda
- Department of Minimally Invasive Surgical and Medical Oncology, Fukushima Medical University, Fukushima, Japan
| | | | - Chikuma Hamada
- Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
| | - Hiromichi Maeda
- Cancer Treatment Center, Kochi Medical School Hospital, Kochi, Japan
| | - Shuhei Mayanagi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Junichi Sakamoto
- Tokai Central Hospital, Kakamigahara, Japan.,Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan
| | - Shigetoyo Saji
- Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
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16
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He WZ, Liao FX, Jiang C, Kong PF, Yin CX, Yang Q, Qiu HJ, Zhang B, Xia LP. Primary Tumor Location as a Predictive Factor for First-line Bevacizumab Effectiveness in Metastatic Colorectal Cancer Patients. J Cancer 2017; 8:388-394. [PMID: 28261339 PMCID: PMC5332889 DOI: 10.7150/jca.16804] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 10/13/2016] [Indexed: 12/27/2022] Open
Abstract
Background: Published papers reported contradictory results about the correlation between bevacizumab effectiveness and primary tumor location of metastatic colorectal cancer (mCRC). Methods: 740 mCRC patients treated with chemotherapy (CT group) and 244 patients treated with bevacizumab plus chemotherapy as first-line setting (CT + B group) were included. Propensity score analyses were used for patients' stratification and matching. Kaplan-Meier curves with log-rank tests were used to detect different overall survival (OS). Results: Patients in CT + B group had similar OS comparing with CT group only when the primary tumor located at right-side colon (20.2 for CT + B versus 19.7 months for CT group, p = 0.269). For left-side colon and rectal cancer patients, significantly longer OS were observed in CT + B than CT group. Conclusion: Our data suggested only patients with left-side colon or rectal cancer could get survival benefit from the addition of bevacizumab to first-line chemotherapy.
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Affiliation(s)
- Wen-Zhuo He
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Fang-Xin Liao
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Chang Jiang
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Peng-Fei Kong
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Chen-Xi Yin
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Qiong Yang
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Hui-Juan Qiu
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Bei Zhang
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
| | - Liang-Ping Xia
- VIP Region, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P. R. China
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17
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Sasaki K, Andreatos N, Margonis GA, He J, Weiss M, Johnston F, Wolfgang C, Antoniou E, Pikoulis E, Pawlik TM. The prognostic implications of primary colorectal tumor location on recurrence and overall survival in patients undergoing resection for colorectal liver metastasis. J Surg Oncol 2017; 114:803-809. [PMID: 27792291 DOI: 10.1002/jso.24425] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 08/12/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND OBJECTIVES The prognostic impact of primary colorectal cancer (CRC) location following resection of colorectal liver metastasis (CRLM) remains largely unknown. We sought to characterize the prognostic implications of primary tumor location among patients who underwent curative-intent hepatectomy for CRLM. METHODS Tumors of the cecum, ascending, and transverse colon were defined as right-sided; tumors of the sigmoid flexure, descending, and sigmoid colon were defined as left-sided. Clinicopathologic and long-term survival data were collected and assessed using univariable and multivariable analyses. RESULTS About 475 patients who underwent CRLM resection at a single institution were included; most patients had left-sided tumors (n = 284). Median and 5-year RFS was 20.2 months and 28.0%, respectively. Patients who had a left-sided primary tumor had a shorter RFS compared with patients who had a right-sided tumor (P = 0.01). Although site of and time to recurrence did not differ between the two groups (P > 0.05), patients with right-sided primary tumors were more likely to recur with advanced disease (i.e., ≥4 recurrent lesions) (P < 0.01). In turn, patients with right-sided tumors had both worse OS (P = 0.03) and worse survival after recurrence (P = 0.01). CONCLUSION While patients with right-sided tumors experienced longer RFS, when these patients did recur following CRLM resection, disease extent was more advanced. In turn, OS following recurrence was shorter among patients with right-sided CRC. J. Surg. Oncol. 2016;114:803-809. © 2016 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Kazunari Sasaki
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nikolaos Andreatos
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Georgios A Margonis
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jin He
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Matthew Weiss
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Fabian Johnston
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher Wolfgang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Efstathios Antoniou
- Second, Department of Propaedeutic Surgery, Laiko Hospital, University of Athens, Athens, Greece
| | - Emmanouil Pikoulis
- First Department of Surgery, Laiko Hospital, University of Athens, Athens, Greece
| | - Timothy M Pawlik
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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18
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Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0326-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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19
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Hanna DL, Lenz HJ. Novel therapeutics in metastatic colorectal cancer: molecular insights and pharmacogenomic implications. Expert Rev Clin Pharmacol 2016; 9:1091-108. [PMID: 27031164 PMCID: PMC7493705 DOI: 10.1586/17512433.2016.1172961] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Although the survival of metastatic colorectal cancer (mCRC) patients has improved five-fold over the last century, CRC remains a significant global health burden. Impressive strides have been made in identifying new regimens, employing maintenance strategies to limit treatment toxicities, and combining multidisciplinary approaches to achieve cure in oligometastatic disease. Attempts at personalized integration of targeted agents have been limited by the ability to identify molecularly enriched patient populations most likely to benefit. In this review, we discuss novel therapeutics and regimens recently approved and in development for mCRC. In addition, we discuss using older agents in novel combination and maintenance strategies, and highlight evidence for implementing pharmacogenomic data and non-invasive monitoring into the personalized management of mCRC patients.
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Affiliation(s)
- Diana L. Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- Hoag Family Cancer Institute, Newport Beach, CA, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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20
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Leuci V, Maione F, Rotolo R, Giraudo E, Sassi F, Migliardi G, Todorovic M, Gammaitoni L, Mesiano G, Giraudo L, Luraghi P, Leone F, Bussolino F, Grignani G, Aglietta M, Trusolino L, Bertotti A, Sangiolo D. Lenalidomide normalizes tumor vessels in colorectal cancer improving chemotherapy activity. J Transl Med 2016; 14:119. [PMID: 27149858 PMCID: PMC4857418 DOI: 10.1186/s12967-016-0872-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 04/20/2016] [Indexed: 12/19/2022] Open
Abstract
Background Angiogenesis inhibition is a promising approach for treating metastatic colorectal cancer (mCRC). Recent evidences support the seemingly counterintuitive ability of certain antiangiogenic drugs to promote normalization of residual tumor vessels with important clinical implications. Lenalidomide is an oral drug with immune-modulatory and anti-angiogenic activity against selected hematologic malignancies but as yet little is known regarding its effectiveness for solid tumors. The aim of this study was to determine whether lenalidomide can normalize colorectal cancer neo-vessels in vivo, thus reducing tumor hypoxia and improving the benefit of chemotherapy. Methods We set up a tumorgraft model with NOD/SCID mice implanted with a patient-derived colorectal cancer liver metastasis. The mice were treated with oral lenalidomide (50 mg/Kg/day for 28 days), intraperitoneal 5-fluorouracil (5FU) (20 mg/Kg twice weekly for 3 weeks), combination (combo) of lenalidomide and 5FU or irrelevant vehicle. We assessed tumor vessel density (CD146), pericyte coverage (NG2; alphaSMA), in vivo perfusion capability of residual vessels (lectin distribution essay), hypoxic areas (HP2-100 Hypoxyprobe) and antitumor activity in vivo and in vitro. Results Treatment with lenalidomide reduced tumor vessel density (p = 0.0001) and enhanced mature pericyte coverage of residual vessels (p = 0.002). Perfusion capability of tumor vessels was enhanced in mice treated with lenalidomide compared to controls (p = 0.004). Accordingly, lenalidomide reduced hypoxic tumor areas (p = 0.002) and enhanced the antitumor activity of 5FU in vivo. The combo treatment delayed tumor growth (p = 0.01) and significantly reduced the Ki67 index (p = 0.0002). Lenalidomide alone did not demonstrate antitumor activity compared to untreated controls in vivo or against 4 different mCRC cell lines in vitro. Conclusions We provide the first evidence of tumor vessel normalization and hypoxia reduction induced by lenalidomide in mCRC in vivo. This effect, seemingly counterintuitive for an antiangiogenic compound, translates into indirect antitumor activity thus enhancing the therapeutic index of chemotherapy. Our findings suggest that further research should be carried out on synergism between lenalidomide and conventional therapies for treating solid tumors that might benefit from tumor vasculature normalization.
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Affiliation(s)
- V Leuci
- Department of Oncology, University of Torino, Turin, Italy.,Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - F Maione
- Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - R Rotolo
- Department of Oncology, University of Torino, Turin, Italy.,Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - E Giraudo
- Laboratory of Transgenic Mouse Models, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy.,Department of Science and Drug Technology, University of Torino, Turin, Italy
| | - F Sassi
- Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - G Migliardi
- Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - M Todorovic
- Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - L Gammaitoni
- Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - G Mesiano
- Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - L Giraudo
- Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - P Luraghi
- Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - F Leone
- Department of Oncology, University of Torino, Turin, Italy.,Division and Laboratory of Medical Oncology, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - F Bussolino
- Department of Oncology, University of Torino, Turin, Italy.,Laboratory of Vascular Oncology, Candiolo Cancer Institute, Candiolo, Turin, Italy
| | - G Grignani
- Division and Laboratory of Medical Oncology, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - M Aglietta
- Department of Oncology, University of Torino, Turin, Italy.,Division and Laboratory of Medical Oncology, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - L Trusolino
- Department of Oncology, University of Torino, Turin, Italy.,Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - A Bertotti
- Department of Oncology, University of Torino, Turin, Italy.,Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy
| | - D Sangiolo
- Department of Oncology, University of Torino, Turin, Italy. .,Laboratory of Medical Oncology-Experimental Cell Therapy, Candiolo Cancer Institute-FPO- IRCCS, Candiolo, Turin, Italy.
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21
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Wong HL, Lee B, Field K, Lomax A, Tacey M, Shapiro J, McKendrick J, Zimet A, Yip D, Nott L, Jennens R, Richardson G, Tie J, Kosmider S, Parente P, Lim L, Cooray P, Tran B, Desai J, Wong R, Gibbs P. Impact of Primary Tumor Site on Bevacizumab Efficacy in Metastatic Colorectal Cancer. Clin Colorectal Cancer 2016; 15:e9-e15. [PMID: 26968236 DOI: 10.1016/j.clcc.2016.02.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 02/03/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for individual patients. While the prognostic impact of primary tumor site on colorectal cancer (CRC) outcomes is established, emerging data suggest potential differences in response to biologic therapies. We studied the impact of tumor site on bevacizumab efficacy in patients with metastatic CRC. PATIENTS AND METHODS We analyzed data of patients in an Australian prospective multicenter metastatic CRC (mCRC) registry who received first-line chemotherapy. Tumor site was defined as right colon, cecum to transverse; left colon, splenic flexure to rectosigmoid; and rectum. Kaplan-Meier and Cox models were used for survival analyses. RESULTS Of 926 patients, 297 had right colon, 354 left colon, and 275 rectum primary disease. Median age was 68.6, 65.9, and 63.3 years, respectively (P = .001). Right colon disease was significantly associated with intraperitoneal spread (P < .0001), while left colon and rectum disease preferentially metastasized to the liver and lungs, respectively (P < .0001 in both settings). A total of 636 patients (68.7%) received bevacizumab. Progression-free survival was superior for bevacizumab-treated patients in all groups but appeared greatest in right colon disease (hazard ratio, 0.46; 95% confidence interval, 0.36-0.60; P ≤ .001). Overall survival was longest in patients with disease of the rectum, followed by left colon and right colon (median, 26.2, 23.6, and 18.2 months, respectively; P = .0004). CONCLUSION Tumor site appears to be prognostic in mCRC, with rectum and right colon disease associated with the best and worst outcomes, respectively. Patients who received bevacizumab in addition to chemotherapy had superior outcomes, with the effect appearing greatest in patients with right colon disease.
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Affiliation(s)
- Hui-Li Wong
- Systems Biology and Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research (WEHI), Parkville, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia
| | - Belinda Lee
- Systems Biology and Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research (WEHI), Parkville, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.
| | - Kathryn Field
- Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia
| | - Anna Lomax
- Eastern Health, Department of Medical Oncology, Melbourne, Victoria, Australia
| | - Mark Tacey
- Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia; Department of Health Education and Research, Melbourne EpiCentre, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia
| | - Jeremy Shapiro
- Cabrini Health, Department of Oncology, Malvern, Melbourne, Victoria, Australia; Department of Medicine, Nursing & Health Sciences, Monash University, Parkville, Melbourne, Victoria, Australia
| | - Joe McKendrick
- Eastern Health, Department of Medical Oncology, Melbourne, Victoria, Australia
| | - Allan Zimet
- Department of Oncology, Epworth Hospital, Richmond, Victoria, Australia
| | - Desmond Yip
- Department of Medical Oncology, Canberra and Calvary Hospitals, Garran, Australian Capital Territory, Australia
| | - Louise Nott
- Department of Medical Oncology, Royal Hobart Hospital, Hobart, Tasmania, Australia
| | - Ross Jennens
- Department of Oncology, Epworth Hospital, Richmond, Victoria, Australia
| | - Gary Richardson
- Cabrini Health, Department of Oncology, Malvern, Melbourne, Victoria, Australia
| | - Jeanne Tie
- Systems Biology and Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research (WEHI), Parkville, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia; Western Health, Department of Medical Oncology, Footscray, Melbourne, Victoria, Australia
| | - Suzanne Kosmider
- Western Health, Department of Medical Oncology, Footscray, Melbourne, Victoria, Australia
| | - Phillip Parente
- Eastern Health, Department of Medical Oncology, Melbourne, Victoria, Australia
| | - Lionel Lim
- Eastern Health, Department of Medical Oncology, Melbourne, Victoria, Australia; Department of Oncology, Ringwood Private Hospital, Ringwood East, Victoria, Australia
| | - Prasad Cooray
- Eastern Health, Department of Medical Oncology, Melbourne, Victoria, Australia
| | - Ben Tran
- Systems Biology and Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research (WEHI), Parkville, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia
| | - Jayesh Desai
- Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia
| | - Rachel Wong
- Systems Biology and Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research (WEHI), Parkville, Melbourne, Australia; Eastern Health, Department of Medical Oncology, Melbourne, Victoria, Australia; Department of Medicine, Nursing & Health Sciences, Monash University, Parkville, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Systems Biology and Personalised Medicine Division, Walter & Eliza Hall Institute of Medical Research (WEHI), Parkville, Melbourne, Australia; Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Melbourne, Victoria, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia; Western Health, Department of Medical Oncology, Footscray, Melbourne, Victoria, Australia
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22
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Matsusaka S, Hanna DL, Cao S, Zhang W, Yang D, Ning Y, Sunakawa Y, Okazaki S, Berger MD, Miyamato Y, Parekh A, Stintzing S, Loupakis F, Lenz HJ. Prognostic Impact of IL6 Genetic Variants in Patients with Metastatic Colorectal Cancer Treated with Bevacizumab-Based Chemotherapy. Clin Cancer Res 2016; 22:3218-26. [PMID: 26839145 DOI: 10.1158/1078-0432.ccr-15-2422] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 01/19/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE The IL6/STAT3 axis promotes inflammation, angiogenesis, and cancer. The effect of genetic variants within this pathway on benefit from antiangiogenic cancer therapy is unknown. We tested whether SNPs in genes involved in IL6/STAT3 signaling can predict efficacy of bevacizumab-based chemotherapy in metastatic colorectal cancer (mCRC) patients. EXPERIMENTAL DESIGN Associations between potentially functional IL6 (rs2069837 and rs1800795) and STAT3 (rs744166 and rs4796793) SNPs and clinical outcomes [progression-free survival (PFS), overall survival, and tumor response rate] were evaluated in mCRC patients receiving first-line FOLFIRI plus bevacizumab in two randomized phase III trials: TRIBE (n = 223, training cohort) and FIRE-3 (n = 288, validation cohort). Patients receiving FOLFIRI plus cetuximab in FIRE-3 (n = 264) served as a control cohort. The interaction between genotype and primary tumor location with clinical outcomes was examined. Genomic DNA isolated from whole blood or tumor tissue was analyzed by PCR-based direct sequencing. RESULTS Patients with an IL6 rs2069837 G allele treated with FOLFIRI plus bevacizumab had an inferior PFS than those with the A/A genotype in TRIBE [9.4 vs. 11.1 months; HR = 1.53; 95% confidence interval (CI), 1.12-2.10; P = 0.004] and FIRE-3 (8.8 vs. 10.9 months; HR = 1.40; 95% CI, 1.06-1.85; P = 0.015). These associations were confirmed in multivariable analyses and were not seen in the control cohort. In subgroup analysis, the effect of IL6 rs2069837 on PFS was present only in patients with left-sided cancers, but the test for interaction was not significant. CONCLUSIONS IL6 rs2069837 genotype is a clinically relevant prognostic factor in mCRC patients treated with first-line bevacizumab-based chemotherapy. Clin Cancer Res; 22(13); 3218-26. ©2016 AACR.
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Affiliation(s)
- Satoshi Matsusaka
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Diana L Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Shu Cao
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Dongyun Yang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yan Ning
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yu Sunakawa
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Satoshi Okazaki
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Yuji Miyamato
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Anish Parekh
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Sebastian Stintzing
- Department of Hematology and Oncology, University of Munich, Munich, Germany
| | - Fotios Loupakis
- Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
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23
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Abstract
Recognition of the molecular heterogeneity of colorectal cancer (CRC) has led to the classification of CRC based on a variety of clinical and molecular characteristics. Although the clinical significance of the majority of these molecular alterations is still being ascertained, it is widely anticipated that these characteristics will improve the accuracy of our ability to determine the prognosis and therapeutic response of CRC patients. A few of these markers, such as microsatellite instability and the CpG island methylator phenotype (CIMP), show promise as predictive markers for cytotoxic chemotherapy. KRAS is a validated biomarker for epidermal growth factor receptor (EGFR)-targeted therapy, while NRAS and PI3KCA are evolving markers for targeted therapies. Multiple new actionable drug targets and potential response biomarkers are being identified on a regular basis, but most are not ready for clinical use at this time. This review focuses on key molecular features of CRCs and the application of these molecular alterations as predictive biomarkers for CRC.
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Shen H, Yang J, Huang Q, Jiang MJ, Tan YN, Fu JF, Zhu LZ, Fang XF, Yuan Y. Different treatment strategies and molecular features between right-sided and left-sided colon cancers. World J Gastroenterol 2015; 21:6470-6478. [PMID: 26074686 PMCID: PMC4458758 DOI: 10.3748/wjg.v21.i21.6470] [Citation(s) in RCA: 162] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/24/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
The colon is derived from the embryological midgut and hindgut separately, with the right colon and left colon having different features with regards to both anatomical and physiological characteristics. Cancers located in the right and left colon are referred to as right colon cancer (RCC) and left colon cancer (LCC), respectively, based on their apparent anatomical positions. Increasing evidence supports the notion that not only are there differences in treatment strategies when dealing with RCC and LCC, but molecular features also vary between them, not to mention the distinguishing clinical manifestations. Disease-free survival after radical surgery of both RCC and LCC are similar. In the treatment of RCC, the benefit gained from adjuvant FOLFIRI chemotherapy is superior, or at least similar, to LCC, but inferior to LCC if FOLFOX regimen is applied. On the other hand, metastatic LCC exhibits longer survival than that of RCC in a palliative chemotherapy setting. For KRAS wild-type cancers, LCC benefits more from cetuximab treatment than RCC. Moreover, advanced LCC shows a higher sensitivity to bevacizumab treatment in comparison with advanced RCC. Significant varieties exist at the molecular level between RCC and LCC, which may serve as the cause of all apparent differences. With respect to carcinogenesis mechanisms, RCC is associated with known gene types, such as MMR, KRAS, BRAF, and miRNA-31, while LCC is associated with CIN, p53, NRAS, miRNA-146a, miRNA-147b, and miRNA-1288. Regarding protein expression, RCC is related to GNAS, NQO1, telomerase activity, P-PDH, and annexin A10, while LCC is related to Topo I, TS, and EGFR. In addition, separated pathways dominate progression to relapse in RCC and LCC. Therefore, RCC and LCC should be regarded as two heterogeneous entities, with this heterogeneity being used to stratify patients in order for them to have the optimal, current, and novel therapeutic strategies in clinical practice. Additional research is needed to uncover further differences between RCC and LCC.
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25
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Ganss R. Keeping the Balance Right. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 133:93-121. [DOI: 10.1016/bs.pmbts.2015.02.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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