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Corrias G, Lai E, Ziranu P, Mariani S, Donisi C, Liscia N, Saba G, Pretta A, Persano M, Fanni D, Spanu D, Balconi F, Loi F, Deidda S, Restivo A, Pusceddu V, Puzzoni M, Solinas C, Massa E, Madeddu C, Gerosa C, Zorcolo L, Faa G, Saba L, Scartozzi M. Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging. Cancers (Basel) 2024; 16:1364. [PMID: 38611042 PMCID: PMC11011199 DOI: 10.3390/cancers16071364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 03/24/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes.
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Affiliation(s)
- Giuseppe Corrias
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Eleonora Lai
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Pina Ziranu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Stefano Mariani
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Donisi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Nicole Liscia
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Giorgio Saba
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Andrea Pretta
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Mara Persano
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Daniela Fanni
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Dario Spanu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesca Balconi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Francesco Loi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Simona Deidda
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Angelo Restivo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Valeria Pusceddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Marco Puzzoni
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Cinzia Solinas
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Elena Massa
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clelia Madeddu
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
| | - Clara Gerosa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luigi Zorcolo
- Colorectal Surgery Unit, A.O.U. Cagliari, Department of Surgical Science, University of Cagliari, 09042 Cagliari, Italy; (S.D.); (A.R.); (L.Z.)
| | - Gavino Faa
- Division of Pathology, Department of Medical Sciences and Public Health, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy; (D.F.); (C.G.); (G.F.)
| | - Luca Saba
- Department of Radiology, University of Cagliari, 09042 Cagliari, Italy;
| | - Mario Scartozzi
- Medical Oncology Unit, University Hospital and University of Cagliari, 09042 Cagliari, Italy; (E.L.); (P.Z.); (S.M.); (C.D.); (G.S.); (A.P.); (M.P.); (D.S.); (F.B.); (F.L.); (V.P.); (M.P.); (C.S.); (E.M.); (C.M.); (M.S.)
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Liu Z, Kong Y, Dang Q, Weng S, Zheng Y, Ren Y, Lv J, Li N, Han Y, Han X. Liquid Biopsy in Pre-Metastatic Niche: From Molecular Mechanism to Clinical Application. Front Immunol 2022; 13:958360. [PMID: 35911705 PMCID: PMC9334814 DOI: 10.3389/fimmu.2022.958360] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Metastatic dissemination represents a hallmark of cancer that is responsible for the high mortality rate. Recently, emerging evidence demonstrates a time-series event—pre-metastatic niche (PMN) has a profound impact on cancer metastasis. Exosomes, cell-free DNA (cfDNA), circulating tumor cells (CTC), and tumor microenvironment components, as critical components in PMN establishment, could be monitored by liquid biopsy. Intensive studies based on the molecular profile of liquid biopsy have made it a viable alternative to tissue biopsy. Meanwhile, the complex molecular mechanism and intercellular interaction are great challenges for applying liquid biopsy in clinical practice. This article reviews the cellular and molecular components involved in the establishment of the PMN and the promotion of metastasis, as well as the mechanisms of their interactions. Better knowledge of the characteristics of the PMN may facilitate the application of liquid biopsy for clinical diagnosis, prognosis, and treatment.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Ying Kong
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qin Dang
- Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Youyang Zheng
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinxiang Lv
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Na Li
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yilin Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Interventional Institute of Zhengzhou University, Zhengzhou, China
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
- *Correspondence: Xinwei Han,
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Interleukin-6 as an enhancer of anti-angiogenic therapy for ovarian clear cell carcinoma. Sci Rep 2021; 11:7689. [PMID: 33833265 PMCID: PMC8032732 DOI: 10.1038/s41598-021-86913-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/16/2021] [Indexed: 11/08/2022] Open
Abstract
Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer (EOC) that is associated with elevated interleukin-6 (IL-6) expression, resistance to chemotherapy, and increased mortality. Although bevacizumab (Bev) is a widely used anti-angiogenic agent for EOC, the efficacy of Bev and the role of IL-6 in modulating angiogenesis in OCCC are unknown. We performed tube formation assays using human umbilical vein endothelial cells (HUVEC) cultured in OCCC cell-conditioned medium and using cells directly co-cultured with OCCC cells. We observed that IL-6 inhibition significantly mitigated the ability of Bev to impede tube formation in both cases. Furthermore, IL-6 blockade disrupted the anti-angiogenic efficacy of Bev and its concomitant anti-tumor activity. In addition, IL-6 inhibition resulted in a significant increase in angiopoietin-1 (Ang1) secretion and decreased vascular endothelial growth factor (VEGF) expression. Clinical specimens also exhibited this reciprocal relationship between IL-6 and Ang1 expression. Finally, depletion of Ang1 abrogated the effects of IL-6 inhibition on Bev activity, demonstrating that IL-6 supports the anti-angiogenic activity of Bev by suppressing Ang1 expression and promoting dependence on VEGF for angiogenesis. Altogether, our data suggest that OCCC tumors with high IL-6 levels are candidates for Bev therapy.
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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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Cozzolino M, Cocco S, Piezzo M, Celia G, Costantini S, Abate V, Capone F, Barberio D, Girelli L, Cavicchiolo E, Ascierto PA, Madonna G, Budillon A, De Laurentiis M. A Psychosocial Genomics Pilot Study in Oncology for Verifying Clinical, Inflammatory and Psychological Effects of Mind-Body Transformations-Therapy (MBT-T) in Breast Cancer Patients: Preliminary Results. J Clin Med 2021; 10:E136. [PMID: 33401546 PMCID: PMC7796278 DOI: 10.3390/jcm10010136] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 01/12/2023] Open
Abstract
Several studies have highlighted the key role of chronic inflammation in breast cancer development, progression, metastasis, and therapeutic outcome. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation. Recent findings suggest that positive psychosocial experiences, including psychotherapeutic interventions and therapeutic mind-body protocols, can modulate the inflammatory response by reducing the expression of genes/proteins associated with inflammation and stress-related pathways. Our preliminary results indicate that a specific mind-body therapy (MBT-T) could induce a significant reduction of the release of different cytokines and chemokines, such as SCGFβ, SDF-1α, MCP3, GROα, LIF, and IL-18, in the sera of breast cancer patients compared to a control group, suggesting that MBT-T could represent a promising approach to improve the wellness and outcome of breast cancer patients.
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Affiliation(s)
- Mauro Cozzolino
- Department of Human, Philosophical and Educational Sciences, University of Salerno, 84084 Fisciano (SA), Italy; (M.C.); (G.C.); (L.G.); (E.C.)
| | - Stefania Cocco
- Department of Breast and Thoracic Oncology, Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (S.C.); (M.P.)
| | - Michela Piezzo
- Department of Breast and Thoracic Oncology, Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (S.C.); (M.P.)
| | - Giovanna Celia
- Department of Human, Philosophical and Educational Sciences, University of Salerno, 84084 Fisciano (SA), Italy; (M.C.); (G.C.); (L.G.); (E.C.)
| | - Susan Costantini
- Experimental Pharmacology Unit—Mercogliano Laboratory, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (S.C.); (F.C.); (A.B.)
| | - Valentina Abate
- Psychology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (V.A.); (D.B.)
| | - Francesca Capone
- Experimental Pharmacology Unit—Mercogliano Laboratory, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (S.C.); (F.C.); (A.B.)
| | - Daniela Barberio
- Psychology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (V.A.); (D.B.)
| | - Laura Girelli
- Department of Human, Philosophical and Educational Sciences, University of Salerno, 84084 Fisciano (SA), Italy; (M.C.); (G.C.); (L.G.); (E.C.)
| | - Elisa Cavicchiolo
- Department of Human, Philosophical and Educational Sciences, University of Salerno, 84084 Fisciano (SA), Italy; (M.C.); (G.C.); (L.G.); (E.C.)
| | - Paolo Antonio Ascierto
- Department Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (P.A.A.); (G.M.)
| | - Gabriele Madonna
- Department Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (P.A.A.); (G.M.)
| | - Alfredo Budillon
- Experimental Pharmacology Unit—Mercogliano Laboratory, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (S.C.); (F.C.); (A.B.)
| | - Michelino De Laurentiis
- Department of Breast and Thoracic Oncology, Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy; (S.C.); (M.P.)
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Pączek S, Łukaszewicz-Zając M, Mroczko B. Chemokines-What Is Their Role in Colorectal Cancer? Cancer Control 2020; 27:1073274820903384. [PMID: 32103675 PMCID: PMC7066593 DOI: 10.1177/1073274820903384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death. It
is the second most frequently diagnosed malignancy in Europe and third
worldwide. Colorectal malignancies diagnosed at an early stage offer a promising
survival rate. However, advanced tumors often present distant metastases even
after the complete resection of a primary tumor. Therefore, novel biomarkers of
CRC are sorely needed in the diagnosis and prognosis of this common malignancy.
A family of chemokines are composed of small, secreted proteins. They are best
known for their ability to stimulate the migration of several cell types. Some
investigations have indicated that chemokines are involved in cancer
development, including CRC. This article presents current knowledge regarding
chemokines and their specific receptors in CRC progression. Moreover, the prime
aim of this review is to summarize the potential role of these proteins as
biomarkers in the diagnosis and prognosis of CRC.
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Affiliation(s)
- Sara Pączek
- Department of Biochemical Diagnostics, Medical University of Bialystok, Poland
| | | | - Barbara Mroczko
- Department of Biochemical Diagnostics, Medical University of Bialystok, Poland.,Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Poland
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Expression of pro-angiogenic factors as potential biomarkers in experimental models of colon cancer. J Cancer Res Clin Oncol 2020; 146:1427-1440. [PMID: 32300865 DOI: 10.1007/s00432-020-03186-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/14/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE RAS mutational status in colorectal cancer (CRC) represents a predictive biomarker of response to anti-EGFR therapy, but to date it cannot be considered an appropriate biomarker of response to anti-VEGF therapy. To elucidate the function of K-Ras in promoting angiogenesis, the effect of conditioned media from KRAS mutated and wild type colon cancer cell lines on HUVECs tubule formation ability and the correspondent production of pro-angiogenic factors have been evaluated by a specific ELISA assay. METHODS Ras-activated signaling pathways were compared by western blot analysis and RTq-PCR. In addition, VEGF, IL-8, bFGF and HIF-1α expression was determined in K-RAS silenced cells. Furthermore, we conducted an observational study in a cohort of RAS mutated metastatic CRC patients, treated with first-line bevacizumab-based regimens, evaluating VEGF-A and IL-8 plasma levels at baseline, and during treatment. RESULTS K-RAS promotes VEGF production by cancer cell lines. At the transcriptional level, this is reflected to a K-RAS dependent HIF-1α over-expression. Moreover, the HIF-1α, VEGF and FGF expression inhibition in KRAS knocked cells confirmed these results. Within the clinical part, no statistically significant correlation has been found between progression-free survival (PFS) and VEGF-A/IL-8 levels, but we cannot exclude that these biomarkers could be further investigated as predictive or prognostic biomarkers in this setting. CONCLUSION Our study confirmed the direct involvement of K-Ras in promoting angiogenesis into colon cancer cell lines.
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Bevacizumab-Based Chemotherapy Triggers Immunological Effects in Responding Multi-Treated Recurrent Ovarian Cancer Patients by Favoring the Recruitment of Effector T Cell Subsets. J Clin Med 2019; 8:jcm8030380. [PMID: 30889935 PMCID: PMC6462947 DOI: 10.3390/jcm8030380] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [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: 03/13/2019] [Indexed: 12/09/2022] Open
Abstract
Increasing evidence strongly suggests that bevacizumab compound impacts the immunological signature of cancer patients and normalizes tumor vasculature. This study aims to investigate the correlation between the clinical response to bevacizumab-based chemotherapy and the improvement of immune fitness of multi-treated ovarian cancer patients. Peripheral blood mononuclear cells (PBMCs) of 20 consecutive recurrent ovarian cancer patients retrospectively selected to have received bevacizumab or non-bevacizumab-based chemotherapy (Bev group and Ctrl group, respectively) were analyzed. CD4, CD8, and regulatory T cell (Treg) subsets were monitored at the beginning (T0) and after three and six cycles of treatment, together with IL10 production. A lower activated and resting Treg subset was found in the Bev group compared with the Ctrl group until the third therapy cycle, suggesting a reduced immunosuppressive signature. Indeed, clinically responding patients in the Bev group showed a high percentage of non-suppressive Treg and a significant lower IL10 production compared with non-responding patients in the Bev group after three cycles. Furthermore, clinically responding patients showed a discrete population of effector T cell at T0 independent of the therapeutic regimen. This subset was maintained throughout the therapy in only the Bev group. This study evidences that bevacizumab could affect the clinical response of cancer patients, reducing the percentage of Treg and sustaining the circulation of the effector T cells. Results also provide a first rationale regarding the positive immunologic synergism of combining bevacizumab with immunotherapy in multi-treated ovarian cancer patients.
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Napoletano C, Ruscito I, Bellati F, Zizzari IG, Rahimi H, Gasparri ML, Antonilli M, Panici PB, Rughetti A, Nuti M. Bevacizumab-Based Chemotherapy Triggers Immunological Effects in Responding Multi-Treated Recurrent Ovarian Cancer Patients by Favoring the Recruitment of Effector T Cell Subsets. J Clin Med 2019. [PMID: 30889935 DOI: 10.3390/jcm8030380] [] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Increasing evidence strongly suggests that bevacizumab compound impacts the immunological signature of cancer patients and normalizes tumor vasculature. This study aims to investigate the correlation between the clinical response to bevacizumab-based chemotherapy and the improvement of immune fitness of multi-treated ovarian cancer patients. Peripheral blood mononuclear cells (PBMCs) of 20 consecutive recurrent ovarian cancer patients retrospectively selected to have received bevacizumab or non-bevacizumab-based chemotherapy (Bev group and Ctrl group, respectively) were analyzed. CD4, CD8, and regulatory T cell (Treg) subsets were monitored at the beginning (T0) and after three and six cycles of treatment, together with IL10 production. A lower activated and resting Treg subset was found in the Bev group compared with the Ctrl group until the third therapy cycle, suggesting a reduced immunosuppressive signature. Indeed, clinically responding patients in the Bev group showed a high percentage of non-suppressive Treg and a significant lower IL10 production compared with non-responding patients in the Bev group after three cycles. Furthermore, clinically responding patients showed a discrete population of effector T cell at T0 independent of the therapeutic regimen. This subset was maintained throughout the therapy in only the Bev group. This study evidences that bevacizumab could affect the clinical response of cancer patients, reducing the percentage of Treg and sustaining the circulation of the effector T cells. Results also provide a first rationale regarding the positive immunologic synergism of combining bevacizumab with immunotherapy in multi-treated ovarian cancer patients.
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Affiliation(s)
- Chiara Napoletano
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
| | - Ilary Ruscito
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
- Tumor Bank Ovarian Cancer Network (TOC), Department of Gynecology, European Competence Center for Ovarian Cancer, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany.
| | - Filippo Bellati
- Department of Medical and Surgical Sciences and Translational Medicine, Sant'Andrea University Hospital, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy.
| | - Ilaria Grazia Zizzari
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
| | - Hassan Rahimi
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
| | - Maria Luisa Gasparri
- Department of Maternal and Child and Urological Sciences, Policlinico Umberto I "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Morena Antonilli
- Department of Maternal and Child and Urological Sciences, Policlinico Umberto I "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Pierluigi Benedetti Panici
- Department of Maternal and Child and Urological Sciences, Policlinico Umberto I "Sapienza" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
| | - Aurelia Rughetti
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
| | - Marianna Nuti
- Laboratory of Tumor Immunology and Cell Therapy, Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
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10
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Liang X, Li H, Coussy F, Callens C, Lerebours F. An update on biomarkers of potential benefit with bevacizumab for breast cancer treatment: Do we make progress? Chin J Cancer Res 2019; 31:586-600. [PMID: 31564802 PMCID: PMC6736652 DOI: 10.21147/j.issn.1000-9604.2019.04.03] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As the first monoclonal antibody against vascular endothelial growth factor (VEGF), bevacizumab (BEV) is a definitely controversial antiangiogenic therapy in breast cancer. The initial excitement over improvements in progression-free survival (PFS) with BEV was tempered by an absence of overall survival (OS) benefit and serious adverse effects. Missing targeted population urged us to identify the predictive biomarkers for BEV efficacy. In this review we focus on the research in breast cancer and provide recent investigations on clinical, radiological, molecular and gene profiling markers of BEV efficacy, including the new results from randomized phase III clinical trials evaluating the efficacy of BEV in combination with comprehensive biomarker analyses. Current evidences indicate some predictive values for genetic variants, molecular imaging, VEGF pathway factors or associated factors in peripheral blood and gene profiling. The current challenge is to validate those potential biomarkers and implement them into clinical practice.
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Affiliation(s)
- Xu Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.,Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris 75005, France
| | - Huiping Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Florence Coussy
- Department of Medical Oncology, Institut Curie, PSL Research University, Paris 75005, France
| | - Celine Callens
- Pharmacogenomic Unit, Department of Genetics, Curie Institute, PSL Research University, Paris 75005, France
| | - Florence Lerebours
- Department of Medical Oncology, Institut Curie, René Huguenin Hospital, Saint-Cloud 92210, France
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11
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Hagman H, Bendahl PO, Lidfeldt J, Belting M, Johnsson A. Protein array profiling of circulating angiogenesis-related factors during bevacizumab containing treatment in metastatic colorectal cancer. PLoS One 2018; 13:e0209838. [PMID: 30592740 PMCID: PMC6310295 DOI: 10.1371/journal.pone.0209838] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 12/12/2018] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Prolonged angiogenesis inhibition may improve treatment outcome in metastatic colorectal cancer (mCRC) patients. However, due to the complexity of the angiogenic pathways there is a lack of valid predictive biomarkers for anti-angiogenic agents. Here, we describe and optimize a procedure for simultaneous dynamic profiling of multiple angiogenesis related proteins in patient serum to explore associations with the response and acquired resistance to anti-angiogenic therapy. MATERIALS AND METHODS Patients (n=22) were selected from a clinical trial investigating maintenance treatment with bevacizumab alone after response to induction chemotherapy + bevacizumab in mCRC. Serum samples were analysed for 55 unique angiogenesis related proteins using a commercial proteome profiler array and a publicly available image analysis program for quantification. Samples were collected at baseline before induction treatment start, at start of maintenance treatment, and at end of treatment after tumour progression. MAIN RESULTS AND CONCLUSION For eight proteins, the antibody array signals were below detection range in all patient samples. None of the proteins showed levels at baseline or at start of maintenance with strong evidence for correlation to time to progression (lowest nominal p-value 0.03). The dynamic ranges of protein levels measured during the induction treatment period and during the maintenance period were analysed separately for time trends. Evidence for changing trends (up/down) in the levels of MMP-8, TIMP-4 and EGF was observed both during response to induction treatment and at progressive disease, respectively. For three of the proteins (IL-8, Activin A and IGFBP-2), weak evidence for correlation between increasing protein levels during induction with chemotherapy and bevacizumab and time to progression was observed. In conclusion, semi-quantitative profiling of angiogenesis related proteins in patient serum may be a versatile tool to screen for protein patterns aiming at identifying resistance mechanisms of anti-angiogenic treatment in patients with mCRC.
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Affiliation(s)
- Helga Hagman
- Department of Clinical Sciences Lund, Section of Oncology and Pathology, Lund University, Lund, Sweden
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Pär-Ola Bendahl
- Department of Clinical Sciences Lund, Section of Oncology and Pathology, Lund University, Lund, Sweden
| | - Jon Lidfeldt
- Department of Clinical Sciences Lund, Section of Oncology and Pathology, Lund University, Lund, Sweden
| | - Mattias Belting
- Department of Clinical Sciences Lund, Section of Oncology and Pathology, Lund University, Lund, Sweden
- Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Anders Johnsson
- Department of Clinical Sciences Lund, Section of Oncology and Pathology, Lund University, Lund, Sweden
- Department of Oncology, Skåne University Hospital, Lund, Sweden
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12
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Marisi G, Scarpi E, Passardi A, Nanni O, Pagan F, Valgiusti M, Casadei Gardini A, Neri LM, Frassineti GL, Amadori D, Ulivi P. IL-8 and thrombospondin-1 as prognostic markers in patients with metastatic colorectal cancer receiving bevacizumab. Cancer Manag Res 2018; 10:5659-5666. [PMID: 30532588 PMCID: PMC6241685 DOI: 10.2147/cmar.s181570] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Purpose Bevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer. Molecular predictors of B efficacy have still not been identified. We analyzed the role of 22 angiogenesis-associated proteins in patient outcome. Patients and methods Serum samples collected at baseline and at the first clinical evaluation were available for 58 patients enrolled in the randomized multicenter ITACa trial and who received CT+ B. Serum protein levels were determined using multiplex ELISA. Results Patients with baseline ≥145 pg/mL IL-8 showed shorter median progression-free survival and overall survival (OS) than those with lower levels (6.5 vs 6. 12.6 months; HR 7.39, P<0.0001 and 8.7 vs 28.8 months, HR 7.68, P<0.001, respectively). Moreover, patients with baseline thrombospondin-1 levels ≥12,000 ng/mL had a better median OS than those with lower levels (34.5 vs 13.1 months, HR 0.43, P=0.007). Patients with a ≥20% reduction in IL-8 levels from baseline to first clinical evaluation showed a better progression-free survival and OS than the others (HR 0.41, P=0.005 and HR 0.43, P=0.007, respectively). Conclusion Baseline IL-8 and thrombospondin-1 levels and reduced IL-8 during B treatment could represent potential prognostic markers in metastatic colorectal cancer.
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Affiliation(s)
- Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy,
| | - Emanuela Scarpi
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Oriana Nanni
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Flavia Pagan
- Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Martina Valgiusti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Luca Maria Neri
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44100, Italy
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Dino Amadori
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy,
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13
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Heras SCDL, Martínez-Balibrea E. CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer. World J Gastroenterol 2018; 24:4738-4749. [PMID: 30479461 PMCID: PMC6235799 DOI: 10.3748/wjg.v24.i42.4738] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/27/2018] [Accepted: 10/15/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women, worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates. In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines (CXCL1 to 17) are small (8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors (CXCR) 1 to 8. Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively. In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore, the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer. These pathways have been studied in tumor tissues (using immunohistochemistry or measuring mRNA levels) or serum [using enzyme-linked immuno sorbent assay (ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes the most recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/immunology
- Biomarkers, Tumor/metabolism
- Chemokines, CXC/antagonists & inhibitors
- Chemokines, CXC/immunology
- Chemokines, CXC/metabolism
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/immunology
- Colorectal Neoplasms/mortality
- Colorectal Neoplasms/pathology
- Humans
- Neoplasm Recurrence, Local/diagnosis
- Prognosis
- Receptors, CXCR/antagonists & inhibitors
- Receptors, CXCR/immunology
- Receptors, CXCR/metabolism
- Signal Transduction/drug effects
- Survival Rate
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Affiliation(s)
- Sara Cabrero-de las Heras
- Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Germans Trias i Pujol health research institute (IGTP), Badalona, Barcelona 08916, Catalunya, Spain
- Program of Predictive and Personalized Cancer Medicine (PMPPC), Germans Trias i Pujol health research institute (IGTP), Badalona, Barcelona 08916, Catalunya, Spain
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14
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Varol U, Yildiz I, Salman T, Karabulut B, Uslu R. Markers to Predict the Efficacy of Bevacizumab in the Treatment of Metastatic Colorectal Cancer. TUMORI JOURNAL 2018. [DOI: 10.1177/1636.17888] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Umut Varol
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Ibrahim Yildiz
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Tarik Salman
- Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir
| | - Bulent Karabulut
- Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey
| | - Ruchan Uslu
- Division of Medical Oncology, Tulay Aktas Oncology Hospital, School of Medicine, Ege University, Izmir, Turkey
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15
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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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16
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Di Salvatore M, Pietrantonio F, Orlandi A, Del Re M, Berenato R, Rossi E, Caporale M, Guarino D, Martinetti A, Basso M, Mennitto R, Santonocito C, Mennitto A, Schinzari G, Bossi I, Capoluongo E, Danesi R, de Braud F, Barone C. IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients. Oncotarget 2017; 8:16887-16898. [PMID: 28129643 PMCID: PMC5370008 DOI: 10.18632/oncotarget.14810] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 11/02/2016] [Indexed: 12/19/2022] Open
Abstract
Background Predictive biomarkers of efficacy and toxicity of bevacizumab have not yet been validated. This study assessed the influence of IL-8, eNOS and VEGF-A polymorphisms in RAS mutated metastatic colorectal cancer patients receiving bevacizumab-based chemotherapy. Methods 120 patients treated with first-line combination FOLFOX6 plus bevacizumab were included. A historical cohort of 112 RAS mutated colorectal cancer patients treated with FOLFOX6 alone served as control group. The following SNPs were analyzed: IL-8 c.-251T>A; eNOS c.-786T>C and c.-894G>T; VEGF-A c.936C>T, c.958T>C, c.1154A>G and c.2578C>A. Correlation of SNPs, baseline IL-8 serum levels and bevacizumab-efficacy was done. Results In the bevacizumab group, carriers of the IL-8 alleles c.-251TA+AA showed a shorter PFS (P=0.002) and OS (P=0.03) compared to TT alleles. Patients with pre-treatment IL-8 < 18.25 pg/ml showed significantly longer median PFS and OS (PFS: 10.9 vs 7.6 months, P=0.005; OS: 30.7 vs 18.2 months, P<0.001) compared to patients with IL-8 higher levels (>18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P<0.0001). Multivariate analysis confirmed association of IL-8 polymorphism with PFS, and of IL-8 baseline levels with both PFS and OS. IL-8 SNP did not affect the outcome in the control group. The eNOS polymorphism c.-894G>T was found associated with higher severe toxicity (P=0.0002) in patients carrying the c.-894TT genotype. Conclusions Although our data need prospective validation, IL-8 and eNOS SNPs may be have a role as predictive biomarkers for bevacizumab efficacy and toxicity.
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Affiliation(s)
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Armando Orlandi
- Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Marzia Del Re
- Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Rosa Berenato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Ernesto Rossi
- Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Marta Caporale
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Donatella Guarino
- Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Antonia Martinetti
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Michele Basso
- Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Roberta Mennitto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Concetta Santonocito
- Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Alessia Mennitto
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Giovanni Schinzari
- Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ilaria Bossi
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Ettore Capoluongo
- Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Romano Danesi
- Clinical Pharmacology and Pharmacogenetic Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Carlo Barone
- Unit of Clinical Oncology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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17
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Zuo X, Xu W, Xu M, Tian R, Moussalli MJ, Mao F, Zheng X, Wang J, Morris JS, Gagea M, Eng C, Kopetz S, Maru DM, Rashid A, Broaddus R, Wei D, Hung MC, Sood AK, Shureiqi I. Metastasis regulation by PPARD expression in cancer cells. JCI Insight 2017; 2:e91419. [PMID: 28097239 DOI: 10.1172/jci.insight.91419] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Peroxisome proliferator-activated receptor-δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer.
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Affiliation(s)
- Xiangsheng Zuo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Weiguo Xu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Surgical Oncology, Affiliated Hospital of Hebei United University, Tangshan, China
| | - Min Xu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Rui Tian
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Fei Mao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Jing Wang
- Department of Bioinformatics and Computational Biology
| | | | - Mihai Gagea
- Department of Veterinary Medicine and Surgery
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | | | | | | | | | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, and.,Department of Cancer Biology and.,Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Imad Shureiqi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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18
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Preclinical validation of the small molecule drug quininib as a novel therapeutic for colorectal cancer. Sci Rep 2016; 6:34523. [PMID: 27739445 PMCID: PMC5064353 DOI: 10.1038/srep34523] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 09/15/2016] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths. Molecularly targeted therapies (e.g. bevacizumab) have improved survival rates but drug resistance ultimately develops and newer therapies are required. We identified quininib as a small molecule drug with anti-angiogenic activity using in vitro, ex vivo and in vivo screening models. Quininib (2-[(E)-2-(Quinolin-2-yl) vinyl] phenol), is a small molecule drug (molecular weight 283.75 g/mol), which significantly inhibited blood vessel development in zebrafish embryos (p < 0.001). In vitro, quininib reduced endothelial tubule formation (p < 0.001), cell migration was unaffected by quininib and cell survival was reduced by quininib (p < 0.001). Using ex vivo human CRC explants, quininib significantly reduced the secretions of IL-6, IL-8, VEGF, ENA-78, GRO-α, TNF, IL-1β and MCP-1 ex vivo (all values p < 0.01). Quininib is well tolerated in mice when administered at 50 mg/kg intraperitoneally every 3 days and significantly reduced tumour growth of HT-29-luc2 CRC tumour xenografts compared to vehicle control. In addition, quininib reduced the signal from a αvβ3 integrin fluorescence probe in tumours 10 days after treatment initiation, indicative of angiogenic inhibition. Furthermore, quininib reduced the expression of angiogenic genes in xenografted tumours. Collectively, these findings support further development of quininib as a novel therapeutic agent for CRC.
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Eichten A, Su J, Adler AP, Zhang L, Ioffe E, Parveen AA, Yancopoulos GD, Rudge J, Lowy I, Lin HC, MacDonald D, Daly C, Duan X, Thurston G. Resistance to Anti-VEGF Therapy Mediated by Autocrine IL6/STAT3 Signaling and Overcome by IL6 Blockade. Cancer Res 2016; 76:2327-39. [PMID: 26921327 DOI: 10.1158/0008-5472.can-15-1443] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 12/29/2015] [Indexed: 11/16/2022]
Abstract
Anti-VEGF therapies benefit several cancer types, but drug resistance that limits therapeutic response can emerge. We generated cell lines from anti-VEGF-resistant tumor xenografts to investigate the mechanisms by which resistance develops. Of all tumor cells tested, only A431 (A431-V) epidermoid carcinoma cells developed partial resistance to the VEGF inhibitor aflibercept. Compared with the parental tumors, A431-V tumors secreted greater amounts of IL6 and exhibited higher levels of phospho-STAT3. Notably, combined blockade of IL6 receptor (IL6R) and VEGF resulted in enhanced activity against A431-V tumors. Similarly, inhibition of IL6R enhanced the antitumor effects of aflibercept in DU145 prostate tumor cells that displays high endogenous IL6R activity. In addition, post hoc stratification of data obtained from a clinical trial investigating aflibercept efficacy in ovarian cancer showed poorer survival in patients with high levels of circulating IL6. These results suggest that the activation of the IL6/STAT3 pathway in tumor cells may provide a survival advantage during anti-VEGF treatment, suggesting its utility as a source of response biomarkers and as a therapeutic target to heighten efficacious results. Cancer Res; 76(8); 2327-39. ©2016 AACR.
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Affiliation(s)
| | - Jia Su
- Regeneron Pharmaceuticals, Tarrytown, New York
| | | | - Li Zhang
- Regeneron Pharmaceuticals, Tarrytown, New York
| | - Ella Ioffe
- Regeneron Pharmaceuticals, Tarrytown, New York
| | | | | | - John Rudge
- Regeneron Pharmaceuticals, Tarrytown, New York
| | - Israel Lowy
- Regeneron Pharmaceuticals, Tarrytown, New York
| | | | | | | | - Xunbao Duan
- Regeneron Pharmaceuticals, Tarrytown, New York
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20
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Roy DN, Goswami R. Drugs of abuse and addiction: A slippery slope toward liver injury. Chem Biol Interact 2015; 255:92-105. [PMID: 26409324 DOI: 10.1016/j.cbi.2015.09.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 09/14/2015] [Accepted: 09/18/2015] [Indexed: 02/08/2023]
Abstract
Substances of abuse induce alteration in neurobehavioral symptoms, which can lead to simultaneous exacerbation of liver injury. The biochemical changes of liver are significantly observed in the abused group of people using illicit drugs or drugs that are abused. A huge amount of work has been carried out by scientists for validation experiments using animal models to assess hepatotoxicity in cases of drugs of abuse. The risk of hepatotoxicity from these psychostimulants has been determined by different research groups. Hepatotoxicity of these drugs has been recently highlighted and isolated case reports always have been documented in relation to misuse of the drugs. These drugs induce liver toxicity on acute or chronic dose dependent process, which ultimately lead to liver damage, acute fatty infiltration, cholestatic jaundice, liver granulomas, hepatitis, liver cirrhosis etc. Considering the importance of drug-induced hepatotoxicity as a major cause of liver damage, this review emphasizes on various drugs of abuse and addiction which induce hepatotoxicity along with their mechanism of liver damage in clinical aspect as well as in vitro and in vivo approach. However, the mechanisms of drug-induced hepatotoxicity is dependent on reactive metabolite formation via metabolism, modification of covalent bonding between cellular components with drug and its metabolites, reactive oxygen species generation inside and outside of hepatocytes, activation of signal transduction pathways that alter cell death or survival mechanism, and cellular mitochondrial damage, which leads to alteration in ATP generation have been notified here. Moreover, how the cytokines are modulated by these drugs has been mentioned here.
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Affiliation(s)
- Dijendra Nath Roy
- Department of Bio Engineering, National Institute of Technology (NIT)-Agartala, West Tripura, Tripura 799046, India.
| | - Ritobrata Goswami
- Institute of Life Sciences, Ahmedabad University, Ahmedabad 380009, Gujarat, India
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21
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Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting. Br J Cancer 2015; 113:1027-34. [PMID: 26355232 PMCID: PMC4651136 DOI: 10.1038/bjc.2015.329] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 07/27/2015] [Accepted: 08/04/2015] [Indexed: 12/20/2022] Open
Abstract
Background: Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC. Methods: Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs). Results: Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs. Conclusions: This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.
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22
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Di Salvatore M, Lo Giudice L, Rossi E, Santonocito C, Nazzicone G, Rodriquenz MG, Cappuccio S, Inno A, Fuso P, Orlandi A, Strippoli A, Capoluongo E, Astone A, Cassano A, Barone C. Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis. Clin Transl Oncol 2015; 18:40-6. [PMID: 26141413 DOI: 10.1007/s12094-015-1334-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Accepted: 06/20/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND The role of bevacizumab in metastatic breast cancer is controversial. Identification of predictive biomarkers could help to select patients who really benefit from it. We evaluated the association of angiogenesis-related gene polymorphisms with the treatment outcome of bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS eNOS-786T/C and -894G/T, IL-8-251T/A genomic polymorphisms were assessed in 31 metastatic breast cancer patients treated with bevacizumab plus chemotherapy in the first-line setting. Testing for association between each polymorphism and treatment outcome was performed. RESULTS Patients with IL-8 251 AA genotype showed a significantly lower progression-free survival in each combination comparison: "TT" vs "AA" (13 vs 8 months; p = 0.008); TT vs TA vs AA (13 vs 11 vs 8 months; p = 0.02); TT vs TA +AA (13 vs 11 months; p = 0.01); TT + TA vs AA (12 vs 8 months; p = 0.01) and a lower overall survival when compared with TT +TA genotype (26 vs 51 months, p = 0.04). Patients carrying eNOS 894 TT genotype showed a statistically significant lower progression-free survival than patients with GG genotype (11.5 vs 26.5 months; p = 0.04) with no differences in the overall survival. No association with response rate was found with any of the polymorphisms analyzed. CONCLUSION These findings suggest that IL-8 251T/A and eNOS-894 G/T polymorphisms might have a role in predicting treatment outcome of bevacizumab in metastatic breast cancer. Our results are hypothesis generating and need to be confirmed in larger clinical trials.
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Affiliation(s)
- M Di Salvatore
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy.
| | - L Lo Giudice
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - E Rossi
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - C Santonocito
- Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - G Nazzicone
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - M G Rodriquenz
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - S Cappuccio
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - A Inno
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy.,Medical Oncology, Sacro Cuore Don Calabria Hospital, Via Don A. Sempreboni 5, 37024, Negrar, VR, Italy
| | - P Fuso
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - A Orlandi
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - A Strippoli
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - E Capoluongo
- Laboratory of Clinical Molecular Biology, Institute of Biochemistry and Clinical Biochemistry, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - A Astone
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - A Cassano
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
| | - C Barone
- Unit of Clinical Oncology, Catholic University of the Sacred Heart, L.go F. Vito 1, 00168, Rome, Italy
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23
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Combining bevacizumab and chemoradiation in rectal cancer. Translational results of the AXEBeam trial. Br J Cancer 2015; 112:1314-25. [PMID: 25867261 PMCID: PMC4402460 DOI: 10.1038/bjc.2015.93] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 12/04/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Background: This study characterises molecular effect of bevacizumab, and explores the relation of molecular and genetic markers with response to bevacizumab combined with chemoradiotherapy (CRT). Methods: From a subset of 59 patients of 84 rectal cancer patients included in a phase II study combining bevacizumab with CRT, tumour and blood samples were collected before and during treatment, offering the possibility to evaluate changes induced by one dose of bevacizumab. We performed cDNA microarrays, stains for CD31/CD34 combined with α-SMA and CA-IX, as well as enzyme-linked immunosorbent assay (ELISA) for circulating angiogenic proteins. Markers were related with the pathological response of patients. Results: One dose of bevacizumab changed the expression of 14 genes and led to a significant decrease in microvessel density and in the proportion of pericyte-covered blood vessels, and a small but nonsignificant increase in hypoxia. Alterations in angiogenic processes after bevacizumab delivery were only detected in responding tumours. Lower PDGFA expression and PDGF-BB levels, less pericyte-covered blood vessels and higher CA-IX expression were found after bevacizumab treatment only in patients with pathological complete response. Conclusions: We could not support the ‘normalization hypothesis' and suggest a role for PDGFA, PDGF-BB, CA-IX and α-SMA. Validation in larger patient groups is needed.
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24
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Dirican A, Varol U, Kucukzeybek Y, Alacacioglu A, Erten C, Somali I, Can A, Demir L, Bayoglu IV, Akyol M, Yildiz Y, Koyuncu B, Coban E, Tarhan MO. Treatment of metastatic colorectal cancer with or without bevacizumab: can the neutrophil/lymphocyte ratio predict the efficiency of bevacizumab? Asian Pac J Cancer Prev 2015; 15:4781-6. [PMID: 24998541 DOI: 10.7314/apjcp.2014.15.12.4781] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The purpose of this study was to analyze the predictive value of neutrophil/lymphocyte ratio (NLR) to better clarify which patient groups will benefit the most from particular treatments like bevacizumab. MATERIALS AND METHODS A total of 245 treatment-naive metastatic colorectal cancern (mCRC) patients were retrospectively enrolled and divided into 2 groups: 145 group A patients were treated with chemotherapy in combination with bevacizumab, and 100 group B patients were treated as above without bevacizumab. RESULTS Group A patients had better median overall survival (OS) and progression-free survival (PFS) (24.0 and 9.0 months) than group B patients (20 and 6.0 months) (p=0.033; p=0.015). In patients with low NLR, OS and PFS were significantly longer in group A patients (27 vs 18 months, p=0.001; 11 vs 7 months, p=0.017). CONCLUSIONS We conclude that NLR, a basal cancer related inflammation marker, is associated with the resistance to bevacizumab- based treatments in mCRC patients.
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Affiliation(s)
- Ahmet Dirican
- Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey E-mail :
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Serum protein profiling reveals baseline and pharmacodynamic biomarker signatures associated with clinical outcome in mCRC patients treated with chemotherapy ± cediranib. Br J Cancer 2014; 111:1590-604. [PMID: 25121956 PMCID: PMC4200086 DOI: 10.1038/bjc.2014.436] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 06/10/2014] [Accepted: 07/09/2014] [Indexed: 02/07/2023] Open
Abstract
Background: This study evaluated soluble serum proteins as biomarkers to subset patients with metastatic colorectal cancer (mCRC) treated with chemotherapy±cediranib, a vascular endothelial growth factor (VEGF) signalling inhibitor (VEGFi). Exploring biomarkers at pre- and on-treatment may identify patient subgroups showing clinical benefit on cediranib combination. Methods: Two hundred and seven serum proteins were analysed in 588 mCRC patients at pre- and on-treatment with chemotherapy (FOLFOX/CAPOX)±cediranib 20 mg. Patients were enrolled in the phase III trial HORIZON II. We correlated baseline biomarker signatures and pharmacodynamic (PD) biomarkers with PFS and OS. Results: We identified a baseline signature (BS) of 47 biomarkers that included VEGFA, VEGFD, VEGFR2, VEGFR3 and TIE-2, which defined two distinct subgroups of patients. Patients treated with chemotherapy plus cediranib who had ‘high' BS had shorter PFS (HR=1.82, P=0.003) than patients with ‘low' BS. This BS did not correlate with PFS of the patients treated with chemotherapy plus placebo. In addition, we identified a profile of 16 PD proteins on treatment associated with PFS (HR=0.58, P<0.001) and OS (HR=0.52, P<0.001) in patients treated with chemotherapy plus cediranib. This PD profile did not correlate with PFS and OS in patients treated with chemotherapy plus placebo. Conclusions: Serum proteins may represent relevant biomarkers to predict the outcome of patients treated with VEGFi-based therapies. We report a BS and PD biomarkers that may identify mCRC patients showing increased benefit of combining cediranib with chemotherapy. These exploratory findings need to be validated in future prospective studies.
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26
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Aprile G, Lutrino SE, Ferrari L, Casagrande M, Bonotto M, Ongaro E, Puglisi F. Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients. World J Gastroenterol 2013; 19:8474-88. [PMID: 24379565 PMCID: PMC3870493 DOI: 10.3748/wjg.v19.i46.8474] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 11/13/2013] [Accepted: 12/03/2013] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a significant health problem, with around 1 million new cases and 500000 deaths every year worldwide. Over the last two decades, the use of novel therapies and more complex treatment strategies have contributed to progressively increase the median survival of patients with unresectable advanced CRC up to approximately 30 mo. The availability of additional therapeutic options, however, has created new challenges and generated more complicated treatment algorithms. Moreover, several clinically important points are still in debate in first-line, such as the optimal treatment intensity, the most appropriate maintenance strategy, the preferred biologic to be used upfront in patients with KRAS wild-type CRC, and the need for more detailed information on tumor biology. In this moving landscape, this review analyses why the first-line treatment decision is crucial and how the choice may impact on further treatment lines. In addition, it focuses on results of major phase III randomized trials.
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27
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Varol U, Oktay E, Yildirim M, Surmeli ZG, Dirican A, Meydan N, Karaca B, Karabulut B, Uslu R. Tumor characteristics and metastatic sites may predict bevacizumab efficacy in the first-line treatment of metastatic colorectal cancer. Mol Clin Oncol 2013; 2:166-170. [PMID: 24649328 DOI: 10.3892/mco.2013.212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 11/04/2013] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is among the most frequently diagnosed cancers and a major cause of cancer-related mortality worldwide. The aim of the present study was to determine whether there was an improvement in the time to disease progression (TTP) in patients with metastatic colorectal cancer (mCRC) treated with first-line bevacizumab plus chemotherapy, according to tumor characteristics and metastatic sites. Tumor characteristics and tumor burden were considered to be predictive markers of the therapeutic efficacy of bevacizumab. The medical records of 705 patients with mCRC were retrospectively reviewed in three oncology centers between January, 2005 and September, 2012. A total of 101 patients completed their first-line bevacizumab-containing treatment. The median TTP was 6.93 months [interquartile range (IQR)=4.20-9.80 months] in patients treated with irinotecan, 5-fluorouracil (5-FU) and bevacizumab vs. 7.42 months (IQR=6.08-10.68 months) in those treated with oxaliplatin, 5-FU and bevacizumab (P=0.589). When we compared patients with pulmonary metastases (median TTP, 9.9000 months) or other metastatic patients without pulmonary metastasis (median TTP, 6.9000 months), we observed a statistically significant difference (P=0.046). However, when the efficacy of bevacizumab was compared in terms of other tumor characteristics (tumor grade, size and lymph node involvement) and metastatic sites, the differences were not significant (P>0.05). We concluded that bevacizumab may be effective in all subgroups of patients with mCRC. Furthermore, bevacizumab with combination chemotherapy may be superior to combination chemotherapy only as the first-line treatment of patients with mCRC and pulmonary metastasis.
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Affiliation(s)
- Umut Varol
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Esin Oktay
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Adnan Menderes University, Aydın
| | - Mustafa Yildirim
- Department of Medical Oncology, Antalya Research and Training Hospital, Antalya
| | - Zeki Gokhan Surmeli
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Ahmet Dirican
- Department of Medical Oncology, Izmir Ataturk Research and Training Hospital, Bornova, Izmir, Turkey
| | - Nezih Meydan
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Adnan Menderes University, Aydın
| | - Burcak Karaca
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Bulent Karabulut
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
| | - Ruchan Uslu
- Department of Internal Medicine, Division of Medical Oncology, Faculty of Medicine, Ege University, Bornova, Izmir
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28
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Torino F, Sarmiento R, Gasparini G. The contribution of targeted therapy to the neoadjuvant chemoradiation of rectal cancer. Crit Rev Oncol Hematol 2013; 87:283-305. [DOI: 10.1016/j.critrevonc.2013.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 12/24/2012] [Accepted: 02/13/2013] [Indexed: 12/26/2022] Open
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29
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Shao YY, Hsu CH, Cheng AL. Predictive biomarkers of antiangiogenic therapy for advanced hepatocellular carcinoma: where are we? Liver Cancer 2013; 2:93-107. [PMID: 24159601 PMCID: PMC3740718 DOI: 10.1159/000343845] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Antiangiogenic therapy, especially treatment with sorafenib, is the primary treatment for patients with advanced hepatocellular carcinoma (HCC). However, the efficacy of such therapy is modest, with low objective response rates and limited prolongation of survival times. Several researchers have investigated predictive biomarkers to help identify patients who can benefit most from antiangiogenic therapy. The largest study on this topic to date was based on the pivotal phase III study of sorafenib (the SHARP study) and did not find any plasma markers that could predict the efficacy of sorafenib. Other studies based on single-arm phase II clinical trials found some potential predictive markers, such as early alpha-fetoprotein response, the serum insulin-like growth factor-1 level at baseline, and the volume transfer constants of dynamic contrast-enhanced magnetic resonance imaging. These findings require validation by further studies. Identifying predictive biomarkers of antiangiogenic therapy for HCC remains challenging and warrants further investigations.
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Affiliation(s)
- Yu-Yun Shao
- Departments of Oncology, National Taiwan University Hospital, Taiwan, ROC,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan, ROC
| | - Chih-Hung Hsu
- Departments of Oncology, National Taiwan University Hospital, Taiwan, ROC,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan, ROC
| | - Ann-Lii Cheng
- Departments of Oncology, National Taiwan University Hospital, Taiwan, ROC,Internal Medicine, National Taiwan University Hospital, Taiwan, ROC,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan, ROC,*Departments of Oncology and Internal Medicine, National Taiwan University Hospital,7 Chung-Shan South Road, Taipei, Taiwan 10002 (ROC), Tel. +886 2 23123456 ext. 67251, E-mail
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30
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Hagan S, Orr MCM, Doyle B. Targeted therapies in colorectal cancer-an integrative view by PPPM. EPMA J 2013; 4:3. [PMID: 23356214 PMCID: PMC3584939 DOI: 10.1186/1878-5085-4-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 12/26/2012] [Indexed: 12/12/2022]
Abstract
In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.
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Affiliation(s)
- Suzanne Hagan
- Department of Life Sciences Glasgow, Caledonian University, Glasgow, G4 0BA, UK
| | - Maria C M Orr
- Personalised Healthcare and Biomarkers, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
| | - Brendan Doyle
- Department of Histopathology, Trinity College, St. James's Hospital, Dublin, 8, Ireland
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31
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Antiangiogenic therapy of colorectal cancer: state of the art, challenges and new approaches. Int J Biol Markers 2012; 27:e286-94. [PMID: 23280126 DOI: 10.5301/jbm.2012.10441] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2012] [Indexed: 01/29/2023]
Abstract
Advanced colorectal cancer is the first tumor type for which an antiangiogenic agent, namely bevacizumab, has been approved by the Food and Drug Administration for therapy in humans; it has been in use since February 2004. This review paper summarizes and discusses the results obtained with this agent and highlights the main open or controversial issues on antiangiogenic therapy, taking into account that the clinical results obtained are below the expectations, particularly in the adjuvant setting.
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