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Article ; Online: On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models.

Savel, Hélène / Barbier, Sandrine / Proust-Lima, Cécile / Rondeau, Virginie / Thiébaut, Rodolphe / Meyer-Losic, Florence / Richert, Laura

Cancer research communications

2023 Volume 3, Issue 1, Page(s) 140–147

Abstract: In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or ... ...

Abstract	In translational oncology research, the patient-derived xenograft (PDX) model and its use in mouse clinical trials (MCT) are increasingly described. This involves transplanting a human tumor into a mouse and studying its evolution during follow-up or until death. A MCT contains several PDXs in which several mice are randomized to different treatment arms. Our aim was to compare longitudinal modeling of tumor growth using mixed and joint models. Mixed and joint models were compared in a real MCT ( Significance: This work brings new arguments to a controversy on the correct choice of statistical modeling methods for the analysis of MCTs. We conclude that mixed models are more robust than joint models.
MeSH term(s)	Humans ; Animals ; Mice ; Heterografts ; Models, Statistical ; Computer Simulation ; Disease Models, Animal ; Neoplasms/drug therapy
Language	English
Publishing date	2023-01-26
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-22-0238
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Article ; Online: Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer.

Barbier, Sandrine / Beaufils, Benjamin / de Miguel, Ricardo / Reyre, Melissa / Le Meitour, Yannick / Lortie, Andreanne / de Boisferon, Marc Hillairet / Chaumeron, Sophie / Espirito, Anne / Fossati, Lina / Lagarde, Pauline / Klinz, Stephan / Thiagalingam, Arunthathi / Lezmi, Stéphane / Meyer-Losic, Florence

Oncology and therapy

2023 Volume 11, Issue 1, Page(s) 111–128

Abstract: Introduction: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal ...

Abstract	Introduction: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan. Methods: We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week. Results: Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively. Conclusion: This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer.
Language	English
Publishing date	2023-01-16
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2848647-X
ISSN	2366-1089 ; 2366-1070
ISSN (online)	2366-1089
ISSN	2366-1070
DOI	10.1007/s40487-022-00215-2
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Article: Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models.

Cancers

2021 Volume 13, Issue 10

Abstract: ... ...

Abstract	Purpose
Language	English
Publishing date	2021-05-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13102473
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Article ; Online: Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.

Nature

2015 Volume 523, Issue 7558, Page(s) 92–95

Abstract: The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure ... ...

Abstract	The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and β-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of β-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by β-catenin nuclear translocation after 15 days. As a consequence, increased expression of β-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic β-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.
MeSH term(s)	Active Transport, Cell Nucleus ; Animals ; Carcinogenesis/pathology ; Colonic Neoplasms/physiopathology ; Epithelial Cells/cytology ; Epithelial Cells/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Magnets ; Male ; Metal Nanoparticles ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Pressure ; Proto-Oncogene Proteins c-ret/metabolism ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Signal Transduction ; Tumor Microenvironment ; beta Catenin/genetics ; beta Catenin/metabolism
Chemical Substances	Receptors, Notch ; beta Catenin ; Proto-Oncogene Proteins c-ret (EC 2.7.10.1) ; Ret protein, mouse (EC 2.7.10.1)
Language	English
Publishing date	2015-07-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature14329
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans.

Martinez-Torres, Ana-Carolina / Quiney, Claire / Attout, Tarik / Boullet, Heloïse / Herbi, Linda / Vela, Laura / Barbier, Sandrine / Chateau, Danielle / Chapiro, Elise / Nguyen-Khac, Florence / Davi, Frédéric / Le Garff-Tavernier, Magali / Moumné, Roba / Sarfati, Marika / Karoyan, Philippe / Merle-Béral, Hélène / Launay, Pierre / Susin, Santos A

PLoS medicine

2015 Volume 12, Issue 3, Page(s) e1001796

Abstract: Background: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug ... ...

Abstract	Background: Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by the accumulation of abnormal CD5+ B lymphocytes, which results in a progressive failure of the immune system. Despite intense research efforts, drug resistance remains a major cause of treatment failure in CLL, particularly in patients with dysfunctional TP53. The objective of our work was to identify potential approaches that might overcome CLL drug refractoriness by examining the pro-apoptotic potential of targeting the cell surface receptor CD47 with serum-stable agonist peptides. Methods and findings: In peripheral blood samples collected from 80 patients with CLL with positive and adverse prognostic features, we performed in vitro genetic and molecular analyses that demonstrate that the targeting of CD47 with peptides derived from the C-terminal domain of thrombospondin-1 efficiently kills the malignant CLL B cells, including those from high-risk individuals with a dysfunctional TP53 gene, while sparing the normal T and B lymphocytes from the CLL patients. Further studies reveal that the differential response of normal B lymphocytes, collected from 20 healthy donors, and leukemic B cells to CD47 peptide targeting results from the sustained activation in CLL B cells of phospholipase C gamma-1 (PLCγ1), a protein that is significantly over-expressed in CLL. Once phosphorylated at tyrosine 783, PLCγ1 enables a Ca2+-mediated, caspase-independent programmed cell death (PCD) pathway that is not down-modulated by the lymphocyte microenvironment. Accordingly, down-regulation of PLCγ1 or pharmacological inhibition of PLCγ1 phosphorylation abolishes CD47-mediated killing. Additionally, in a CLL-xenograft model developed in NOD/scid gamma mice, we demonstrate that the injection of CD47 agonist peptides reduces tumor burden without inducing anemia or toxicity in blood, liver, or kidney. The limitations of our study are mainly linked to the affinity of the peptides targeting CD47, which might be improved to reach the standard requirements in drug development, and the lack of a CLL animal model that fully mimics the human disease. Conclusions: Our work provides substantial progress in (i) the development of serum-stable CD47 agonist peptides that are highly effective at inducing PCD in CLL, (ii) the understanding of the molecular events regulating a novel PCD pathway that overcomes CLL apoptotic avoidance, (iii) the identification of PLCγ1 as an over-expressed protein in CLL B cells, and (iv) the description of a novel peptide-based strategy against CLL.
MeSH term(s)	Aged ; Aged, 80 and over ; Animals ; Apoptosis/drug effects ; B-Lymphocytes/metabolism ; CD47 Antigen/metabolism ; Drug Resistance, Neoplasm ; Female ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/blood ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Male ; Mice ; Mice, Inbred NOD ; Middle Aged ; Peptides/pharmacology ; Peptides/therapeutic use ; Phospholipase C gamma/metabolism ; Thrombospondin 1/therapeutic use
Chemical Substances	CD47 Antigen ; Peptides ; Thrombospondin 1 ; Phospholipase C gamma (EC 3.1.4.3)
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2185925-5
ISSN	1549-1676 ; 1549-1277
ISSN (online)	1549-1676
ISSN	1549-1277
DOI	10.1371/journal.pmed.1001796
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Zs.A 6042: Show issues

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Article ; Online: Caspase-independent type III programmed cell death in chronic lymphocytic leukemia: the key role of the F-actin cytoskeleton.

Barbier, Sandrine / Chatre, Laurent / Bras, Marlène / Sancho, Patricia / Roué, Gaël / Virely, Clémence / Yuste, Victor J / Baudet, Sylvie / Rubio, Manuel / Esquerda, Josep E / Sarfati, Marika / Merle-Béral, Hélène / Susin, Santos A

Haematologica

2009 Volume 94, Issue 4, Page(s) 507–517

Abstract: Background: Programmed cell death has been traditionally related with caspase activation. However, it is now accepted that caspase-independent forms of programmed cell death also regulate cell death. In chronic lymphocytic leukemia, CD47 ligation ... ...

Abstract	Background: Programmed cell death has been traditionally related with caspase activation. However, it is now accepted that caspase-independent forms of programmed cell death also regulate cell death. In chronic lymphocytic leukemia, CD47 ligation induces one of these alternative forms of cell death: type III programmed cell death. This poorly understood process is characterized by cytoplasmic hallmarks, such as mitochondrial damage. To gain insights into the molecular pathways regulating type III programmed cell death in chronic lymphocytic leukemia, we performed extensive biochemical and cell biology assessments. Design and methods: After CD47 triggering, purified B-cells from 20 patients with chronic lymphocytic leukemia were studied by flow cytometry, immunofluorescence and three-dimensional imaging, immunoblotting, electron microscopy, and fibrillar/globular actin measurements. Finally, we subjected CD47-treated chronic lymphocytic leukemia cells to a phagocytosis assay. Results: We first confirmed that induction of type III programmed cell death is an efficient means of triggering cell death in chronic lymphocytic leukemia. Further, we demonstrated that the signaling events induced by CD47 ligation provoked a reduction in cell size. This alteration is related to F-actin disruption, as the two other cytoskeleton networks, microtubules and intermediate filaments, remain undisturbed in type III programmed cell death. Strikingly, we revealed that the pharmacological modulation of F-actin dynamics regulated this type of death. Finally, our data delineated a new programmed cell death pathway in chronic lymphocytic leukemia initiated by CD47 triggering, and followed by serine protease activation, F-actin rearrangement, mitochondrial damage, phosphatidylserine exposure, and cell clearance. Conclusions: Our work reveals a key molecular tool in the modulation of cell death in chronic lymphocytic leukemia: F-actin. By assessing the regulation of F-actin and type III programmed cell death, this analysis provides new options for destroying chronic lymphocytic leukemia cells, such as a combination of therapies based on apoptosis regulators (e.g., caspases, Bcl-2, Bax) along with alternative therapies based on type III death effectors (e.g., F-actin).
MeSH term(s)	Actins/metabolism ; Apoptosis/immunology ; B-Lymphocytes/pathology ; Caspases ; Cytoskeleton/immunology ; Cytoskeleton/pathology ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/immunology ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Tumor Cells, Cultured
Chemical Substances	Actins ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2009-03-10
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.13690
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Article: Drp1 mediates caspase-independent type III cell death in normal and leukemic cells.

Bras, Marlène / Yuste, Victor J / Roué, Gaël / Barbier, Sandrine / Sancho, Patricia / Virely, Clémence / Rubio, Manuel / Baudet, Sylvie / Esquerda, Josep E / Merle-Béral, Hélène / Sarfati, Marika / Susin, Santos A

Molecular and cellular biology

2007 Volume 27, Issue 20, Page(s) 7073–7088

Abstract: Ligation of CD47 triggers caspase-independent programmed cell death (PCD) in normal and leukemic cells. Here, we characterize the morphological and biochemical features of this type of death and show that it displays the hallmarks of type III PCD. A ... ...

Abstract	Ligation of CD47 triggers caspase-independent programmed cell death (PCD) in normal and leukemic cells. Here, we characterize the morphological and biochemical features of this type of death and show that it displays the hallmarks of type III PCD. A molecular and biochemical approach has led us to identify a key mediator of this type of death, dynamin-related protein 1 (Drp1). CD47 ligation induces Drp1 translocation from cytosol to mitochondria, a process controlled by chymotrypsin-like serine proteases. Once in mitochondria, Drp1 provokes an impairment of the mitochondrial electron transport chain, which results in dissipation of mitochondrial transmembrane potential, reactive oxygen species generation, and a drop in ATP levels. Surprisingly, neither the activation of the most representative proapoptotic members of the Bcl-2 family, such as Bax or Bak, nor the release of apoptogenic proteins AIF (apoptosis-inducing factor), cytochrome c, endonuclease G (EndoG), Omi/HtrA2, or Smac/DIABLO from mitochondria to cytosol is observed. Responsiveness of cells to CD47 ligation increases following Drp1 overexpression, while Drp1 downregulation confers resistance to CD47-mediated death. Importantly, in B-cell chronic lymphocytic leukemia cells, mRNA levels of Drp1 strongly correlate with death sensitivity. Thus, this previously unknown mechanism controlling caspase-independent type III PCD may provide the basis for novel therapeutic approaches to overcome apoptotic avoidance in malignant cells.
MeSH term(s)	Active Transport, Cell Nucleus/physiology ; CD47 Antigen/genetics ; CD47 Antigen/metabolism ; Caspases/metabolism ; Cell Death/physiology ; Cell Shape ; Cells, Cultured ; Electron Transport/physiology ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Humans ; Leukemia/metabolism ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Mitochondria/pathology ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Serine Endopeptidases/metabolism ; T-Lymphocytes/cytology ; T-Lymphocytes/physiology
Chemical Substances	CD47 Antigen ; CD47 protein, human ; Microtubule-Associated Proteins ; Mitochondrial Proteins ; Proto-Oncogene Proteins c-bcl-2 ; Serine Endopeptidases (EC 3.4.21.-) ; Caspases (EC 3.4.22.-) ; GTP Phosphohydrolases (EC 3.6.1.-) ; DNM1L protein, human (EC 3.6.5.5)
Language	English
Publishing date	2007-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.02116-06
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Article ; Online: On the Choice of Longitudinal Models for the Analysis of Antitumor Efficacy in Mouse Clinical Trials of Patient-derived Xenograft Models.

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Article ; Online: Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer.

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Article: Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models.

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Article ; Online: Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure.

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Article ; Online: CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans.

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Article ; Online: Caspase-independent type III programmed cell death in chronic lymphocytic leukemia: the key role of the F-actin cytoskeleton.

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Article: Drp1 mediates caspase-independent type III cell death in normal and leukemic cells.

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