High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma

Maréchal, Raphaël; Demetter, Pieter; Nagy, Nathalie; Berton, Alix; Decaestecker, Christine; Polus, Marc; Closset, Jean; Devière, Jacques; Salmon, Isabelle; Laethem, Jean‐Luc Van

doi:10.1038/sj.bjc.6605020

Cited by 156 publications

(145 citation statements)

References 32 publications

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“…Genes intimately involved in pancreatic carcinogenesis are another source of investigation, for example, SMAD4 (111). Likewise, proteins not linked directly to PDAC involvement are less rigorously studied, for example, CXCR4 (81).…”

Section: Discussionmentioning

confidence: 99%

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

Jamieson

Carter

McKay

et al. 2011

Clinical Cancer Research

114

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Purpose: The management of pancreatic ductal adenocarcinoma (PDAC) continues to present a great challenge particularly with regard to prediction of outcome following pancreaticoduodenectomy. Molecular markers have been extensively investigated by numerous groups with the aim of enhancing prognostication; however, despite hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the clinical course following resection of PDAC, at this time, no molecular marker assay forms part of recommended clinical practice.Experimental Design: We conducted a systematic review and meta-analysis of the published literature for immunohistochemistry-based biomarkers of PDAC outcome. A dual search strategy was applied to the PubMed database on January 6, 2010, to identify cohort studies that reported associations between immunohistochemical biomarker expression and survival outcomes in PDAC, and conformed to the REMARK (REporting recommendations for tumor MARKer prognostic studies) criteria.Results: A total of 103 distinct proteins met all inclusion criteria. Promising markers that emerged for the prediction of overall survival included BAX (HR ¼ 0.31, 95% CI: 0.71-0.56), Bcl-2 (HR ¼ 0.41, 95% CI: 0.27-0.63), survivin (HR ¼ 0.46, 95% CI: 0.29-0.73), Ki-67: (HR ¼ 2.42, 95% CI: 1.87-3.14), COX-2 (HR ¼ 1.39, 95% CI: 1.13-1.71), E-cadherin (HR ¼ 1.80, 95% CI: 1.33-2.42), and S100 calcium-binding proteins, in particular S100A2 (HR ¼ 3.23, 95% CI: 1.58-6.62).Conclusions: We noted that that there was incomplete adherence to the REMARK guidelines with inadequate methodology reporting as well as failure to perform multivariate analysis. Addressing the persistent incomplete adoption of these criteria may eventually result in the incorporation of molecular marker assessment within PDAC management algorithms. Clin Cancer Res; 17(10); 3316-31. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

Jamieson

Carter

McKay

et al. 2011

Clinical Cancer Research

114

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“…CXCR4 is a key chemokine receptor involved in many processes during tumorigenesis and critical for cancer dissemination (1,(5)(6)(7)(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

“…With its cognate ligand stromal cell-derived factor 1a (2,3), its main role in the hematopoietic system is to control stem cell retention and the homing of hematopoietic cells to the bone marrow (4). In addition to these physiologic roles, CXCR4 has been found to be overexpressed by various human cancers, including breast, lung, colon, and pancreatic cancer; melanoma; and hematopoietic malignancies such as multiple myeloma (1,(5)(6)(7)(8)(9)(10). Furthermore, a growing body of evidence shows that the CXCR4 stromal cell-derived factor 1a axis plays a crucial role in the mechanism of cancer and metastasis.…”

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confidence: 99%

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

et al. 2016

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CXCR4 is a chemokine receptor that is overexpressed in various human cancers and is involved in tumor metastasis. The aim of this proof-of-concept study was to evaluate a novel CXCR4-targeted PET probe in patients with solid cancers with reported in vitro evidence of CXCR4 overexpression and to estimate its potential diagnostic value. Methods: Twenty-one patients with histologically proven pancreatic cancer, laryngeal cancer, non-small cell lung cancer, prostate cancer, melanoma, breast cancer, hepatocellular carcinoma, glioblastoma, sarcoma, or cancer of unknown primary underwent PET imaging using the novel CXCR4 nuclear probe 68 Ga-pentixafor. The SUV max of the liver, spleen, and bone marrow was measured to determine physiologic tracer distribution. For evaluation of tracer accumulation in solid cancers, SUV max and tumor-tobackground (T/B) ratios were determined in a total of 43 malignant lesions, including 8 primary tumors, 3 locally recurrent tumors, and 32 metastases. When available, the SUV max of malignant lesions was compared with the corresponding SUV max measured in routine 18 F-FDG PET. Results: Moderate tracer accumulation was detectable in the liver, bone marrow, and spleen, with a mean SUV max of 3.1, 3.7, and 5.6, respectively. By visual interpretation criteria, 9 of 11 primary and locally recurrent tumors were detectable, exhibiting a mean SUV max of 4.7 (range, 2.1-10.9) and a mean T/B ratio of 2.9. Twenty of 32 evaluated metastases were visually detectable (mean SUV max , 4.5 [range, 3.2-13.8]; mean T/B ratio, 2.8). The highest signal was detected in a patient with non-small cell lung cancer (SUV max , 10.9; T/B ratio, 8.4) and a patient with cancer of unknown primary (SUV max , 13.8; T/B ratio, 8.1). Compared with 18 F-FDG PET, which was additionally performed in 10 patients, 68 Gapentixafor PET had a lower SUV max in all measured malignant lesions. Conclusion: On the basis of these first observations in a small and heterogeneous patient cohort, the in vitro CXCR4 expression profile of solid cancers and metastases described in the previous literature does not seem to sufficiently depict the in vivo distribution revealed by CXCR4-targeted PET. Moreover, the detectability of solid cancers seems to be generally lower for 68 Ga-pentixafor than for 18 F-FDG PET.

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“…In addition, this pathway is implicated in stimulating the metastatic process in multiple neoplasms (10). In clinical studies, CXCR4 has been associated with increased propensity for metastasis and decreased survival and was identified as a prognostic indicator for acute myeloid leukemia (AML), breast, colorectal, non-small cell lung, ovarian, and pancreatic carcinoma in which greater expression of CXCR4 correlates with disease severity (11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies

Kuhne

Mulvey

Belanger

et al. 2013

Clinical Cancer Research

195

152

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Purpose: CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its application for therapy of AML, non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and multiple myeloma.Experimental Design: Human transgenic mice were immunized with CXCR4-expressing cells, and antibodies reactive with CXCR4 were analyzed for apoptosis induction and ability to interfere with CXCL12-induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple myeloma xenograft tumors in severe combined immunodeficient mice.Results: BMS-936564/MDX-1338 is a fully human IgG 4 monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12-induced migration and calcium flux with low nanomolar EC 50 values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth inhibition.Conclusions: BMS-936564/MDX-1338 is a potent CXCR4 antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma.

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High expression of CXCR4 may predict poor survival in resected pancreatic adenocarcinoma

Cited by 156 publications

References 32 publications

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis In Vitro and Shows Antitumor Activity In Vivo in Hematologic Malignancies

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