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ANNUAL REPORT 2016 CANCER RESEARCH CENTER OF TOULOUSE
ANNUAL REPORT 2016
CANCER RESEARCH CENTER OF TOULOUSE
[1]
Annual Report 2016
Content Message from the Director ............................................................................. 3
Research teams .............................................................................................. 5
Team 1 – Antitumor immunity and immunotherapy .......................................................................... 6
Team 2 – Regulation of DNA Replication & Genetic Instability in Cancers ......................................... 8
Team 3 - Cellular signaling, oncogenesis and therapeutics .............................................................. 10
Team 4 - Sphingolipid metabolism, cell death & tumor progression ................................................ 12
Team 5 – RNA-binding proteins and post-transcriptional regulation in cancer ............................... 14
Team 6 – Protein Synthesis & Secretion in Oncogenesis .................................................................. 16
Team 7 – RNA biology in hematological cancers .............................................................................. 18
Team 8 – Cell cycle and cancer .......................................................................................................... 20
Team 9 – Therapeutic Innovations in B lymphomas ......................................................................... 22
Team 10 – Molecular heterogeneity of pancreatic tumors .............................................................. 24
Team 11 – Glioblastoma radioresistance: from signaling pathways to clinical trials ....................... 26
Team 12 – Cholesterol metabolism and therapeutic innovations .................................................... 28
Team 13 – Pharmacogenomics of multiple myeloma ....................................................................... 30
Team 14 - Dose individualization of anticancer drugs ...................................................................... 32
Team 15 – Multiscale dosimetry for radiotherapy optimization ...................................................... 34
Team 16 – Alteration of transcription factors in acute leukemias .................................................... 36
Team 17 - SIGDYN Group - PI3K isoforms, Signalling & Cancerogenesis .......................................... 38
Team 18 - RESISTAML – Drug resistance and oncometabolism in acute myeloid leukemia ............ 40
Core facilities ................................................................................................ 43
Technology Cluster of the CRCT ........................................................................................................ 44
Biological Resource Centre (BRC) ...................................................................................................... 46
Cytometry & Cell sorting ................................................................................................................... 46
Cell Imaging ....................................................................................................................................... 46
Monoclonal Antibodies ..................................................................................................................... 46
Genomics & Transcriptomics............................................................................................................. 47
Proteomics ......................................................................................................................................... 47
Gene transfer Vector ......................................................................................................................... 47
Post-graduate education programmes .......................................................... 49
[2]
Scientific and administrative staff ................................................................. 50
Flow chart .......................................................................................................................................... 50
CRCT administration .......................................................................................................................... 51
CRCT Resources ............................................................................................. 52
Scientific Advisory Board ............................................................................... 54
Scientific production ..................................................................................... 55
Publications in 2016 .......................................................................................................................... 56
Awards in 2016 .................................................................................................................................. 70
International symposium : Toulouse Onco Week 2016 (TOW 2016) ................................................ 70
Seminars held in the CRCT................................................................................................................. 71
[3]
Message from the Director
I am pleased to present the first activity report of the Cancer Research Center of Toulouse (CRCT) for 2016.
Five years after its creation and two years only after its establishment on the Oncopole site, the CRCT has seen its staff and team numbers rapidly growing. This report describes their activities and scientific production. The technological facilities have been gradually built and also enriched in order to give researchers an ever more efficient environment.
The CRCT is a new Center which is going to rise in importance in close relationship with the « Institut Universitaire du Cancer de Toulouse » and through the recruitment of new teams. The next years will allow the CRCT to gain international recognition.
I hope that this report will provide information about the CRCT to more people, induce numerous exchanges, and initiate successful collaborations with the scientific community.
I wish you a pleasant reading of this report.
Gilles Favre Director
[4]
[5]
Research teams
[6]
Objectives
Despite its efficacy across several malignancies, only a proportion of treated patients experience clinical benefit from immune checkpoint modulation monotherapy. In addition, a number of tumor types, while being immunogenic, do not respond to current immunotherapies. In order to understand the molecular and cellular mechanisms of tumors sensitivity/resistance to spontaneous or therapeutic immune responses, our studies are focused on: i) Deciphering the impact of tumor antigen-specific adaptive responses to tumor immune sensitivity through the assessment of T cell responses to neoantigens, oncoviral antigens and cancer testis antigens, of the mechanisms
underlying the immunogenicity of these antigen categories and of the evolution of tumor-specific T cell responses along immune checkpoint modulation therapy; ii) Investigating the contribution of the T cell response type (type 1/Th1/Tc1; type 2/th2; type 3/Th17; Treg) to anti-tumor immunity according to tumor histological type and anatomic location. The results of our studies have potential impact on the identification of clinically meaningful biomarkers of response to immunotherapy and on the development of combination therapies, in particular cancer vaccines associated to immune checkpoint modulation, which can enhance the extent of clinical responses to immunotherapy.
Keywords: Antitumor T cell response, CD4 T cell populations, immune checkpoint modulators, anticancer vaccines
Staff
Françoise Lauzéral-Vizcaino, Research associate Clara-Maria Scarlata, Research associate Jamila Elhmioui, Research assistant Alejandra Martinez, Hospital practitioner
PhD students Camille-Charlotte Balança Carlos Martinez Gomez
M2 Students Marie Michelas Victor Sarradin
Team 1 – Antitumor immunity and immunotherapy Decades-long efforts in tumor immunology research have recently
come to fruition with the clinical success of monoclonal antibodies
targeting immune checkpoints. These therapies have allowed, on
one hand, to confirm the central role of adaptive immunity in the
control of tumor growth and, on the other, to underline the
importance of immune regulatory mechanisms in the ability of
tumors to escape immune control. The aim of our research is to
decipher the molecular and cellular mechanisms underlying
tumors sensitivity/resistance to immunotherapy in order to design
combination therapies able to prevail over resistance.
Team Leader Maha Ayyoub
University Professor-Hospital practitioner, Faculty of Pharmacy -
IUCT
[7]
Highlights
We joined CRCT in 2017 to establish a new research team. Our research focus at CRCT is based on the team’s expertise in the analysis of tumor antigens specific T cells, the immune monitoring of patients receiving immunotherapy and the investigation of the development and plasticity of human CD4 T cell subsets (Figure).
Labels / Grants: Cancer Vaccine Collaborative Clinical Trials Network (Cancer Research
Institute/Ludwig Cancer Research); ImCore network of cancer immunotherapy centers of
excellence (Roche/Genentech).
Some publications in 2016 Zitvogel, L., M. Ayyoub, B. Routy, and G. Kroemer. Microbiome and anticancer immunosurveillance. Cell. 2016 Apr 7;165(2):276-87. Zitvogel, L., S. Rusakiewicz, B. Routy, M. Ayyoub, and G. Kroemer. Immunological off-target effects of the first precision drug, imatinib mesylate. Nat Rev Clin Oncol. 2016 Jul;13(7):431-46.
Jacquelot, N., M. P. Roberti, D. P. Enot, S. Rusakiewicz, M. Semeraro, S. Jégou, C. Flores, L. Chen, B. S. Kwon, C. Borg, B. Weide, F. Aubin, S. Dalle, H. Kohrt, M. Ayyoub, G. Kroemer, A. Marabelle, A. Cavalcanti, A. Eggermont, and L. Zitvogel. Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis. J Invest Dermatol. 2016 May; 136(5):994-1001.
Halabi N.M., A. Martinez, H. Al-Farsi, E. Mery, L. Puydenus, P. Pujol, H.G. Khalak, C. McLurcan, G. Ferron, D. Querleu, I. Al-Azwani, E. Al-Dous, Y.A. Mohamoud, J.A. Malek, and A. Rafii. Preferential Allele Expression Analysis Identifies Shared Germline and Somatic Driver Genes in Advanced Ovarian Cancer. PLoS Genet. 2016 Jan 6;12(1):e1005755.
[8]
Objectives
The team, by exploring these issues, have ultimately opened novel research lines. We have discovered that daughter cells can modify their own replication program to better ensure replication of DNA sequences that experienced problems in the previous cell cycle. This process may explain why a cancer cellular clone could sustain efficient DNA replication and cell proliferation despite a high degree of endogenous replicative stress and unstable genome, a major question that is still unsolved. Our research lines have also revealed a novel crosstalk pathway between replication and repair of damaged DNA, a process that could equip a malignant cellular clone with an escape mechanism in presence of chemotherapeutic treatments which target DNA replication forks
and exacerbate replicative stress and, hence, provoke therapeutic resistance. Our main objectives are (i) to study the mechanisms used by mother cells to limit the transmission of the replication problems, (ii) to monitor the fate of the transmitted damages in G1 daughter cells, (iii) to analyze a totally unexplored field, the impact of transmitted DNA damage on the DNA Replication initiation program, (iv) to explore the physiological and pathological relevance of the process of DNA damage transmission and its impact on DNA replication of daughter cells, and (v) to evaluate how these processes contribute to the therapeutic response of tumors treated with the multiple anticancer agents that impede the progression of the replication forks.
Keywords: Replicative stress, genetic instability, therapeutic resistance
Staff
Marie-Jeanne Pillaire, CR1 Inserm Valérie Bergoglio, CR1 CNRS Malik Lutzmann, CR1 CNRS Sophie Queille, Research assistant Guillaume Labrousse, Research associate
Postdoc fellows Rémy Bétous Alessandra Pellegrini Dana Hodroj
PhD students Elodie Bournique Marina Dal’Osto Lilas Courtot
Team 2 – Regulation of DNA Replication & Genetic Instability in Cancers The past decade has seen a dramatic advance in our
understanding of how genomic integrity is compromised in
cancer and has revealed that replicative stress (RS) in S phase,
which leads to chromosomal breakage and unresolved DNA, is a
highly relevant mechanism, placing RS studies at the forefront of
cancer research. Our team is exploring (i) how genetic,
environmental, and cell signaling sources can explain RS in
several types of cancers and (ii) how the transmission of
unresolved DNA regions to the next cell generation can be
essential for cancer progression and therapeutic resistance.
Team Leader Jean-Sébastien
Hoffmann DR1 Inserm
[9]
Highlights
Labels / Grants: Label Equipe LNCC ; LabEx TOUCAN Some publications in 2016 Garcia-Exposito L* Bournique E*, Bergoglio V*, Bose A, Barroso-Gonzalez J, Zhang S, Roncaioli JL, Lee M, Wallace CT, Watkins SC, Opresko PL, Hoffmann JS**, O'Sullivan RJ.**. Proteomic Profiling Reveals a Specific Role for Translesion DNA Polymerase η in the Alternative Lengthening of Telomeres. Cell Rep. 2016; 17(7):1858-71. T. Goullet de Rugy, M. Bashkurov, A. Datti, R. Betous, L. Guitton-Sert, C. Cazaux, D. Durocher and J. S. Hoffmann, Excess Polθ functions in response to replicative stress in homologous recombination-proficient cancer cells, Biology Open (2016) 5, 1485-92.
Mansilla SF, Bertolin AP, Bergoglio V, Pillaire MJ, González Besteiro MA, Luzzani C, Miriuka SG, Cazaux C, Hoffmann JS, Gottifredi V. Cyclin Kinase-independent role of p21CDKN1A in the promotion of nascent DNA elongation in unstressed cells. Elife. 2016 Oct 14;5. Grgurevic S, Berquet L, Quillet-Mary A, Laurent G, Récher C, Ysebaert L, Cazaux C, and Hoffmann JS*, 3R gene expression in chronic lymphocytic leukemia reveals the chromatin remodeling factor ASF1A as an independent prognostic marker of disease evolution, Blood Cancer Res. 2016, 6, e429; doi:10.1038/bcj.2016.39
David L*, Fernandez-Vidal A*, Bertoli S, Grgurevic S, Lepage B, Deshaies D, Prade N, Cartel M, Larrue C, Sarry JE, Delabesse E, Cazaux C, Didier C, Récher C**, Manenti S**, & Hoffmann JS**. CHK1 as a therapeutic target to bypass chemoresistance in AML. Science Signal. 2016;9(445). Bétous R, Renoud ML, Hoede C, Gonzalez I, Jones N, Longy M, Sensebé L, Cazaux C, & Hoffmann JS*. Human Adipose-Derived Stem Cells Expanded Under Ambient Oxygen Concentration Accumulate Oxidative DNA Lesions and Experience Procarcinogenic DNA Replication Stress. Stem Cells Transl Med. 2016 Aug 24.
Pol contributes to the replication of
telomeric sequences in human cells
CHK1 as a therapeutic target to bypass
chemoresistance to Cytarabine in AML
[10]
ObjectiveOur general aim is to understand molecular pathway abnormalities in cancer cells and to translate these laboratory results into the development of new therapeutic strategies. We focus first on the receptor tyrosine kinase (RTK)/RAS/MAPK and RHOGTPase pathways to understand their connections with the control of cell proliferation, survival and tumor progression, and to design new therapeutic strategies. Second, we study the signaling and repair mechanisms of DNA double-strand breaks (DSB) produced in transcribed regions in order to understand their role
in oncogenesis and resistance to targeted therapies. Team strengths in the leading-edge biotechnologies of GFP-based protein/protein interaction and nanobody-based biosensors contribute to the discovery of new biological and clinical findings. Expertise in signal transduction and DNA damage response pathway has contributed directly and indirectly to new concepts in the resistance to targeted therapies and new target discovery. In close collaboration with clinical departments, we develop translational and clinical research in lung cancers and melanoma.
Keywords: Oncogenic signaling, RTK/RAS/MAPK and RHOGTPase pathways, cell stress and double-strand break signaling, biotechnology, nanobodies, Split GFP, lung cancers, melanoma, translational research, biomarkers, clinical trials
Staff Researchers, clinicians Olivier Sordet Stéphanie Cabantous Aurélien Olichon Sylvie Monferran Isabelle Lajoie-Mazenc Anne Pradines Julien Mazières Nicolas Meyer
Laura Keller
Research associates
Claire Medale-Giamarchi Patrick Chinestra Post-doctoral fellows Olivier Calvayrac Julia Cherrier Faten Koraichi Claudine Tardy PhD students Laetita Mouly Sarah Figarol Magdalena Pohorecka Simona Salimbeni Technicians Catherine Bouchenot Anne Casanova Rémy Gence
Team 3 - Cellular signaling, oncogenesis and therapeutics
Cancer cells have deregulated signaling pathways that are
involved in cell proliferation, survival, and tumor progression.
Our team is working to better understand the molecular
mechanisms of these deregulations and to allow the
development of new cancer treatments by the transfer of our
findings to the clinic, in particular in lung cancers and melanoma.
Team Leader Gilles Favre
Professor
[11]
Highlights
Labels / Grants: ARC, Fondation de France, Ligue contre le cancer, IdEx, ANR
Some publications in 2016 DNA-PK triggers histone ubiquitination and signaling in response to DNA double-strand breaks produced during the repair of transcription-blocking topoisomerase I lesions. Cristini A et al. Nucleic Acids Res. 2016;44(3):1161-78. RhoB loss induces Rac1-dependent mesenchymal cell invasion in lung cells through PP2A inhibition. Bousquet E et al. Oncogene. 2016;35(14):1760-9. NaLi-H1: A universal synthetic library of humanized nanobodies providing highly functional antibodies and intrabodies. Moutel S et al. Elife. 2016;5.
RHOB expression controls the activity of serine/threonine protein phosphatase PP2A to modulate mesenchymal phenotype and invasion in non-small cell lung cancers. Calvayrac O et al. Small GTPases. 2016:1-6. Detection and Monitoring of the BRAF Mutation in Circulating Tumor Cells and Circulating Tumor DNA in BRAF-Mutated Lung Adenocarcinoma. Guibert N et al. J Thorac Oncol. 2016;11(9):e109-12. Identification of a circulating MicroRNA Profile as a Biomarker of Metastatic Cutaneous Melanoma. Armand-Labit V et al. Acta Derm Venereol. 2016;96(1) :29-34.
Dynamic effects of Topoisomerase I inhibition on R-Loops and short trans-cripts at active promoters. Marinello J et al. PLoS One. 2016;11(1):e0147053. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a rando-mised, controlled, open-label, phase 3 trial. Zalcman G et al. 2016. Lancet. 387:1405-14. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi FS et al. Lancet Oncol. 2016 ; 17(11):1558-68.
Emphasizing RHOB/PP2A/AKT/RAC1 signaling axis in lung cancer progression Metastatic dissemination is the cause of death in the vast majority of cancers including lung cancers. In order to metastasize tumor cells must undergo a well-known series of changes. However, the molecular details of how they manage to overcome the barriers at each stage remain incomplete. One critical step is acquiring the ability to migrate through the extracellular matrix. We previously demonstrated that loss of expression of the RAS-related small GTPase RHOB is a common feature of lung cancer progression. We report here that RHOB loss induces epithelial-to-mesenchymal transition (EMT) characterized by a 3-D cell shape reorganization and the increased invasiveness of bronchial cells. These effects depend on SLUG overexpression and E-Cadherin inhibition. RHOB loss maintains AKT1 activation which in turn activates RAC1 through its GEF TRIO. Further investigation revealed that RHOB interacts with and activates PP2A, one of the major serine-threonine phosphatases, by recruiting its regulatory subunit B55. Altogether, these results highlight a novel RHOB/PP2A/AKT1/RAC1 signaling axis and describe new molecular mechanisms that could explain the tumor suppressor role of RHOB in lung cancer.
Genomic instability by transcription-induced DNA double-strand breaks DNA double-strand breaks (DSBs) can cause genomic instability and contributes to the genesis of many human diseases including cancer. Although the majority of mammalian cells are non- or slow-replicating (stem cells, most cells in solid tumors…) the processes of the production and signaling of DSBs in the absence of replication are largely unknown. We previously reported that DSBs are generated in non-replicating cells when an ongoing transcription complex encounters a trapped topoisomerase I-DNA cleavage complex (Top1cc) onto chromatin. Top1cc trapping is a frequent event that results from a wide range of DNA alterations, as well as from genetic defects (e.g. ATM, TDP1) found in some tumors. Here we showed that transcription- and Top1-dependent DSBs are generated from single-strand DNA break intermediates generated during Top1cc removal by the TDP1 pathway. Analysis of DSB signaling further reveals a novel function of the kinase DNA-PK in promoting protein ubiquitination leading to enhancement of Top1cc removal in a feedback loop as well as to full ATM activity at DSB sites. Altogether, these findings provide new molecular insights on the genesis of genomic instability in non-replicating cells.
[12]
Objectives
Two main questions are addressed: - How SL metabolism controls melanoma cells and their microenvironment? The purpose of our project is triple: (i) The identification and role of variants in genes encoding enzymes of SL metabolism in familial melanoma; (ii) The delineation of the effects of the oncometabolite sphingosine 1-phosphate (S1P) and its receptors on the communication between melanoma cells and their cellular microenvironment during initial progression; (iii) The understanding of the molecular mechanisms underlying the role of SL metabolism in the resistance of melanoma cells to current therapies.
- How SL metabolism affects the anticancer immune response? We postulate that SL metabolism alterations in cancer cells modulate immune response, facilitating tumor escape from the immune system. We will investigate : (i) the levels of SL metabolites in plasma and tumors according to the tumor infiltration by leukocytes, (ii) the causal role of SL metabolism alterations in the immunogenicity of cancer cells and their responses to immune and death effector molecules, and (iii) the role of tumor SLs on tumor-infiltrating leukocytes in mouse models.
Staff Senior scientists Céline Colacios Joëlle Riond Frédérique Sabourdy Bruno Ségui
Technicians Stéphane Carpentier Patricia Clavé Marine Fraisse Virginie Garcia
Post-doctoral fellows Florie Bertrand Anne Montfort Alexandre Ghenassia (recruited in 2017)
PhD students Leonardo Astudillo* Fatima Bilal David Garandeau* Caroline Imbert Marguerite Mrad* Michaël Peres Justine Noujarède Maxime Sahun *PhD defended in 2016
Team 4 - Sphingolipid metabolism, cell death & tumor progression Abnormal lipid profiles are often associated with an altered metabolic phenotype in tumor cells, which has been recognized as a hallmark of cancer. Our aim is to elucidate how sphingolipid (SL) metabolism affects key biological processes underlying cancer development including cell death, proliferation, migration, tumor stroma remodeling as well as immune response. In particular, the contribution of SLs to skin melanoma and breast cancer is examined. Not only these forms of cancer are frequent and/or resistant to current therapies, but also they exhibit altered SL metabolism. Our ultimate goal is to target SL metabolism in order to improve therapeutic approach, i.e., to prevent tumor progression and overcome resistance to anticancer drugs, cytokines and immune cells.
Team Leaders Thierry Levade
Professor
& Nathalie Andrieu Inserm DR
[13]
Keywords: Ceramide, sphingosine 1-phosphate, melanoma, metabolism, oncometabolite, oncoimmunology, tumor microenvironment, tumor necrosis factor
Highlights
Team 4: Clinical trials - metastatic melanoma - PI: Prof N. Meyer (IUCT)
Labels / Grants: Ligue contre le Cancer, Inserm Transfert, Inserm, Université Paul Sabatier,
INCa, Cancéropôle Grand Sud-Ouest
Some publications in 2016 Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting M1 macrophage response in melanoma. Mrad M, Imbert C, Garcia V, Rambow F, Therville N, Carpentier S, Ségui B, Levade T, Azar R, Marine JC, Diab-Assaf M, Colacios C, Andrieu-Abadie N. Oncotarget 2016, 7(44):71873-86. PARKIN Inactivation Links Parkinson's Disease to Melanoma. Hu HH, Kannengiesser C, Lesage S, André J, Mourah S, Michel L, Descamps V, Basset-Seguin N, Bagot M, Bensussan A, Lebbé C, Deschamps L, Saiag P, Leccia MT, Bressac-de-Paillerets B, Tsalamlal A, Kumar R, Klebe S, Grandchamp B, Andrieu-Abadie N, Thomas L, Brice A, Dumaz N, Soufir N. J Natl Cancer Inst 2016, 108(3) djv340. Chromatin-Bound MDM2 Regulates Serine Metabolism and
Redox Homeostasis Independently of p53. Riscal R, Schrepfer E, Arena G, Cissé MY, Bellvert F, Heuillet M, Rambow F, Bonneil E, Sabourdy F, Vincent C, Ait-Arsa I, Levade T, Thibaut P, Marine JC, Portais JC, Sarry JE, Le Cam L, Linares LK. Mol Cell 2016, 62(6):890-902. Targeting TNFalpha as a novel strategy to enhance CD8+ T cell-dependent immune response in melanoma? Bertrand F, Rochotte J, Colacios C, Montfort A, Andrieu-Abadie N, Levade T, Benoist H, Ségui B. Onco-immunology 2016, 5(1) e1068495. Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy. Rolando M, Escoll P, Nora T, Botti J, Boitez V, Bedia C, Daniels C, Abraham G, Stogios PJ, Skarina T, Christophe C, Dervins-Ravault D, Cazalet C, Hilbi H, Rupasinghe TW, Tull D, McConville MJ, Ong SY, Hartland EL, Codogno
P, Levade T, Naderer T, Savchenko A, Buchrieser C. Proc Natl Acad Sci U S A 2016, 113(7):1901-6. A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuro-inflammation. Kassem S, Gaud G, Bernard I, Benamar M, Dejean AS, Liblau R, Fournié GJ, Colacios C, Malissen B, Saoudi A. PLoS Genet 2016 Jul 20;12(7):e1006185. A sequential bioorthogonal dual strategy: ManNAl and SiaNAl as distinct tools to unravel sialic acid metabolic pathways. Gilormini PA, Lion C, Vicogne D, Levade T, Potelle S, Mariller C, Guérardel Y, Biot C, Foulquier F. Chem Commun (Camb) 2016, 52(11):2318-21. Glucosylceramidases and malignancies in mammals. Astudillo L, Therville N, Colacios C, Ségui B, Andrieu-Abadie N, Levade T. Biochimie 2016, 125:267-80.
SPHINGOLIPIDS
TNF
IMMUNE ESCAPE
IMMUSPHINX
Sphingolipids
Funded by the European program Transcan-2
H2020-SC1
(PI: Dr. N. Andrieu)
Patents
WO2017129769A1
WO2017134116A1
EP16306138.5
EP16306139.3
TICIMEL
TNF inhibitors A Phase Ib clinical study
MELANFα TNF
Patents
WO2015173259A1
EP16305085
[14]
ObjectivesAlteration of post-transcriptional gene expression regulation is a hallmark of cancer. RNA-binding proteins (RBPs) are master regulators required for all post-transcriptional processes, including transcript maturation, mRNA stability and translation. These factors allow dynamic regulation in normal and various stress conditions, and contribute to deregulations in the RNA metabolism of cancer cells. They can also directly impact genome instability by establishing a direct link between DNA- and RNA-mediated processes. RBPs recognize specific elements of diverse sequences and structures. Among these, RNA G-quadruplex structures have been shown to affect the expression of cancer relevant genes by modulating post-transcriptional steps.
Our research focuses on understanding the role of RBPs in post-transcriptional gene expression reprogramming in response to stress and to the deregulation associated to cancer pathobiology. Our objectives are: 1- to provide a mechanistic and functional understanding into how RBPs impact on cancer development, progression and treatment, 2- to improve our understanding of RNA G-quadruplexes regulation and targeting in cancer cells, 3- to investigate the emerging concept that DNA-damage proteins, beside effects on DNA and signaling, target mRNAs to regulate post-transcriptional gene expression.
Keywords: Post-transcriptional gene expression, mRNA, RNA-binding proteins, mRNA translation, DNA damage response, RNA G-quadruplex structure
Staff
Anne Cammas* Hervé Prats* Florence Cabon Eric Lacazette Corinne Hieblot* Catherine Zanibellato*
Non permanent Juliette Bertorello* (AI)
Post-doc fellows Raouia Ben-Naya Marie Cargnello*
PhD students Morgane Le Bras* Guillaume Labrousse Julie Tenet Florence Bonnet
*Present members
Nina CAILLET
Team 5 – RNA-binding proteins and post-transcriptional regulation in cancer
Post-transcriptional gene expression is deregulated in cancer,
resulting in altered programs of protein biosynthesis that can
drive tumor progression and resistance to therapy. Our research
program brings together clinicians, biologists and experts in
biostatistics to unveil how molecular mechanisms of
translational regulation by RNA-binding proteins are
orchestrated in cancer cells and are linked to patient outcome.
Team Leader Stefania Millevoi
CR1 Inserm
[15]
Highlights
Labels / Grants: Ligue contre le cancer, ARC, Cancéropôle Grand Sud-Ouest, Fondation de
l’Avenir, Région Midi-Pyrénées, LabEx TOUCAN
Some publications in 2016 A novel cytoprotective function for the DNA repair protein Ku in regulating p53 mRNA translation and function. (2016) Lamaa et al., EMBO Reports; 17(4):508-18. hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA
linked to tumor progression. (2016) Cammas et al., Oncotarget 7:16793-805. Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer. (2016) Quemener et al., Cancer Research 76: 6507-19. PERK mediates the IRES-dependent translational activation of mRNAs encoding
angiogenic growth factors after ischemic stress. (2016) Philippe C et al., Sci. Signal; 9(426):ra44. Hypoxia and ER stress promote Staufen1 expression through an alternative translation mechanism. (2016) Bonnet-Magnaval et al., Biochem Biophys Res Commun 2: 365-71.
RNA G-quadruplex structures impact
protein synthesis in cancer
High expression of the RNA-binding protein
hnRNP-A1 is associated to metastatic relapse in
patients with invasive breast cancer.
Cytoplasmic hnRNP-A1 increases the translation of the mRNA encoding the tyrosine kinase receptor RON/MST1R through RNA G-quadruplex structures in the RON 5’-untranslated region (UTR).
Cammas et al., (2016) Oncotarget 2016
Ku acts as a post-transcriptional
regulator of gene expression
The DNA repair protein Ku suppresses p53
mRNA translation in cells grown under normal
conditions, thereby contributing to the low steady‐
state level of p53.
In cells stressed with DNA‐damaging agents,
Ku acetylation abrogates the Ku‐dependent
suppression of translation and permits increased
translation of p53 mRNA.
Lamaa et al., (2016) EMBO Reports
[16]
Objectives
Through biochemical, cellular and in vivo models our fundamental objective is to understand how mRNA translation into protein is regulated. The function of both global (through canonical translation initiation complexes) and mRNA-specific translational factors and their respective regulations by selective signaling pathways are explored. These new mechanistic insights are then very helpful in searching whether and how alterations in the control of protein synthesis play a role in oncogenesis and in resistance to treatment. Thanks to collaborations with clinicians and local and international industrial partners, the
uncovered mechanisms are validated in patient samples, and known or new pharmaceutical compounds are tested for their therapeutic potential. We have a solid background in pancreatic tumors (and accumulating evidence in acute myeloid leukemia) showing that selective translational regulators and/or signaling pathways appears as attractive therapeutic targets. Their targeting can affect tumor growth, metastatic spreading or response to conventional treatments through either direct effects on cancer cells or indirect effects on tumor microenvironment.
Staff
Yvan Martineau
Christine Jean
Marjorie Fanjul
Philippe Caron
Delphine Vezzosi
Catherine Marboeuf
Stéphanie Cassant-
Sourdy
Amandine Alard
Manon Strehaïano
Emilie Decaup
Julia Rochotte
Zeina Bash Imam
Rémi Samain
Christophe Quémerais
Sauyeun Shin
Sonia Zaghdoudi
Team 6 – Protein Synthesis & Secretion in Oncogenesis
Cancer cells must double their protein content before dividing
(proliferation), and both cancer and surrounding cells (especially
cancer-activated fibroblasts) synthetize and secrete proteins
critical for tumor growth, metastasis spreading and resistance to
treatment. Our group searches how protein synthesis and related
signaling pathways are regulated in healthy cells, how they
become altered in malignant tumors and whether they can be
targeted for therapeutic intervention.
Team Leaders Stéphane Pyronnet
DR Inserm
& Corinne Bousquet DR Inserm
[17]
Keywords: Protein synthesis, mRNA translation, signaling pathways, tumor microenvironment, somatostatin, pancreatic cancer, acute myeloid leukemia
Highlights
Labels / Grants: Ligue contre le cancer, LabEx TOUCAN, PHUC CAPTOR
Some publications in 2016 Anti-metastatic potential of somatostatin analog SOM230: Indirect pharmacological targeting of pancreatic cancer-associated fibroblasts. Moatassim-Billah S, et al. Oncotarget. 2016; 7:41584-98. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. Leca J, et al. J Clin Invest. 2016; 126:4140-56.
S6K1 Is Required for Increasing Skeletal Muscle Force during Hypertrophy. Marabita M, et al. Cell Rep. 2016; 17:501-13. Nucleolin Promotes Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangiogenesis. Morfoisse F, et al. Cancer Res. 2016; 76:4394-405. PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after
ischemic stress. Philippe C et al. Sci Signal. 2016; 9(426):ra44. Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer. Bouquerel P, et al. Oncogenesis. 2016; 5:e209. Challenging the Roles of NSP3 and Untranslated Regions in Rotavirus mRNA Translation. Gratia M, et al. PLoS One. 2016; 11:e0145998.
During the last years, we have identified protein synthesis mechanisms and their
regulation pathways which are altered in cancer cells, and showed that they could be
potential therapeutic targets.
More recently, our work focused on the tumor microenvironment:
We recently showed that targeting the mTOR/4E-BP1-protein synthesis pathway
selectively in cancer-activated fibroblasts (CAFs) restrains metastases spreading and
sensitizes pancreatic tumors to chemotherapy.
Duluc EMBO Mol Med 2015
Moatassim-Billah Oncotarget 2016
[18]
Objectives
In the last decade, it has become increasingly clear that post-transcriptional control of gene expression plays an essential role in tumor cell dysregulation. Studies at the RNA level have been focused for a long time on mRNA, the best known RNA family that represents only a small part of transcripts (2 to 5% of total RNAs). However, the human genome contains much more than just protein-coding genes and the majority of transcribed RNAs are non-coding (ncRNA) such as microRNAs (miRNA), long non-coding RNAs (lncRNA), interfering RNAs, piwiRNAs, or small nucleolar RNAs (snoRNA). Evidence is accumulating that these ncRNAs play key roles in regulating numerous pathways involved in cancer development and progression. The lab explores the expression profiles and functions of microRNAs and lncRNAs in hematological malignancies, their interaction with proteins and their protein coding potential (with a focus on primary miRNA transcripts, pri-miR). Two types of tumors for which our team has an international expertise or represent cancers with
potential of resistance are investigated: T-cell lymphoma including anaplastic large cell lymphoma and acute myeloid leukemia. Our objectives are: - to decipher how ncRNAs dysregulation in leukemias/lymphomas could impact their prognosis (relapse, response and resistance to treatment), and ideally to identify prognostic biomarkers, - to investigate the role of ER stress on ncRNAs expression in leukemia and their impact on tumor progression and response to treatment, - to study the physiological and pathological role of these ncRNA including the identification of their downstream target genes, whose role in classical (proliferation, survival, invasion) pathways of cancerogenesis will be functionally characterized, - to study the upstream mechanisms of ncRNA
regulation (epigenetic control of their expression,
control of their expression by microRNA encoded
peptites (miPEPs), control of their stability by
specific endoribonucleases).
Staff
Fabienne Meggetto Laurence Lamant Christian Touriol Marina Bousquet Estelle Espinos Coralie Hoareau-Aveilla Margherita Ghisi Avédis Torossian Céline Philippe Morgane Gourvest Nina Caillet Cathy Quelen Ouafa Zaki Annabelle Congras Nicolas Broin
Nina CAILLET
Team 7 – RNA biology in hematological cancers
Non coding RNA (ncRNA) are RNA without protein-coding potential. Despite intensive research on ncRNA, our overall knowledge of ncRNA function in carcinogenesis remains very limited. One of the main challenges of our team in understanding the function of a specific non-coding RNA such as long and micro ncRNA in cancer, is deciphering their interactome (other RNAs, specific protein complexes, regions of DNA…), and regulations.
Team Leader Pierre Brousset
Professor
[19]
Keywords: miRNA, lncRNA, acute myeloid leukemia, anaplastic large cell lymphoma, ALK, target therapy, ER stress, resistance
Highlights
Label / Grants: Ligue Contre le Cancer, LabEx TOUCAN, ITN-Horizon 2020 ALKATRAS
Some publications in 2016 RNA editing in acute myeloid leukaemia with normal karyotype. Quelen C, Eloit Y, Noirot C, Bousquet M, Brousset P. Br J Haematol. 2016;173(5):788-90. Small nucleolar RNA expression profiles refine the prognostic impact of IGHV mutational status on treatment-free survival in chronic lymphocytic leukaemia. Berquet L, Valleron W, Grgurevic S, Quelen C, Zaki O, Quillet-Mary A, Davi F, Brousset P, Bousquet M,
Ysebaert L. Br J Haematol. 2016;172(5):819-23. PERK mediates the IRES-dependent translational activation of mRNAs encoding angiogenic growth factors after ischemic stress. Philippe C, Dubrac A, Quelen C, Desquesnes A, Van Den Berghe L, Ségura C, Filleron T, Pyronnet S, Prats H, Brousset P, Touriol C. Sci Signal. 2016;9(426):ra44. NPM-ALK mimics thymic pre-T cell receptor (TCR) expansion but requires transient TCR expression for thymic egress and peripheral Anaplastic Large
Cell Lymphoma development. Malcolm TI*, Villarese P*, Fairbairn C, Lamant L, Trinquand A, Hook CE, Burke GA, Brugières L, Hughes K, Payet D, Merkel O, Schiefer AI, Mian S, Wasik M, Turner M, Kenner L, Asnafi V, Macintyre E, Turner SD. Nat Commun 2016;7:10087 (* co-first authors). Anaplastic Large Cell Lymphoma. Turner SD, Lamant L, Kenner L, Brugieres L. Br J Haematol 2016; 173 :560-72 (review).
• Identification of a specific new lncRNA biomarker in AML LncRNA XLOC_109948 expression levels can predict clinical outcome especially in NPM1-mutated AML patients. De Clara et al, Haematologica, 2017, 2017 102: 1718-26.
• Decitabine treatment, via the STAT3/miR-150/MYB axis, inhibits growth of the crizotinib-resistant KARPAS-299-CR06 mutant.
Hoareau-Aveilla et al, J Clin Invest. 2015 Sep;125(9):3505-18.
[20]
Objectives Our general aim is to decipher the mechanisms that link oncogenic signaling, cell cycle regulation, and autophagy. We try to understand how cell signaling pathways activated by oncogenes, in particular mutated tyrosine kinases, regulate key cell cycle actors, like the CDC25A phosphatase or the DNA damage checkpoint kinase CHK1, for instance. We identify by different approaches new regulatory modifications of these proteins, such as new phosphorylation sites or new transcriptional and post-
transcriptional mechanisms of regulation. We also investigate how autophagy regulates signaling pathways (signalophagy) in cancer cells, more specifically in acute myeloid leukemia subtypes. We estimate in parallel how these cell cycle actors or autophagy impact the response and the resistance of these cancer cells to therapeutic agents. We finally translate these basic research questions into the identification of potential therapeutic targets in acute myeloid leukemia.
Keywords: Cell cycle, autophagy, signaling, acute myeloid leukemia, checkpoints, CDK inhibitor
Staff Sarah Bertoli, Hospital practionner Véronique De Mas, Associate professor Christine Didier, CR CNRS Christine Dozier, CR CNRS Carine Joffre, CR Inserm Laurent Mazzolini, CR CNRS Alexandre Gay, Research assistant PhD students Justine Creff Quentin Heydt Ada Nowosad Renaud Perchey Gabrielle Sueur Maëlle Cartel
Team 8 – Cell cycle and cancer
We try to identify proteins which are important for the response of leukemic cells to therapeutic drugs. We then investigate how these proteins work in these cells, and how they are regulated by the oncogenes responsible of the disease. We focus our studies on proteins which have important functions in cell cycle regulation, as well as in autophagy, a cellular process recently identified as an important pathway of resistance to several therapeutic drugs.
Team Leaders Arnaud Besson
DR CNRS & Stéphane Manenti
DR CNRS
[21]
Highlights
Labels / Grants: Labex TOUCAN, Label Ligue contre le Cancer 2016
Some publications in 2016 Larrue C, Saland E, Boutzen H, David M, Joffre C, Hospital MA Tamburini J, Delabesse E, Manenti S, Sarry JE, Récher C. Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells. Blood 2016;127(7):882-92. Duquesnes N, Callot C, Jeannot P, Daburon V, Nakayama K.I., Manenti S, Davy A
and Besson
A.
p57Kip2
knock-in mouse reveals CDK-independent contribution in the development of Beckwith-Wiedemann syndrome. J Pathol, 2016, 239(3):250-61. Jungas T, Perchey RT, Fawal M, Callot C, Froment C, Burlet-Schiltz O, Besson A* and Davy A*. Eph-mediated tyrosine phospho-rylation of Citron Kinase controls abscission.
2016. J. Cell Biol. 214: 555-69. (cover article). *Equal contribution. Faculty of 1000 recommended article. Barrow R*, Kishi N*, Joffre C*, Menard L, Hervieu A, Mai A, Robert-Masson L, Iturrioz X, Hulit J, Brennan C, Hart IR, Parker PJ, Ivaska J, Kermorgant S. Beta 1-integrin- c-Met cooperation : an inside-in survival signalling on Autophagy Related Endomem-branes. Nature Commun, 2016; 7:11942 (*equal participation). Bettoun A, Joffre C, Zago G, Surdez D, Vallerand D, Gundogdu R, Sharif AA, Gomez M, Cascone I, Meunier B, White MA, Codogno P, Parrini MC, Camonis JH, Hergovich A. Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell
transformation. Oncotarget. 2016 7(28):44142-60. Mazzolini L, Broban A, Froment C, Burlet-Schiltz O, Besson A, Manenti S
and Dozier C.
Phosphorylation of CDC25A on ser283 in G2 by CDK/Cyclin complexes accelerates mitotic entry. Cell Cycle, 2016; 15(20): 2742-52. David L*, Fernandez-Vidal A*, Bertoli S, Grgurevic S, Lepage B, Deshaies D, Prade N, Cartel M, Larrue C, Sarry JE, Delabesse E, Cazaux C, Didier C, Récher C**, Manenti S** and Hoffmann JS**. Chk1 as a therapeutic target to bypass chemo-resistance in AML. Science Signaling, 2016;9 (445): ra90 (*equal participation; **co-corresponding authors).
The CDC25A phosphatase is regulated by CDK phosphorylations at the G2/M transition. We identified Ser 283 as a new phosphorylation site on the CDC25A phosphatase by mass spectrometry analysis. The G2 and mitotic CDK complexes are involved into the phosphorylation of this residue, which is important for the G2/M transition functions of CDC25A. This phosphorylation loop participates to the tight regulation necessary for correct completion of mitosis in normal and cancer cells. The CHK1 protein kinase is an independent prognostic marker and a therapeutic target in AML. Patients presenting the highest levels of CHK1 mRNA and protein have lower survival probability and higher risks of relapse. CHK1 is involved in the resistance of AML cells of these patients to the therapeutic drug cytarabin, and inhibiting CHK1 consequently sensitizes leukemic cells to this genotoxic drug. CHK1 is also involved in the deregulated proliferation of these leukemic cells, since cells from patients with high CHK1 level are characterized by higher clonogenic potential. FLT3-ITD induces autophagy through an ATF4-dependent pathway in AML (Heydt et al, in revision). We demonstrate that the mutant receptor FLT3-ITD, expressed in 25% of AML and associated with a poor prognosis for the patients, induces basic constitutive autophagy in AML cells. This autophagy drives the proliferation of AML cells in vitro, as well as in vivo in a NSG mice xenograft model. The transcription factor ATF4 is tightly regulated by FLT3-ITD, and we identified it as a master inducer of the autophagic process in this model.
[22]
Objectives :
Objectives
More specifically, we develop novel tools including analytic methods and biological models to find new molecular pathways for targeting NHL by novel drugs, and assess them in preclinical models, prior to translate our most promising new approaches in Phase l/ll clinical trials of IUC-Toulouse Oncopole.
This includes : 1- Predicting response of patients to
treatment (ibrutinib in CLL, ICB in NHL) 2- Harnessing innate immunity against
lymphoma models 3- Development of a humanized anti-
TAM mAb neutralizing the stromal support of NHL.
Keywords: Lymphoma, MALC models, datamining, bioinformatics, deep learning, RNAseq,
therapy, drugs, immune checkpoints, flow cytometry
Staff Anne Quillet-Mary, DR2 CNRS, HDR Mary Poupot, CR1 Inserm, HDR Christine Bezombes, CR1 Inserm, HDR Camille Laurent, MCU-PH IUCT, HDR Loïc Ysebaert, PH IUCT, HDR Olivia Lanvin, IE2 Inserm, Pauline Gravelle, IE IUCT Marie Tosolini, IE IUCT Sarah Cadot, TR Inserm Post-Doc Fellows Don-Marc Franchini Guillaume Poiroux PhD students Cedric Rossi, MD Julie Bordenave
Team 9 – Therapeutic Innovations in B lymphomas Non-Hodgkin B cell lymphoma (NHL) including chronic
lymphocytic leukemia (CLL) are increasingly frequent
hematopoietic malignancies. The patients care relies on
chemotherapies, immunotherapies and radiotherapy
combinations, but relapse and/or unresponsiveness are far too
frequent.
So our team aims at improving the efficacy of treatments for NHL,
notably by assessing immune checkpoint blockade (ICB) in this
context.
Team leader Jean-Jacques Fournié
DRCE1 CNRS
[23]
Highlights
Four stages of immune escape in DLBCL (Diffuse Large B-cell lymphoma) patients
Genome-wide gene expression profiles from 1200 DLBCL tumours evidence four stages of immune
escape in these cancer patients. The patients at stage 2 (Green: high T cell activation, low immune
escape) benefit longer OS than those with immune escape stage 3 (red: high T cell activation and
immune escape) Stage 4 patients (low activation high immune escape) have the shortest survival. Stage
1 patients are currently under study (Tosolini et al. OncoImmunology, 2016).
Labels / Grants: LabEx TOUCAN, Institut Carnot III : CALYM, PHUC CAPTOR
Some publications in 2016 Tosolini M, Algans C, Pont F, Ycart B, Fournié JJ. Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphoma. Oncoimmunology 2016. 5: e1188246. Poupot M, Turrin CO, Caminade AM, Fournié JJ, Attal M, Poupot R, Fruchon S. Poly(phosphor-hydrazone) dendrimers: yin and yang of monocyte activation for human NK cell amplification applied to immunotherapy against multiple myeloma. Nanomedicine – Nanotechno-logy, Biology and Medicine 2016. 12: 2321-30.
Guggino G, Ciccia F, Di Liberto D, Lo Pizzo M, Ruscitti P, Cipriani P, Ferrante A, Sireci G, Dieli F, Fournié JJ, Giacomelli R, Triolo G. Interleukin (IL)-9/IL-9R axis drives gamma delta T cells activation in psoriatic arthritis patients. Clin Exp Immunol 2016. 186: 277-83. Duault C, Franchini DM, Familliades J, Cayrol C, Roga S, Girard JP, Fournié JJ, Poupot M TCRV gamma 9 gamma delta T Cell Response to IL-33: A CD4 T Cell-Dependent Mechanism. J Immunol 2016. 196: 493-502. Boissard F, Tosolini M, Ligat L, Quillet-Mary A, Lopez F, Fournié JJ, Ysebaert L, Poupot M. Nurse-like cells promote CLL survival
through LFA-3/CD2 interactions. Oncotarget 2016. Boissard F, Laurent C, Ramsay AG, Quillet-Mary A, Fournié JJ, Poupot M, Ysebaert L. Nurse-like cells impact on disease progression in chronic lymphocytic leukemia. Blood Cancer J 2016. 6:e381. Betrian S, Ysebaert L, Heider KH, Delord JP, Fournié JJ, Quillet-Mary A. Idelalisib improves CD37 antibody BI 836826 cytotoxicity against chemo-resistant /relapse-initiating CLL cells: a rationale for combination treatment. Blood Cancer J 2016. 6 : e496.
[24]
Objectives
Our general objective is to better understand the complex relationship between molecular heterogeneity and therapeutic resistance of pancreatic adenocarcinoma (PDAC), to help alleviate the dismal prognosis of this disease with no cure. To this end, we developed basic research programs to investigate the function of candidate proteins involved in the fine-tuning of mitosis, DNA damage repair and replication, and tumor metabolism. We found that these proteins are heterogeneously expressed in patients and control experimental tumors growth. In cohorts of patients, we identified specific molecular signatures, including circulating, noninvasive nucleic acids for patients’ stratification. In parallel
we created with LAAS-CNRS novel nanodevices for candidate biomarker identification / quantification. Last, we are engaged in bench-to-bedside, personalized, translational preclinical programs and first-in-man clinical trials using gene therapy to defeat pancreatic tumor resistance to conventional chemotherapy and next-generation immunotherapies. We expect that our scientific program will bring new insights in the molecular heterogeneity of tumors, to develop innovative strategies that will overcome pancreatic adenocarcinoma resistance to treatment.
Keywords: Pancreatic cancer, molecular heterogeneity, DNA damage repair, mitosis, DNA replication, tumor metabolism, gene therapy, oncolytic virus.
Staff
Audrey Frances
Pierre Garcin
Louis Buscail
Marlène Dufresne
Naima Hanoun
Delphine Pagan
Hubert Lulka
Lorraine Quillet
Manon Brunet
Guillaume Conzatti
Jean Cacheux
Dorian Larrieu
Janick Selves
Rosine Guimbaud
Barbara Bournet
Nicolas Carrère
Jean-Pierre Vinel
Jérome Torrisani
Team 10 – Molecular heterogeneity of pancreatic tumors Pancreatic tumors display a remarkable molecular variability that
results in a unique ability to escape and survive therapy. Our
research effort is dedicated to improve the molecular
understanding of pancreatic tumors and therefore to better
address the role of intra-tumor heterogeneity in diagnosis and
the development of therapeutic resistance.
Team Leader Pierre Cordelier
DR Inserm
[25]
Highlights
Labels / Grants: Oncodevice consortium, Imcore project
Selected publications in 2016 1-Hanoun N, Gayral M, Pointreau A, Buscail L, Cordelier P. Initial Characterization of Integrase-Defective Lentiviral Vectors for Pancreatic Cancer Gene Therapy. Hum Gene Ther. 2016;27(2):184-92. 2-Chaveroux C, Bruhat A, Carraro V, Jousse C, Averous J, Maurin AC, Parry L, Mesclon F, Muranishi Y, Cordelier P, Meulle A, Baril P, Do Thi A, Ravassard P, Mallet J, Fafournoux P. Regulating the expression of therapeutic transgenes by controlled intake of dietary essential amino acids. Nat Biotechnol. 2016; 34(7):746-51.
3-Effect of Intratumoral Injection of Gene Therapy for Locally Advanced Pancreatic Cancer (THERGAP-02), https://clinicaltrials.gov/ct2/show/NCT02806687. 4-Bournet B, Vignolle-Vidoni A, Grand D, Roques C, Breibach F, Cros J, Muscari F, Carrère N, Selves J, Cordelier P, Buscail L. Endoscopic ultrasound-guided fine-needle aspiration plus KRAS and GNAS mutation in malignant intraductal papillary mucinous neoplasm of the pancreas. Endosc Int Open. 2016 ;4(12):E1228-E1235. 5-Bournet B, Muscari F, Buscail C, Assenat E, Barthet M, Hammel P,
Selves J, Guimbaud R, Cordelier P, Buscail L. KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocar-cinoma. Clin Transl Gastroenterol. 2016 Mar 24;7:e157. 6-Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur J Cancer. 2016 ;54:75-83. 7-Vassaux G, Angelova A, Baril P, Midoux P, Rommelaere J, Cordelier P. The Promise of Gene Therapy for Pancreatic Cancer. Hum Gene Ther. 2016 ;27(2):127-33.
Figure 1. Transduction of PDAC cells with IDLV HIV-1 vectors. Cancer cells were transduced with IDLV D64V encoding for GFP. Cells were imaged 4 days later.
Figure 2. Molecular analysis of PDAC tumors. Tumor microbiopsies were sampled following endoscopic ultrasound (EUS). DNA was extracted from Fine-needle aspirates (FNA) and subjected to Taqman allelic discrimination for identification of mutated forms of KRAS and GNAS.
In 2016, we devised novel gene therapy approaches to defeat PDAC. First, we engineered integrase-deficient lentiviral vectors (IDLVs) to prevent insertional mutagenesis while treating experimental tumors (1). Next, we participated to the development of a simple method relying on tumor metabolism to regulate gene expression in experimental pancreatic tumors (2). Both strategies may be applied in the future for the treatment of patients with PDAC. In the meantime, we obtained the approval from ANSM to perform a phase II clinical trial based on non-viral gene transfer to defeat resistance to treatment in hundred patients with advanced tumors (Thergap-2 trial, 3). Inclusion have started in Q1/2017. Also, we made substantial progress in the molecular characterization of pancreatic tumors to demonstrate that i) KRAS mutation testing identifies patients with high-risk precursor lesions who may benefit from surgical resection (4), and ii) KRAS G12D mutation is an independent prognostic marker in advanced pancreatic tumors (5). Last, we collaborated with chemists to generate biomaterials surface with unique bioadhesion properties for tunable pancreatic cell adhesion (6).
[26]
Objectives
Our team is a translational research team in radiobiology, specialized in optimizing the radiotherapy treatment of glioblastoma (GBM). Our research is conducted in 3 complementary approaches: i) first by deciphering the biological mechanisms of tumor radioresistance, ii) by performing preclinical trials to validate targets for new radiosensitizer agents and to identify new predictive markers, and iii) by conceiving and performing early phase clinical trials performed in our Institute (IUCT) associating targeted drugs directed against the target identified in the lab with radiotherapy and integrating metabolic
imaging studies, as well as surrogate biomarkers. This 3-axis strategy to improve the GBM radiotherapy treatment efficiency is now amplified by strengthening our research on tumor heterogeneity and more particular on GBM radiation-induced migration and plasticity as well as GBM stem cells (GSC) involvement in GBM radioresistance. We also pursue our investigation concerning the mechanisms sustaining glioblastoma differentiated cells radioresistance by investigating the role of microenvironment factors as integrins and growth factors.
Keywords: Glioblastoma, resistance to radiotherapy, stem cells, microenvironnement
Staff Catherine Seva Anthony Lemarie Laurent Barricault Emmanuelle Uro-Coste Monique Courtade Solene Evrard Valerie Gouaze Andersson Aline Chauvel M Julie Ghirardi Annie Behar Delmas Caroline Florent Arnauduc Laure Malric Sabrina Boyrie Anouchka Modesto Pauline Deshors Laure Malric
Team 11 – Glioblastoma radioresistance: from signaling pathways to clinical trials Our team is a translational research team specialized in
optimizing the radiotherapy treatment of glioblastoma (GBM).
We first decipher the biological mechanisms of GBM
radioresistance, then perform preclinical and clinical trials to
evaluate the efficiency of combining radiotherapy with specific
inhibitors of the radioresistance mechanisms we previously
identified. We focus our research more particularly on the role
of GBM stem cells in the tumor radioresistance.
Team Leaders Elizabeth Moyal
Professor Christine Toulas
Hospital practionner
[27]
Highlights
Labels / Grants: PHUC CAPTOR, ARC, Ligue contre le cancer, EDF
Some publications in 2016 1- Goldbrunner et al, EANO guidelines for the diagnosis and treatment of meningiomas. Lancet Oncol. 2016;17(9): e383-91.
2- Gouazé-Andersson V et al, FGFR1 Induces Glioblastoma
Radioresistance through the PLCγ/Hif1α Pathway. Cancer Res. 2016; 76(10):3036-44.
3- Khalifa et al, Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation. Eur Radiol.
2016; 26(11):4194-203.
4- Kamoun et al, Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nat Commun. 2016 ;7:11263.
• We have investigated the role of micro-environment factors in tumor radioresistance. We first demonstrated the role of FGFR1 in the radioresistance of GBM cells. Silencing
FGFR1 decreased radioresistance in vitro via PLC and HIF1in vitro and in vivo. These results offer a preclinical proof of concept that FGFR1 targeting can degrade radioresistance in glioblastoma, prompting clinical investigations of the use of FGFR1 inhibitors for radiosensitization (Gouazé-Andersson et al., 2016).
• We pursued our investigations concerning the impact of GBM cells plasticity in GBM
radioresistance. We demonstrated the role of metabolism in GBM reprograming process.
• We identified a candidate biomarker from perfusion MRI to anticipate glioblastoma
progression after chemoradiation (Khalifa et al., 2016). We developed clinical trials investigating the impact of GBM stem cells on tumor response to the treatment.
[28]
Objectives We want to identify and validate new therapeutic targets, to identify new mechanisms of resistance to treatments and to improve outcome through a better stratification of cancers. Specifically, we are studying the contribution of cholesterol metabolism in the response to the endocrine therapy with Tamoxifen (Tam) and aromatase inhibitors (AI). We identified a new metabolic pathway centered on cholesterol-5,6-epoxide hydrolase (ChEH). ChEH controls cholesterol-5,6-epoxide (5,6-EC) metabolism and is a direct target of Tam (de Medina et al, PNAS 2010). We showed its importance in the anticancer action of Tam. ChEH controls the production of metabolites with opposite properties in cancers. We have first identified dendrogenin A (DDA), an amino-oxysterol tumor suppressor produced by healthy tissues (de Medina et al, Nat Commun 2013). Recently we discovered an onco-metabolite tumor promoter produced by cancer cells. The identification of these two end-products of the cholesterol metabolism with opposite
properties opens up new perspectives for the development of novel therapies. It will help to understand fine mechanisms involved in acquired and intrinsic resistances to various therapies (Silvente-Poirot & Poirot, Science 2014). Our objectives are : 1) to characterize the molecular actors controlling this metabolic pathway, 2) to elucidate the mechanism of action of these new metabolites, including their impact on exosome production and phenotypes, 3) to characterize their impact on the tumor microenvironment (in particular on the immune system). Our objectives are also to propose innovative therapeutic approaches to counter or circumvent resistances to therapy and to identify new surrogate biomarkers of responses. Our approach links basic research to medical applications with a goal of valorization in partnership with our spin off, Affichem (9 patents filed over the last 5 years).
Keywords: Tamoxifen, SERM, oxysterols, cholesterol biosynthesis, cholesterol metabolism, dendrogenin, cholesterol-5,6-epoxide hydrolase, cholesteryl esters, nuclear receptors, enzymology, medicinal chemistry, LC/MS, radiolabeling, cell differentiation, cell death, autophagy, immune system, tumor suppressor, tumor promoter, exosomes, imaging
Staff Michel Record Florence Dalenc Frédéric Courbon, Lavinia Vija Séverine Brillouet Régis Soules Elodie Bacquié Aurélie Mougel Post-doctoral fellows R Bartölke, E Huc-Claustre, Julie Leignadier, E Noguer, N Serhan PhD students M Bauriaud-Mallet, N Rossetto, A Mallinger
Team 12 – Cholesterol metabolism and therapeutic innovations
We are studying the role of cholesterol metabolism in the control
or progression of cancers and in resistance to therapies, with a
particular focus in breast cancer.
Team Leaders Sandrine Silvente-
Poirot, DR CNRS Marc Poirot,
DR Inserm
[29]
Highlights
Labels / Grants: GenHomme, CAPTOR, IDEX
Some publications/patents in 2016 From tamoxifen to dendrogenin A: the discovery of a mammalian tumor suppressor and cholesterol metabolite. Silvente-Poirot S et al. Biochimie, 2016:109-14. When cholesterol meets histamine, it gives rise to
dendrogenin A: a tumour suppressor metabolite. Poirot M & Silvente-Poirot S. Biochem Soc Trans, 2016:631-7. Molecular and biochemical analysis of the estrogenic and proliferative properties of vitamin E compounds. Front Oncol. Khallouki F et al. 2016:1-10.
Methods and pharmaceutical compositions for reprograming immune environment in a subject and need thereof. Silvente-Poirot S et al, Patent 2016, EP16306214.4 Methods of diagnosing and treating cancer. Silvente-Poirot S et al. Patent 2016, WO2016034742.
Vitamin E are phytoestrogens: Vitamin E include a family of structurally-related antioxidants which includes tocopherols (TP) and tocotrienols (TT). Using a pharmacophore approach, we found that they are ligands of estrogen receptors (ER), display estrogenic properties and stimulate ER(+) breast cancer (BC) proliferation (Khallouki et al, Front Oncol 2016). These data, in addition to previous studies showing that they inhibit Tam anticancer action through the blockage of 5,6-EC formation, highlight that Vitamin E could represent a risk factor in BC and may impair the therapeutic outcome. This is especially important when considering that patients are often taking vitamin-based auto-medications or vitamin-enriched diets. Oxysterols as potential surrogate markers of response to hormonotherapy in hormone receptor-positive BC. We previously reported that Tam stimulated 5,6-EC formation and accumulation, 5,6-EC being second messengers involved in Tam anticancer action. The analyses of the oxysterol profile in sera from a cohort of 29 patients (Oxytam trial) treated with Tam or AI showed that treatments increased the levels of specific oxysterols, including 5,6-EC. This may reflect an activation of BC cells differentiation and death pathways, confirming our preclinical works. Interestingly, AI increased the levels of estrogenic oxysterols (25HC and 27HC) tumor promoters, and this may reflect a mechanism of acquired resistance and risk of cancer relapse. We planned to confirm these results in larger cohorts of patients.
Chemical structure of vitamin E compounds. They are modulators of estrogen receptors.
Chemical structure of oxygenation products of cholesterol (oxysterols).
Clinical trial using Tamoxifen or aromatase inhibitors in the treatment of ER(+) breast cancers showed that they modulate blood circulating oxysterol levels selectively highlighting new surrogate markers of efficacy or relapse.
[30]
Objectives
Our objective is mainly translational, that is to try
to improve the therapeutic management of the
patients in order to prolong their survival. To
achieve this, we have created a national network
that has enabled to build the world’s largest
tumor bank, linked to a computer database that
brings together the clinical and evolutionary
characteristics of these thousands of patients.
Our first axis aims at sequencing the genome of
these tumors with the aim of identifying
subgroups of patients who would be better able
to respond to specific treatments in order to help
clinicians in their therapeutic choices. In the same
vein, we have developed a technique for
quantifying minimal residual disease in patients in
complete response, in order to adapt the
treatment to the residual tumor mass. The
second axis aims to better characterize the
immune system of patients with MM, with a dual
objective: (i) to understand the causes of
immunodepression of patients by characterizing
the different immune compartments, and (ii) to
propose therapeutic approaches based on
monoclonal antibodies targeting immune cells.
Our third objective is to better understand the
interactions between tumor cells and other
normal bone marrow cells, which contribute
largely to the clinical expression of the disease,
mainly bone fractures. We focus our research on
mesenchymal stem cells.
Keywords: Multiple Myeloma, pharmacogenomics, immunology, microenvironment, NGS
Staff
Ludovic Martinet Michel Attal Jill Corre Murielle Roussel Laure Buisson Nadège Carrié Marie-Lorraine Chrétien Charlotte Fontan Fanny Grimal Augustin Le Naour Léa Lemaitre Marianne Weulersse Virgine Féliu Bettina Couderc Marie-Véronique Joubert Sabrina Mahéo Sébastien Robiou du Pont
Team 13 – Pharmacogenomics of multiple myeloma Our team is entirely focused on multiple myeloma (MM), a cancer of the bone marrow. We develop three main axes:
- Massive sequencing of tumors to understand how molecular abnormalities impact patient survival
- Analysis of the immune system of these patients in order to try to activate it to eliminate the tumor cells
- Analysis of the interactions between tumor cells and the medullary microenvironment.
Team Leader Hervé Avet-Loiseau
Professor
[31]
Highlights
Some publications in 2016
Avet-Loiseau H. Minimal residual disease by next-generation sequencing: pros and cons. Am Soc Clin Oncol Educ Book. 2016; 35:e425-30.
Sonneveld P, Avet-Loiseau H, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016; 127:2955-62.
Avet-Loiseau H, et al. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016; 128:1174-80.
Kumar S, et al. International M, yeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17:e328-46.
Dejoie T, Corre J, et al. Serum free light chains should be the target of response evaluation in light chain multiple myeloma rather than urines. Blood. 2016; 128:2941-8.
Szalat R, Avet-Loiseau H, Munshi NC. Gene Expression Profiles in Myeloma: Ready for the Real World? Clin Cancer Res. 2016; 22:5434-42.
We performed high-throughput RNA sequencing of 350 tumors to detect novel fusion transcripts in myeloma.
This work is currently being published in Nature Communication.
We have shown that the quantification of minimal residual disease (MRD) made it
possible to identify a subset of patients with an excellent prognosis.
[32]
Objectives
The main objective of our team is to promote and carry out translational and clinical studies in the field of pharmacology to drive dose individualization of anticancer drugs. This is made possible by increasing our understanding of the sources of interindividual variability in drug disposition and tumor response. Our main projects focus on pharmacokinetics and pharmacogenetics as interindividual variability factors. More than 99% of anticancer treatments are prescribed according to standard doses (in mg/m² for cytotoxics or in mg for several targeted therapies). However, a number of observations have shown that interindividual pharmacokinetic (PK) variability contributes to differences between patients both in terms of toxicity and antitumor response. The very limited number of examples of individual dosing in everyday
practice in oncology is mainly due to the administration schedule of cytotoxics (i.e. intravenous administration every three weeks). Indeed, these schedules make PK exploration difficult to perform in the first place, as several blood samples are needed in order to determine accurately the area-under-the-curve of drug plasma concentrations versus time (AUC), and secondly the PK results obtained are useless once the administration is over. Our team uses the nonlinear mixed effects approach (commonly known as “population PK”) to improve dose individualization of anticancer drugs. Our research may be divided into 3 areas: (i) covariate identification to explain PK variability, (ii) Bayesian approach to determine individual PK parameters from limited blood sampling, and (iii) pharmacokinetic-pharmacodynamic (PK-PD) modeling.
Keywords: Population pharmacokinetics, Platinum compounds, Tyrosine kinase inhibitors, therapeutic drug monitoring, PK-PD relationships
Team 14 - Dose individualization of anticancer drugs
Our team focuses on pharmacokinetics of anticancer drugs in
order to better individualize the dose.
Staff
Ben Allal Cécile Arellano Caroline Delmas Thierry Lafont Isabelle Lochon Sabrina Marsili Sotheara Moeung Marie-Noëlle Paludetto Florent Puisset Fabienne Thomas Christelle Vachoux Mélanie White-Koning Alicja Puszkiel
Team Leader Etienne Chatelut
Professor
[33]
4 5
1
1 2 3
II
I
III
Full DPYD sequencing reveals a novel mutation
DPYD exon3GGAGAATAATT GAATAATT TTGAT
c.168_175dupGAATAATT
translation stop codon: p.(Phe59Ter)
Truncated protein: 58 amino acids instead of 1025 amino-acids
DPD Phenotype : UH2/U ratio = 0.1
Complete DPD deficiency
Pedigree of the patient’s family = complete DPD deficiency
= partial DPD deficiency = normal DPD activity = individuals not tested= new mutation= c.1679C>T
Uracil U
DihydroUracil UH2
UH2/U = reflects DPD
activity
1) Discovery of novel rare mutations: p.Phe59Ter and p.Thr343Pro
DPYD genotyping focused on 3 SNPsseems insufficient to predict the risk of toxicity to 5-FU
2) Significant correlation betweengenotype and UH2/U (p=0.01)
A good tool to detect DPD deficiency
5-FU toxic deaths could be avoided by DPD deficiency testing with phenotypic analysis (UH2/U) of DPD activity before treatment.
Patient with 5-FU toxic death
Highlights
DPYD Genotype-phenotype relationship within a family with complete DPD deficiency
Thomas F, et al. Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydrouracil/uracil ratio. Clin Pharmacol Ther 2016.
Some publications in 2016 Gandia P, Jaudet C, Everaert H, Heemskerk J, Vanbinst AM, de MJ, Duerinck J, Neyns B, de RM, Chatelut E, Concordet D: Population pharmacokinetic approach applied to positron emission tomography : computed tomography for tumor tissue identification in patients with glioma. Clin Pharmacokinet 2016. Puszkiel A, White-Koning M, Dupin N, Kramkimel N, Thomas-Schoemann A, Noe G, Chapuis N, Vidal M, Goldwasser F, Chatelut E, Blanchet B: Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early
peripheral lymphocytes depletion in BRAF-mutated melanoma patients. Pharmacol Res 2016; 113:709-18. Sauzay C, White-Koning M, Hennebelle I, Deluche T, Delmas C, Imbs DC, Chatelut E, Thomas F: Inhibition of OCT2, MATE1 and MATE2-K as a possible mechanism of drug interaction between pazopanib and cisplatin. Pharmacol Res 2016; 110:89-95. Imbs DC, Dieras V, Bachelot T, Campone M, Isambert N, Joly F, Jimenez M, Lafont T, Chatelut E: Pharmacokinetic interaction between pazopanib and cisplatin regimen. Cancer Chemother Pharmacol 2016; 77:385-92.
Imbs DC, Paludetto MN, Negrier S, Powell H, Lafont T, White-Koning M, Chatelut E, Thomas F: Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site. Invest New Drugs 2016; 34:41- 8. Thomas F, Hennebelle I, Delmas C, Lochon I, Dhelens C, Garnier TC, Bonadona A, Penel N, Goncalves A, Delord JP, Toulas C, Chatelut E: Genotyping of a family with a novel deleterious DPYD mutation supports the pretherapeutic screening of DPD deficiency with dihydro-uracil/uracil ratio. Clin Pharmacol Ther 2016; 99:235-42.
[34]
Objectives
Targeted RadioTherapy (TRT) is a cancer therapy based on the administration of radiolabelled selective vectors. Currently, administration is based on fixed activities, eventually modulated by patient mass or body surface area. This approach disregards pharmacokinetics inter-patient variability, and does not benefit from the possibility to perform a patient-specific assessment of delivered irradiation. Our objective is to implement a paradigm shift from "radioactive chemotherapy" towards "systemic radiotherapy", where
each patient benefits from a personalised treatment. With this aim, our team develops innovative dosimetric approaches at all scales (cell, tissue, patient) by quantifying activity distributions (quantitative imaging) and modelling radiation transport for various emitters (alpha, beta, Auger) used for TRT. These developments in radiation transport modelling are progressively extended to preclinical and clinical external beam radiotherapy, mainly in a context of complex irradiation or/and small irradiation beams.
Keywords: Dosimetry, Monte Carlo modelling
Staff
Marie-Claude Bordage Emmanuelle Cassol Régis Ferrand Xavier Franceries Luc Simon Laure Vieillevigne Maxime Chauvin Julien Bordes Richard Brown Jonathan Tranel Tony Younes Erick Mora Ramirez Gustavo Costa Frédéric Chatrie
Team 15 – Multiscale dosimetry for radiotherapy optimization
Radiotherapy efficacy relies on treatment personalisation:
Irradiation must be elevated in tumour targets, whereas
healthy/critical organs/tissues irradiation must be minimized.
Our team works at optimizing several forms of radiotherapy, by
measuring or modelling radiation transport at various scales,
from cell to patient.
Team Leader Manuel Bardiès
Inserm DR
[35]
Highlights
International collaborations: OpenGate, Geant4/Geant4-DNA, EFOMP, EANM, AIEA Selected publications in 2016 Garcia et al. 2016. Accelerated GPU based SPECT Monte Carlo simulation. Physics in Medicine and Biology 61(11): 4001-18. Marcatili et al. 2016. Realistic multicellular dosi-metry for Lu-177-labelled antibodies: model and application. Physics in Medicine and Biology 61(19): 6935-52.
Arnaud et al. 2016. Complex cell geometry and sources distribution model for Monte Carlo single cell dosimetry with iodine 125 radio-immuno-therapy. Nuclear Instruments & Methods in Physics Research Section B 366: 227-33. Vieillevigne et al. 2016. Dosimetric comparison of flattened and unflattened beams
for stereotactic body radiation therapy: Impact of the size of the PTV on dynamic conformal arc and volumetric modulated arc therapy. Physica Medica 32(11): 1405-14. Bordage et al. 2016. Implementation of new physics models for low energy electrons in liquid water in Geant4-DNA. Physica Medica 32(12): 1833-40.
On-going projects and Highlights
Medirad: NFRP-9 Euratom Fission2016-2017
This 48-month European project aims at studying the effects of low doses in medical applications. Our team is in charge of modelling irradiation at distance of tumour targets for TRT of thyroid cancers, and evaluations the dosimetric consequences of hybrid imaging in nuclear medicine. MRTdosimetry: EMPIR 15HLT06
This 3-year European project started mid-2016, and aims at optimising the metrology of clinical implementation of TRT dosimetry. We are responsible of scintigraphic imaging modelling with the Monte Carlo Gate. Sterepid:
This national sponsored project (ANR PhysiCancer 2016) project aims at defining the performances of portal detectors (EPID) and developing quality control and in vivo dosimetry for complex fields in stereotactic radiotherapy.
OpenDose We initiated at the end of 2016 an international collaboration that aims at generating reference dosimetric data for nuclear medicine, based on the new voxel models proposed by the International Commission on Radiological Protection (ICRP).
ICRP Female Reference Model
Multicellular dosimetry
J Bordes: Modelling energy deposition for several isotopes (131I, 177Lu, 90Y) in realistic 3D models of follicular lymphoma (accepted for oral presentation at the forthcoming European Association of Nuclear Medicine congress – EANM - Vienna October 2017)
[36]
Objectives The deregulation of hematopoiesis at an early stage can lead to the transformation of progenitors and finally to acute leukemia (AL) defined as early blockage of differentiation (blastic stage) and uncontrolled proliferation of blasts. The impact of transcription factors (TF) alterations in the oncogenic process is poorly characterized. Since TF alterations are not directly targeted, we seek to find therapeutic targets by identifying the oncogenic relays of TF alterations: To this purpose, we identify TF alterations, study their impact on normal differentiation and evaluate their role in the leukemic process. Recently, we have identified recurrent mutations in AL patients that involve two PAX5 and GATA2 TFs. The somatic mutations of PAX5 are found in 1/3 of B-ALL (Familiades, 2009). To decipher the oncogenic mechanisms of PAX5 fusions (Bousquet, 2007; Coyaud, 2010), we generated
mice expressing one of these fusion. These mice develop a disease similar to a human B-ALL and we are studying this model by new-generation sequencing, FACS, transcriptomic analyzes to explain how this fusion can lead to oncogenesis. The germline mutations of GATA2 represent a familial disease with diverse clinical features, for which bone marrow transplantation is the only curative treatment (Pasquet, 2013). The absence of genotype / phenotype correlation is in favor of a distinct functional impact of the GATA2 mutants. We have modeled these alterations at the cellular and animal levels in order to establish the molecular links between GATA2 alterations and leukemic phenotype. We have shown in vitro that the R396Q mutation identified in a Toulouse family recapitulates the events of an AML (blockade of myeloid differentiation and excessive blast proliferation).
Staff
Cyril Broccardo CR Inserm, Bastien Gerby CR CNRS, Sylvie Hébrard Technician, Laura Jamrog Research assistant, PhD student Stéphanie Lagarde Research assistant, Marlène Pasquet Oncopediatrician, Isabelle Luquet Hospital practitionner, Naïs Prade Research associate, Stéphanie Struski Research associate
Team 16 – Alteration of transcription factors in acute leukemias Our team's work is part of a translational research through a
hospital component that allows diagnosis and also to investigate
the molecular causes (mutations) in patients with leukemia, and a
fundamental research component that models these causes in
cells or in mouse models in order to identify new therapeutic
targets.
Team Leader Eric Delabesse
Professor
[37]
Keywords: Acute leukemia, transcription factors, Pax5, gata2
Highlights
Labels / Grants:
Some publications in 2016 Homeobox NKX2-3 promotes marginal-zone lymphomage-nesis by activating B-cell receptor signalling and shaping lymphocyte dynamics. Robles EF, Mena-Varas M, Barrio L, Merino-Cortes SV, Balogh P, Du
MQ, Akasaka T, Parker A, Roa S, Panizo C, Martin-Guerrero I, Siebert R, Segura V, Agirre X, Macri-Pellizeri L, Aldaz B, Vilas-Zornoza A, Zhang S, Moody S, Calasanz MJ, Tousseyn T, Broccardo C, Brousset P, Campos-Sanchez E, Cobaleda C, Sanchez-Garcia I, Fernandez-
Luna JL, Garcia-Muñoz R, Pena E, Bellosillo B, Salar A, Baptista MJ, Hernandez-Rivas JM, Gonzalez M, Terol MJ, Climent J, Ferrandez A, Sagaert X, Melnick AM, Prosper F, Oscier DG, Carrasco YR, Dyer MJ, Martinez-Climent JA. Nat Commun. 2016 Jun 14;7:11889.
[38]
Objectives Using innovative technologies, we study the
roles of these PI3K isoforms in inter-cellular
interactions so as to propose innovative
therapies inhibiting PI3K-driven signalling
networks, and thus the tumour progression.
We apply our research to pancreatic cancer &
ovarian cancer, two cancers with a poor
pronostic.
Keywords: Inter- and intra-cellular signaling, membrane lipids, genetically modified mouse models, pancreatic cancer, ovarian cancer, cancerogenesis, PI3K
Staff
Jean-Pierre Delord Professor Céline Basset Professor associate Nicole Therville Research assistant
Postdoc fellow Benoit Thibaud
PhD students Silvia Arcucci Fernanda Ramos-Delgado Aurélie Vertut
Adrien Thole Internship
Team 17 - SIGDYN Group - PI3K isoforms, Signalling & Cancerogenesis
Cancer cells communicate in the organ where they develop: this communication aim to prevent the host to kill them, but cancer cells also use these signals at their advantage to create a favorable environment towards their development. This communication "network" in a tumour called signal network is thus the result of their interaction but also an Achille's heel that could be annihilated by targeted therapies. We accumulated data demonstrating that primary tumour development and its development at distance (metastasis) are directed by a family of molecules at the cross bridge of signaling networks, PI3Ks. They are present in 8 forms, so called "isoforms", both in cancer cells and in surrounding cells. We demonstrated that each of them have different actions.
Team Leader Julie Guillermet-
Guibert CR Inserm
[39]
Highlights
Class I PI3K isoforms & Therapeutic opportunities in Cancer
Towards a signal targeted therapy in pancreatic cancer. Pancreatic cancer is a lethal and aggressive cancer and few therapeutic options are available for these patients. We discovered that the PI3Kα is transmitting the signal of the main oncogene found in pancreatic cancer, KrasG12D, towards pancreatic cancer initiation, also when other cancer-promoting factors are present such as p53 activating mutation or inflammatory conditions. These results could serve as a base for an innovative targeted therapy for pancreatic cancer annihilating this signal. (PMID: 25452273)
Infertility could be the only secondary toxic effect of anti-PI3Kβ targeted therapy. Cancer treatment can be harmful for the normal surrounding cells. We discovered that the only secondary action of PI3Kβ inhibitors is masculine infertility. This occurs in the support cells of spermatogenesis, Sertoli cells, and could be reversible (PMID: 26132308).
Our work was awarded by Prix d'excellence scientifique Forcheur- Jean-Marie Lehn, at the French embassy in Berlin, with Dr Maximilien Reichert, Technische University Munich, Germany, in June 2017.
Labels / Grants: ARC, Fondation pour la Recherche Médicale, Ligue contre le cancer, LabEx
TOUCAN, PHUC CAPTOR
Publications in 2016
Morfoisse F, Tatin F, Hantelys F, Adoue A, Helfer AC, Cassant-Sourdy S, Pujol F, Gomez-
Brouchet A, Ligat L, Lopez F, Pyronnet S, Courty J, Guillermet-Guibert J, Marzi S, Schneider RJ, Prats AC, Garmy-Susini BH. Nucleolin Promotes
Heat Shock-Associated Translation of VEGF-D to Promote Tumor Lymphangio-genesis. Cancer Res. 2016 Aug 1;76(15):4394-405.
[40]
Objectives The biology of therapeutic resistance currently represents an active area of research. However, the molecular mechanisms underlying AML chemoresistance are still poorly understood, especially in the in vivo context. Our specific aim is to understand and target the mechanisms involved in the drug resistance in AML. We primarily focus on the role of the mitochondrial energetic and metabolic flexibility in the drug resistance of AML cells. We also study the interactions with stromal cells, which modulate their therapeutic resistance in the tumoral niche.
Using diverse metabolomic, transcriptomic, pharmacological and functional approaches as well as patient samples and a newly developed AML-engrafted immunodeficient model, we aim to : i) elucidate the stemness and functional heterogeneity of RLCs in response to genotoxics in vivo, ii) determine how mitochondrial energy and metabolic networks drive the drug resistance of RLCs in vivo, and iii) define the role of the energetic symbiosis and metabolic dialogue between the stromal compartment and leukemic blasts in the bone marrow niche.
Keywords: Leukemia, drug resistance, patient derived xenograft, mitochondria, énergetics, oncometabolism, catabolic flexibility, clonal heterogeneity, single cell signature, cancer stem cells, inflammation, signaling, innovative therapeutics
Staff Researchers / Professors Christian Récher François Vergez Florence Cabon Odile Beyne-Rauzy Lucille Stuani Mohsen Hosseini Clément Larrue
Research assistants Latifa Jarrou Estelle Saland Mathilde Gotanegre
PhD students Nesrine Aroua Gabriel Lemercier Pierre-Luc Mouchel Thomas Farge Claudie Bosc
Alumni Héléna Boutzen Sarah Scotland
Team 18 - RESISTAML – Drug resistance and oncometabolism in acute myeloid leukemia
Despite a high rate of complete remission after treatment with genotoxic
agents, the prognosis is poor in human acute myeloid leukemia (AML).
Indeed, 5-year overall survival is about 30 to 40% in patients younger than
60 years old and less than 20% in patients over 60. Front-line
chemotherapy is highly effective in ablating leukemic cells, but distant
relapses are observed in the majority of patients, characterized by a
refractory phase during which no other treatment has shown any efficacy
thus far. Relapses are caused by tumor regrowth initiated by resistant
leukemic clones (RLCs). The goal of our team is to understand the causes
of the drug resistance for the development of new treatments eradicating
RLCs and overcoming patient relapses.
Team Leader Jean-Emmanuel
Sarry CR Inserm
[41]
Highlights Cytarabine (AraC) resistant AML cells are not enriched in immature (CD34+CD38-) cells, quiescent cells, LSCs but have HIGH OXPHOS gene signature and functions, depend on fatty acid oxidation and overexpress fatty acid transporter CD36. Metabolic redirection and flexibility, redox homeostasis, ROS and iron metabolism, MPTP and VDAC-HK2 supra-complex, and autophagy-driven nutriment oxidation are key players in mitochondrial oxidative phosphorylation and AraC resistance in AML cells in vivo. We have established a robust PDX-based preclinical model to predict response to AraC in mice and in patients to characterize MRD and chemoresistance, and to identify new therapeutic targets (CD36, CD39, MPO and new GPCRs). Future studies will address in vivo resistance to other conventional (IDA alone, IDA+AraC) or targeted therapies (FLT3i, BCL2i, MCL1i, IDHmi) in AML cells. Using this robust PDX-chemo model, RESISTAML team will assess single cell-based clonal heterogeneity and predict relapse in patients to assist interventional decision for consolidation chemotherapies and/or treatment at relapse (Project & clinical trial COMPAML: mice COMpanion for Acute Myeloid Leukemia).
Selected grants/awards: Projet Hospitalo-Universitaire en Cancérologie CAPTOR, LabEx TOUCAN, Programme d'Excellence PSPC IMODI, LabEx OncoDevice Co-founder and coordinator of the Cancéropole GSO Network “MetaboCancer GSO”
Some publications in 2016 Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T, Saland E, Castellano R, Pouyet L, Collette Y, Vey N, Chabannon C, Récher C, Sarry JE, Alcor D, Peyron JF, Griessinger E. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 2016;128(2): 253-64.
Boutzen H, Saland E, Larrue C, de Toni F, Gales L, Castelli F, Stuani L, Zaghdoudi S, David M, Mansat-de Mas V, Delabesse E, Kaoma T, Vallar L, Linares L, Junot C, Portais JC, Vergez F, Récher C, Sarry JE. Isocitrate dehydrogenase 1 muta-tions prime the all-trans-retinoic acid myeloid differentiation pathway in
acute myeloid leukemia. J Exp. Med. 2016; 213(4):483-97. Larrue C, Saland E, Boutzen H, Vergez F, David M, Joffre C, Hospital MA, Tamburini J, Delabesse E, Manenti S, Sarry JE, Récher C. Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells. Blood. 2016 ;127(7):882-92.
[42]
[43]
Core facilities
[44]
Overview The members of the Technology Cluster provide scientific and technical expertise in a broad range of areas :
Proteomics (biochemical & mass spectrometry) and molecular interactions (Biacore technology)
Imaging (confocal microscope and video microscope)
Flow cytometry and cell sorting
Gene transfer vector (biosafety L3 lab)
Transcriptomics
Production of monoclonal antibodies
Bioinformatics
Inserm Biological Resource Centre for Blood Malignancies (HIMIP).
Their mission is to provide support for any projects regarding design, experiments, training with specific equipments, and interpretation of results.
Staff
Ouafa Boulahian-Zaki Véronique de Mas Manon Farcé Tiphaine Fraineau Laetitia Ligat Frédéric Pont Nathalie Saint-Laurent Emeline Sarot Christèle Ségura Laure Tonini Carine Valle Loïc van den Berghe
Technology Cluster of the CRCT The Technology Cluster of CRTC gathers several core facilities in order to enable their collegial operation and the sharing of facilities and resources.
Cluster manager Frédéric Lopez
Research associate
[45]
Highlights
Fig.4 : Distribution of income generated by the different services of the technological cluster
0
10000
20000
30000
40000
50000
60000
RECETTES 2016 HT
RECETTES 2015 HT
In 2016, the resources received by the techologival cluster were provided by Inserm, remainder budget from 2015, contracts and services (Fig.1). The services have doubled compared to 2015, and have generated 46 % of the resources (Fig.2). The distribution of the resources generated by the different cores are shown in the Fig.3. Fig.4 shows the comparison between the activity of the different cores in 2015 and 2016.
Fig.1 : Fundings obtained by the cluster Fig.2 : Evolution of the resources resulting from the services
9
20
4
2415
1 12
86
Fig.3: % Total resources
DOTATION INSERM
CYTO Tri Cellulaire
CYTOTHEQUE HIMIP
Vectorologie
Protéomique
INTER MOL Biacore
Imagerie
Transcriptomique
Bioinformatique
[46]
Biological Resource Centre (BRC)
The BRC houses the HIMIP tumour library (samples from Blood Malignancies in the Midi-Pyrénées Region) for storing human samples both for treatment purposes and for research. The tumour library was set up in order to participate in research programmes on blood malignancies concerning both the characterisation of oncogenetic mechanisms, therapeutic optimisation and the identification of new prognostic criteria.
HIMIP includes samples from patients with acute myeloid leukaemia, chronic lymphoid leukaemia, acute lymphoblastic leukaemia, myelodysplastic syndromes, chronic myelomonocytic leukaemia, chronic myeloid leukaemia, myeloproliferative syndromes, lymphomas and lymphoproliferative syndromes.
Cytometry & Cell sorting
The Cytometry and Cell Sorting Core is open to academic and private scientists. The Platform is equipped with 4 analysers, a high-speed cell sorter and a magnetic automated cell sorting system.
Services : Cell analysis and sorting Advice and assistance for users regarding the acquisition, analysis and interpretation of data Training of independant users Cell sorting only by the Platform’s staff Maintenance of all equipment, and technology watch Compilation and communication of analytical results.
Cell Imaging
The Cell Imaging Core is open to the academic and private scientists. The platform is equipped with 3 fluorescence microscopes, and is based in a Biosafety L2 section of the Technology Cluster. The platform also benefits from a fully-equipped cell culture laboratory and a service area dedicated to data analysis.
Services : Cell imaging for public or private sector research organisations Advice and assistance for users regarding image acquisitions and analysis Training of users so they can use the microscopes independently Maintenance of all equipment and technology watch Compilation and communication of analytical results.
Monoclonal Antibodies
The Monoclonal Antibody Core Facility is under the responsibility of Prof. Pierre Brousset, and results from the research activities of his team. The facility provides mouse monoclonal antibodies for the CRCT teams.
[47]
Apart from the Technology Cluster, the researchers of the CRCT are working in close collaboration with the the animal facility – CREFRE – UMS006 - which is located in the same building. This core facility provides its expertise in transgenesis, microsurgery, non invasive
phenotyping, irradiation, exploration and imaging.
Genomics & Transcriptomics
Dedicated to the analysis of nucleic sequences and their expression, the Platform currently benefits from quantitative PCR systems and polysome fractionation equipment for analysis of the traductome. The Platform recently acquired a high-performance array scanner (Illumina iScan) that enables methylation, expression, genotyping, cytogenomics analyses …
Services :
qPCR: two StepOne Plus systems (Applied Biosystems, Life Technologies) qPCR: one Abi7500 (Applied, Life Technologies) polysome profiling: a fraction collector for density gradient (ISCO) iScan array scanner (Illumina)
Proteomics
The Proteomics Core Facility offers technological expertise on protein fractionation and profiling, and on the study of molecular interactions to academic and private teams. The Proteomics Core Facility is operating on technological developments dedicated to issues of both clinical and basic research, from the establishment of protein profiles (2D-DIGE, SELDI-TOF) and peptide (CE-MS, Chip-MS) to the identification by mass spectrometry of interaction partners (BIA-MS) and biomarkers or potential pharmacological targets for the development of diagnostic tools.
Gene transfer Vector
The Vector Core Facility has developed know-how centered on the production of two types of recombinant viral vectors : lentiviruses and adeno-associated viruses (AAV).
[48]
[49]
Post-graduate education programmes
Master students were registered in various education programmes :
• Bioinformatics
– Bioinformatics & Systemic biology
• Biology - Health
– Oncology
– Genes, cells, development
– Immunology & infectious diseases
– Pharmacology Innovation and drug profession
– Pathophysiology : from molecule to medicine
– Digestive health & nutrition
– Gene transfer vector, gene therapy & vaccines
• Biotechnologies
– Gene expression & recombinant proteins
– Molecular microbiology
– Structural and functional biochemistry
• Chemistry
– Chemistry - Health
• Ethics
– Health & Research ethics
• Public health
– Coordination of health care pathway for patients with chronic / degenerative
diseases
In 2016, the CRCT hosted 61 PhD students, from France and 11 other countries.
Other students from graduate (64) and undergraduate (37) programmes as well as students
from Medicine (3) & Pharmacy (1) faculties, and Engineer schools (4) have done training
courses or internships in the CRCT.
[50]
Scientific and administrative staff
In 2016, the CRCT gathered
- 121 researchers, professors,
associate professors, and hospital
practitioners
- 67 researchers with HDR
- 109 research asssociates, research
assistants, and technicians
- 28 post-doctoral fellows
- 61 PhD students
- 112 trainees.
From the creation of the CRCT to the end of 2016, Jean-Jacques Fournié was the director of
the CRCT, with Stéphane Pyronnet as the deputy director and Sébastien Guibert as the
administrative director. Gilles Favre succeeded Jean-Jacques Fournié as the new director on
January 1st, 2017.
Flow chart
Direction of CRCTResearch teams
1 Ayyoub2 Hoffmann
3 Favre4 Levade/Andrieu
5 Millevoi6 Pyronnet/
Bousquet7 Brousset8 Manenti/
Besson9 Fournié
10 Cordelier11 Moyal/Toulas
12 Poirot/ Silvente-Poirot13 Avet-Loiseau
14 Chatelut15 Bardiès
16 Delabesse17 Guillermet-Guibert/Delord18 Sarry/Récher
TechnologyCluster
Bioinformatics
Biologicalressources
Cytometry & cell sorting
Cellular imaging
mABproduction
Proteomics & molecular
interactions
Genomics & transcriptomics
Vectorology
Support services
Administration
General administration
Teams & Techno. Center ressources
management
Trainees conventions
Reception desk
Scientific partnerships & communication
Logistics
Building supervision
Technicalservices
General storehouse
IT
Glass wash & sterilization
Security
HS
Prevention/ H&S
Radio-protection
[51]
CRCT administration
The CRCT benefits from the support of the Administration Déléguée de l’Inserm Midi-
Pyrénées-Limousin (now Occitanie Pyrénées) for the financial and human resources
management of the projects. However, a management team also operates in-door for the
global operating of the CRCT.
As the Administrative
director, Sébastien
Guibert supervises
the management
team.
General administration Laurence Granier Welcome desk Ambre Santin Administrative & financial ressources department Anne-Marie Bénot : Teams 7-9, 11, 18 Marie-Hélène Lalaux : Teams 1-2, 12-16 Marie-Josèphe Lignon : Teams 5-6, 10, 17 Géraldine Touriol : Teams 3-4, and Core facilities Emilie Martin : Management team Trainee conventions department Christiane Bejarano IT department Pierre Cosso Scientific partnerships Dominique Lautier
Health & Safety, Radioprotection Catherine Ordener Magali Diette Building supervision department Pauline Lironcourt Nathalie Delanne Storehouse department Joël Teyssier Nathalie Perez Glass wash & media preparation Nathalie Perez Patricia Clavé Technical services Cédric Capilla Julien Bories
[52]
CRCT Resources
The CRCT received public fundings from
Inserm, Université Toulouse III Paul Sabatier
and CNRS.
In addition to these fundings, Inserm, CNRS,
Université Paul Sabatier, Toulouse hospital and
Institut Claudius Regaud provide salaries for
their respective permanent personal, including
researchers, clinicians, professors and
professor associates, research associates and
assistants, and technicians.
Moreover, non-permanent staff (for an
additional budget of 4,972,080 €) are also
employed by the CRCT.
Following succesful applications to various
Calls for proposals, the CRCT received
competitive grants from :
Agence Nationale de la Recherche, Cancéropole Grand Sud-Ouest, Fondation ARC, Association Laurette Fugain, EURAMET, Euratom, Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, Fondation Toulouse Cancer Santé, Horizon 2020, Institut Claudius Regaud, Institut National du Cancer, Ligue contre le Cancer, Région Occitanie, Toulouse Hospital, Toulouse Métropole, Transcan-2, Université Fédérale Toulouse Midi-Pyrénées.
Other fundings result from contracts with pharmaceuticals Companies (AstraZeneca, Celgene, Cisbio, Evotec, Genentech, GSK, Novartis, Pierre Fabre, Roche, Sanofi… )
9,490,054 €
Inserm
3 944 206
UT3
3 137 851
CNRS
1 236 734
CHU
475 828
ICR
635 949
Other 59 486
780,344 €
5,325,746 €
[53]
5 325 746 €
[54]
Scientific Advisory Board
The scientific Advisory Board (SAB) includes scientists and clinicians from France and abroad.
The SAB members have been chosen for their expertise and their independance from the CRCT
researchers.
Member Institution Town, Country
Maria Blasco Centro Nacional de Investigaciones Oncologicas
Madrid, Spain
Patrick Couvreur Université Paris-Sud Paris, France
Anne Dejean Institut Pasteur Paris, France
Jean-Marc Egly Institut de Génétique et de Biologie Moléculaire et Cellulaire
Strasbourg, France
Bruno Goud Institut Curie Paris, France
John A. Hickman IMI Coordinator Paris, France
Liselotte Hoejgaard Rigshospitalet, University of Copenhagen
Copenhagen, Denmark
Cyril M. Kay University of Alberta Edmonton, Canada
Gillies McKenna Oxford Institute for Radiation Oncology
Oxford, United Kingdom
Jacques Pouysségur Institut de Recherche sur le Cancer et le Vieillissement
Nice, France
Josep Tabernero Vall d'Hebron Institute of Oncology Barcelona, Spain
William Vainchenker Institut Gustave Roussy Villejuif, France
Benoit Van den Eynde Ludwig Institute Bruxelles, Belgium
[55]
Scientific production
[56]
Publications in 2016
Abbo O, Gas J, Pinnagoda K, Tournier E, Bouali O,
Castex MP, Lamant L, Galinier P. Pediatr Blood Cancer.
2016 Nov 1. Sclerosing sweat duct carcinoma of the penis in
a 4-year-old child.
Adsay V, Mino-Kenudson M, Furukawa T, Basturk O,
Zamboni G, Marchegiani G, Bassi C, Salvia R, Malleo G,
Paiella S, Wolfgang CL, Matthaei H, Offerhaus GJ, Adham
M, Bruno MJ, Reid MD, Krasinskas A, Klöppel G, Ohike N,
Tajiri T, Jang KT, Roa JC, Allen P, Fernández-del Castillo C,
Jang JY, Klimstra DS, Hruban RH; Members of Verona
Consensus Meeting, 2013.. Ann Surg. 2016 Jan;263(1):162-
77. Pathologic Evaluation and Reporting of Intraductal
Papillary Mucinous Neoplasms of the Pancreas and Other
Tumoral Intraepithelial Neoplasms of Pancreatobiliary Tract:
Recommendations of Verona Consensus Meeting.
Alberto C, Konstantinou MP, Martinage C, Casassa E,
Tournier E, Bagheri H, Sibaud V, Mourey L, Mazereeuw-
Hautier J, Meyer N, Paul C, Bulai Livideanu C. J Dermatol
Case Rep. 2016 Nov 13;10(2):35-8. Enzalutamide induced
acute generalized exanthematous pustulosis.
Alric L, Besson C, Lapidus N, Jeannel J, Michot JM,
Cacoub P, Canioni D, Pol S, Davi F, Rabiega P, Ysebaert L,
Bonnet D, Hermine O. PLoS One. 2016 Oct
17;11(10):e0162965. Antiviral Treatment of HCV-Infected
Patients with B-Cell Non-Hodgkin Lymphoma: ANRS HC-
13 Lympho-C Study.
Alyami M, Lundberg P, Kepenekian V, Goéré D, Bereder
JM, Msika S, Lorimier G, Quenet F, Ferron G, Thibaudeau E,
Abboud K, Lo Dico R, Delroeux D, Brigand C, Arvieux C,
Marchal F, Tuech JJ, Guilloit JM, Guyon F, Peyrat P, Pezet
D, Ortega-Deballon P, Zinzindohoue F, de Chaisemartin C,
Kianmanesh R, Glehen O, Passot G; BIG-RENAPE and
RENAPE Working Groups.. Ann Surg Oncol. 2016
Dec;23(Suppl 5):737-45. Cytoreductive Surgery and
Hyperthermic Intraperitoneal Chemotherapy for Peritoneal
Carcinomatosis in the Elderly: A Case-Controlled,
Multicenter Study.
Arcondéguy T, Touriol C, Lacazette E. Methods Mol
Biol. 2016;1459:127-34. Quantification of a Non-
conventional Protein Secretion: The Low-Molecular-Weight
FGF-2 Example.
Armand-Labit V, Meyer N, Casanova A, Bonnabau H,
Platzer V, Tournier E, Sansas B, Verdun S, Thouvenot B,
Hilselberger B, Doncescu A, Lamant L, Lacroix-Triki M,
Favre G, Pradines A. Acta Derm Venereol. 2016
Jan;96(1):29-34. Identification of a Circulating MicroRNA
Profile as a Biomarker of Metastatic Cutaneous Melanoma.
Arnaud FX, Paillas S, Pouget JP, Incerti S, Bardies M,
Bordage MC.. Nucl Instrum Meth B. 2016;366:227-33.
Complex cell geometry and sources distribution model for
Monte Carlo single cell dosimetry with iodine 125
radioimmunotherapy.
Astudillo L, Sabourdy F, Touati G, Levade T. Presse
Med. 2016 Mar;45(3):302-12. doi:
10.1016/j.lpm.2015.05.009. Epub 2016 Feb 18. Review.
French. [Hereditary peroxisomal diseases].
Astudillo L, Therville N, Colacios C, Ségui B, Andrieu-
Abadie N, Levade T. Biochimie. 2016 Jun;125:267-80.
Glucosylceramidases and malignancies in mammals.
Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA,
Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova
V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky
R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger
W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M,
Moreau P. Blood. 2016 Sep 1;128(9):1174-80. Carfilzomib
significantly improves the progression-free survival of high-
risk patients in multiple myeloma.
Avet-Loiseau H. Am Soc Clin Oncol Educ Book.
2016;35:e425-30. Minimal Residual Disease by Next-
Generation Sequencing: Pros and Cons.
Baert-Desurmont S, Charbonnier F, Houivet E, Ippolito
L, Mauillon J, Bougeard M, Abadie C, Malka D, Duffour J,
Desseigne F, Colas C, Pujol P, Lejeune S, Dugast C, Buecher
B, Faivre L, Leroux D, Gesta P, Coupier I, Guimbaud R,
Berthet P, Manouvrier S, Cauchin E, Prieur F, Laurent-Puig
P, Lebrun M, Jonveaux P, Chiesa J, Caron O, Morin-Meschin
ME, Polycarpe-Osaer F, Giraud S, Zaanan A, Bonnet D,
Mansuy L, Bonadona V, El Chehadeh S, Duhoux F, Gauthier-
Villars M, Saurin JC, Collonge-Rame MA, Brugières L,
Wang Q, Bressac-de Paillerets B, Rey JM, Toulas C, Buisine
MP, Bronner M, Sokolowska J, Hardouin A, Cailleux AF,
Sebaoui H, Blot J, Tinat J, Benichou J, Frebourg T. Eur J Hum
Genet. 2016 Jan;24(1):99-105. Clinical relevance of 8q23,
15q13 and 18q21 SNP genotyping to evaluate colorectal
cancer risk.
Baranger L, Cuccuini W, Lefebvre C, Luquet I, Perot C,
Radford I, Lafage-Pochitaloff M. Ann Biol Clin (Paris). 2016
Oct 1;74(5):547-60. Review. Cytogenetics in the
management of children and adult acute lymphoblastic
leukemia (ALL): an update by the Groupe francophone de
cytogénétique hématologique (GFCH).
Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J,
Lena H, Ouafik L, Besse B, Rouquette I, Westeel V, Escande
F, Monnet I, Lemoine A, Veillon R, Blons H, Audigier-
Valette C, Bringuier PP, Lamy R, Beau-Faller M, Pujol JL,
Sabourin JC, Penault-Llorca F, Denis MG, Lantuejoul S,
Morin F, Tran Q, Missy P, Langlais A, Milleron B, Cadranel
J, Soria JC, Zalcman G; Biomarkers France contributors..
Lancet. 2016 Apr 2;387(10026):1415-26. Routine molecular
profiling of patients with advanced non-small-cell lung
cancer: results of a 1-year nationwide programme of the
French Cooperative Thoracic Intergroup (IFCT).
Barrow-McGee R, Kishi N, Joffre C, Ménard L, Hervieu
A, Bakhouche BA, Noval AJ, Mai A, Guzmán C, Robert-
Masson L, Iturrioz X, Hulit J, Brennan CH, Hart IR, Parker
PJ, Ivaska J, Kermorgant S. Nat Commun. 2016 Jun
23;7:11942. Beta 1-integrin-c-Met cooperation reveals an
inside-in survival signalling on autophagy-related
endomembranes. Nat Commun. 2016 Jul 22;7:12392.
Corrigendum: Beta 1-integrin-c-Met cooperation reveals an
inside-in survival signalling on autophagy-related
endomembranes.
Becht E, de Reyniès A, Giraldo NA, Pilati C, Buttard B,
Lacroix L, Selves J, Sautès-Fridman C, Laurent-Puig P,
[57]
Fridman WH. Clin Cancer Res. 2016 Aug 15;22(16):4057-
66. Immune and Stromal Classification of Colorectal Cancer
Is Associated with Molecular Subtypes and Relevant for
Precision Immunotherapy.
Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N,
Petitprez F, Selves J, Laurent-Puig P, Sautès-Fridman C,
Fridman WH, de Reyniès A. Genome Biol. 2016 Oct
20;17(1):218. Estimating the population abundance of tissue-
infiltrating immune and stromal cell populations using gene
expression. Erratum in: Genome Biol. 2016 Dec 1;17 (1):249.
Genome Biol. 2016 Dec 1;17(1):249. Erratum to: Estimating
the population abundance of tissue-infiltrating immune and
stromal cell populations using gene expression.
Belliere J, Meyer N, Mazieres J, Ollier S, Boulinguez S,
Delas A, Ribes D, Faguer S. Br J Cancer. 2016 Dec
6;115(12):1457-61. Acute interstitial nephritis related to
immune checkpoint inhibitors.
Bennani Smires Y, Victor G, Ribes D, Berry M, Cognet
T, Méjean S, Huart A, Roussel M, Petermann A, Roncalli J,
Carrié D, Rousseau H, Berry I, Chauveau D, Galinier M,
Lairez O. Int J Cardiovasc Imaging. 2016 Sep;32(9):1403-13.
Pilot study for left ventricular imaging phenotype of patients
over 65 years old with heart failure and preserved ejection
fraction: the high prevalence of amyloid cardiomyopathy.
Béroud C, Letovsky SI, Braastad CD, Caputo SM,
Beaudoux O, Bignon YJ, Bressac-De Paillerets B, Bronner
M, Buell CM, Collod-Béroud G, Coulet F, Derive N,
Divincenzo C, Elzinga CD, Garrec C, Houdayer C, Karbassi
I, Lizard S, Love A, Muller D, Nagan N, Nery CR, Rai G,
Revillion F, Salgado D, Sévenet N, Sinilnikova O, Sobol H,
Stoppa-Lyonnet D, Toulas C, Trautman E, Vaur D, Vilquin
P, Weymouth KS, Willis A; Laboratory Corporation of
America Variant Classification Group.; Quest Diagnostics
Variant Classification Group.; UNICANCER Genetic Group
BRCA Laboratory Network., Eisenberg M, Strom CM. Hum
Mutat. 2016 Dec;37(12):1318-28. BRCA Share: A Collection
of Clinical BRCA Gene Variants.
Berquet L, Valleron W, Grgurevic S, Quelen C, Zaki O,
Quillet-Mary A, Davi F, Brousset P, Bousquet M, Ysebaert
L. Br J Haematol. 2016 Mar;172(5):819-23. Small nucleolar
RNA expression profiles refine the prognostic impact of
IGHV mutational status on treatment-free survival in chronic
lymphocytic leukaemia.
Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca
C, Yee K, Taussig DC, Rezai K, Roumier C, Herait P, Kahatt
C, Quesnel B, Michallet M, Recher C, Lokiec F,
Preudhomme C, Dombret H. Lancet Haematol. 2016
Apr;3(4):e186-95. Bromodomain inhibitor OTX015 in
patients with acute leukaemia: a dose-escalation, phase 1
study.
Bertoli S, Sterin A, Tavitian S, Oberic L, Ysebaert L,
Bouabdallah R, Vergez F, Sarry A, Bérard E, Huguet F,
Laurent G, Prébet T, Vey N, Récher C. Oncotarget. 2016 Dec
27;7(52):85937-47. Therapy-related acute myeloid leukemia
following treatment of lymphoid malignancies.
Bertrand F, Rochotte J, Colacios C, Montfort A, Andrieu-
Abadie N, Levade T, Benoist H, Ségui B. Oncoimmunology.
2016; 5(1): e1068495. Targeting TNF alpha as a novel
strategy to enhance CD8+ T cell-dependent immune response
in melanoma?
Bertucci F, Fekih M, Autret A, Petit T, Dalenc F, Levy C,
Romieu G, Bonneterre J, Ferrero JM, Kerbrat P, Soulie P,
Mouret-Reynier MA, Bachelot T, Lerebours F, Eymard JC,
Deblock M, Lortholary A, Hardy-Bessard AC, Barthelemy P,
Bonnefoi H, Charafe-Jauffret E, Bidard FC, Viens P,
Lemonnier J, Pierga JY. Lancet Oncol. 2016 May;17(5):600-
11. dBevacizumab plus neoadjuvant chemotherapy in
patients with HER2-negative inflammatory breast cancer
(BEVERLY-1): a multicentre, single-arm, phase 2 study.
Besson-Fournier C, Martinez M, Vinel JP, Aguilar-
Martinez P, Coppin H, Roth MP. Hepatology. 2016
Jun;63(6):2054-5. Further support for the association of
GNPAT variant rs11558492 with severe iron overload in
hemochromatosis.
Bétous R, Renoud ML, Hoede C, Gonzalez I, Jones N,
Longy M, Sensebé L, Cazaux C, Hoffmann JS. Stem Cells
Transl Med. 2016 Aug 24. pii: sctm.2015-0401. Human
Adipose-Derived Stem Cells Expanded Under Ambient
Oxygen Concentration Accumulate Oxidative DNA Lesions
and Experience Procarcinogenic DNA Replication Stress.
Betrian S, Ysebaert L, Heider KH, Delord JP, Fournié JJ,
Quillet-Mary A. Blood Cancer J. 2016 Nov 11;6(11):e496.
Idelalisib improves CD37 antibody BI 836826 cytotoxicity
against chemo-resistant /relapse-initiating CLL cells: a
rationale for combination treatment.
Bettoun A, Joffre C, Zago G, Surdez D, Vallerand D,
Gundogdu R, Sharif AA, Gomez M, Cascone I, Meunier B,
White MA, Codogno P, Parrini MC, Camonis JH, Hergovich
A. Oncotarget. 2016 Jul 12;7(28):44142-60. Mitochondrial
clearance by the STK38 kinase supports oncogenic Ras-
induced cell transformation.
Bielle F, Ducray F, Mokhtari K, Dehais C, Adle-Biassette
H, Carpentier C, Chanut A, Polivka M, Poggioli S, Rosenberg
S, Giry M, Marie Y, Duyckaerts C, Sanson M, Figarella-
Branger D, Idbaih A; Pola Network.. Brain Pathol. 2016 Aug
20. Tumor cells with neuronal intermediate progenitor
features define a subgroup of 1p/19q co-deleted anaplastic
gliomas.
Blake SJ, Stannard K, Liu J, Allen S, Yong MC, Mittal
D, Aguilera AR, Miles JJ, Lutzky VP, de Andrade LF,
Martinet L, Colonna M, Takeda K, Kühnel F, Gurlevik E,
Bernhardt G, Teng MW, Smyth MJ. Cancer Discov. 2016
Apr;6(4):446-59. Suppression of Metastases Using a New
Lymphocyte Checkpoint Target for Cancer Immunotherapy.
Boissard F, Laurent C, Ramsay AG, Quillet-Mary A,
Fournié JJ, Poupot M, Ysebaert L. Blood Cancer J. 2016 Jan
15;6:e381. Nurse-like cells impact on disease progression in
chronic lymphocytic leukemia.
Boissard F, Tosolini M, Ligat L, Quillet-Mary A, Lopez
F, Fournié JJ, Ysebaert L, Poupot M. Oncotarget. 2016 Nov
26. Nurse-like cells promote CLL survival through LFA-
3/CD2 interactions.
Bolli N, Li Y, Sathiaseelan V, Raine K, Jones D, Ganly
P, Cocito F, Bignell G, Chapman MA, Sperling AS, Anderson
KC, Avet-Loiseau H, Minvielle S, Campbell PJ, Munshi NC.
Blood Cancer J. 2016 Sep 2;6(9):e467. A DNA target-
enrichment approach to detect mutations, copy number
changes and immunoglobulin translocations in multiple
myeloma.
Bonafé L, Kariminejad A, Li J, Royer-Bertrand B, Garcia
V, Mahdavi S, Bozorgmehr B, Lachman RL, Mittaz-Crettol
L, Campos-Xavier B, Nampoothiri S, Unger S, Rivolta C,
Levade T, Superti-Furga A. Arthritis Rheumatol. 2016
[58]
Sep;68(9):2323-7. Brief Report: Peripheral Osteolysis in
Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A
New Presentation of Farber's Disease.
Bonnefoi H, Grellety T, Tredan O, Saghatchian M,
Dalenc F, Mailliez A, L'Haridon T, Cottu P, Abadie-
Lacourtoisie S, You B, Mousseau M, Dauba J, Del Piano F,
Desmoulins I, Coussy F, Madranges N, Grenier J, Bidard FC,
Proudhon C, MacGrogan G, Orsini C, Pulido M, Gonçalves
A. Ann Oncol. 2016 May;27(5):812-8. A phase II trial of
abiraterone acetate plus prednisone in patients with triple-
negative androgen receptor positive locally advanced or
metastatic breast cancer (UCBG 12-1).
Bonnet-Magnaval F, Philippe C, Van Den Berghe L,
Prats H, Touriol C, Lacazette E. Biochem Biophys Res
Commun. 2016 Oct 14;479(2):365-71. Hypoxia and ER
stress promote Staufen1 expression through an alternative
translation mechanism.
Bordage MC, Bordes J, Edel S, Terrissol M, Franceries
X, Bardiès M, Lampe N, Incerti S. Phys Med. 2016
Dec;32(12):1833-40. Implementation of new physics models
for low energy electrons in liquid water in Geant4-DNA.
Bouchahda M, Boige V, Smith D, Karaboué A, Ducreux
M, Hebbar M, Lepère C, Focan C, Guimbaud R, Innominato
P, Awad S, Carvalho C, Tumolo S, Truant S, De Baere T,
Castaing D, Rougier P, Morère JF, Taieb J, Adam R, Lévi F;
ARTBC International.. Eur J Cancer. 2016 Nov;68:163-72.
Early tumour response as a survival predictor in previously-
treated patients receiving triplet hepatic artery infusion and
intravenous cetuximab for unresectable liver metastases from
wild-type KRAS colorectal cancer.
Bouquerel P, Gstalder C, Müller D, Laurent J, Brizuela L,
Sabbadini RA, Malavaud B, Pyronnet S, Martineau Y, Ader
I, Cuvillier O. Oncogenesis. 2016 Mar 14;5:e209. Essential
role for SphK1/S1P signaling to regulate hypoxia-inducible
factor 2α expression and activity in cancer.
Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L.
Eur J Cancer. 2016 Feb;54:75-83. Targeting KRAS for
diagnosis, prognosis, and treatment of pancreatic cancer:
Hopes and realities.
Bournet B, Muscari F, Buscail C, Assenat E, Barthet M,
Hammel P, Selves J, Guimbaud R, Cordelier P, Buscail L.
Clin Transl Gastroenterol. 2016 Mar 24;7:e157. KRAS G12D
Mutation Subtype Is A Prognostic Factor for Advanced
Pancreatic Adenocarcinoma.
Bournet B, Vignolle-Vidoni A, Grand D, Roques C,
Breibach F, Cros J, Muscari F, Carrère N, Selves J, Cordelier
P, Buscail L. Endosc Int Open. 2016 Dec;4(12):E1228-
E1235. Endoscopic ultrasound-guided fine-needle aspiration
plus KRAS and GNAS mutation in malignant intraductal
papillary mucinous neoplasm of the pancreas.
Bousquet E, Calvayrac O, Mazières J, Lajoie-Mazenc I,
Boubekeur N, Favre G, Pradines A. Oncogene. 2016 Apr
7;35(14):1760-9. RhoB loss induces Rac1-dependent
mesenchymal cell invasion in lung cells through PP2A
inhibition.
Bousquet M, Noirot C, Accadbled F, Sales de Gauzy J,
Castex MP, Brousset P, Gomez-Brouchet A. Ann Oncol.
2016 Apr;27(4):738-44. Whole-exome sequencing in
osteosarcoma reveals important heterogeneity of genetic
alterations.
Boutzen H, Saland E, Larrue C, de Toni F, Gales L,
Castelli FA, Cathebas M, Zaghdoudi S, Stuani L, Kaoma T,
Riscal R, Yang G, Hirsch P, David M, De Mas-Mansat V,
Delabesse E, Vallar L, Delhommeau F, Jouanin I, Ouerfelli
O, Le Cam L, Linares LK, Junot C, Portais JC, Vergez F,
Récher C, Sarry JE. J Exp Med. 2016 Apr 4;213(4):483-97.
Isocitrate dehydrogenase 1 mutations prime the all-trans
retinoic acid myeloid differentiation pathway in acute
myeloid leukemia.
Boyle E, Manier S, Lejeune J, Fouquet G, Guidez S,
Bonnet S, Debarri H, Demarquette H, Dulery R, Gay J,
Hennache B, Onraed B, Faucompré JL, Schraen S, Facon T,
Avet-Loiseau H, Chevret S, Leblond V, Harding S, Leleu X.
Clin Cancer Res. 2016 Oct 15;22(20):5152-8. IgMκ and
IgMλ Measurements for the Assessment of Patients with
Waldenström's Macroglobulinaemia.
Branco B, Metsu D, Dutertre M, Marchou B, Delobel P,
Recher C, Martin-Blondel G. Ann Hematol. 2016
Jun;95(7):1207-9. Use of rifampin for treatment of
disseminated tuberculosis in a patient with primary
myelofibrosis on ruxolitinib.
Buhard O, Lagrange A, Guilloux A, Colas C, Chouchène
M, Wanherdrick K, Coulet F, Guillerm E, Dorard C, Marisa
L, Bokhari A, Greene M, El-Murr N, Bodo S, Muleris M,
Sourouille I, Svrcek M, Cervera P, Blanché H, Lefevre JH,
Parc Y, Lepage C, Chapusot C, Bouvier AM, Gaub MP,
Selves J, Garrett K, Iacopetta B, Soong R, Hamelin R,
Garrido C, Lascols O, André T, Fléjou JF, Collura A, Duval
A. J Med Genet. 2016 Jun;53(6):377-84. HSP110 T17
simplifies and improves the microsatellite instability testing
in patients with colorectal cancer.
Bulai Livideanu C, Apoil PA, Lepage B, Eischen M,
Laurent C, Laharrague P, Lamant L, Tournier E, Tavitian S,
Pouplard C, Recher C, Laroche M, Mailhol C, Dubreuil P,
Hermine O, Blancher A, Paul C. Clin Exp Allergy. 2016
Jan;46(1):133-41. Bone marrow tryptase as a possible
diagnostic criterion for adult systemic mastocytosis.
Bureau C, Laurent J, Robic MA, Christol C, Guillaume
M, Ruidavets JB, Ferrieres J, Péron JM, Vinel JP. J Hepatol.
2016 Feb;64(2):427-32. Central obesity is associated with
non-cirrhotic portal vein thrombosis.
Cabarrou B, Belin L, Somda SM, Falcou MC, Pierga JY,
Kirova Y, Delord JP, Asselain B, Filleron T. Breast Cancer
Res Treat. 2016 Apr;156(3):577-85. Prediction of long-term
cumulative incidences based on short-term parametric model
for competing risks: application in early breast cancer.
Cabarrou B, Boher JM, Bogart E, Tresch-Bruneel E,
Penel N, Ravaud A, Escudier B, Mahier Ait-Oukhatar C,
Delord JP, Roché H, Filleron T. Ann Oncol. 2016
Aug;27(8):1633-8. How to report toxicity associated with
targeted therapies?
Calvayrac O, Pradines A, Favre G. Small GTPases. 2016
Sep 27:1-6. RHOB expression controls the activity of
serine/threonine protein phosphatase PP2A to modulate
mesenchymal phenotype and invasion in non-small cell lung
cancers.
Camilleri J, Mazurier J, Franck D, Dudouet P, Latorzeff
I, Franceries X. Phys Med. 2016 Jan;32(1):133-40. 2D EPID
dose calibration for pretreatment quality control of conformal
and IMRT fields: A simple and fast convolution approach.
[59]
Cammas A, Lacroix-Triki M, Pierredon S, Le Bras M,
Iacovoni JS, Teulade-Fichou MP, Favre G, Roché H, Filleron
T, Millevoi S, Vagner S. Oncotarget. 2016 Mar
29;7(13):16793-805. hnRNP A1-mediated translational
regulation of the G quadruplex-containing RON receptor
tyrosine kinase mRNA linked to tumor progression.
Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M,
Sedláčková E, Cadiot G, Wolin EM, Capdevila J, Wall L,
Rindi G, Langley A, Martinez S, Gomez-Panzani E,
Ruszniewski P; CLARINET Investigators.. Endocr Relat
Cancer. 2016 Mar;23(3):191-9. Anti-tumour effects of
lanreotide for pancreatic and intestinal neuroendocrine
tumours: the CLARINET open-label extension study.
Carré J, Grunenwald S, Vezzosi D, Mazerolles C, Bennet
A, Meduri G, Caron P. Gynecol Endocrinol. 2016
Aug;32(8):662-6. Virilizing oncocytic adrenocortical
carcinoma: clinical and immunohistochemical studies.
Cartier N, Cordelier P. Hum Gene Ther. 2016
Feb;27(2):96-7. Hopes, Promises, and Future Directions of
Gene and Cell Therapies in France.
Chandesris MO, Damaj G, Canioni D, Brouzes C,
Lhermitte L, Hanssens K, Frenzel L, Cherquaoui Z, Durieu I,
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Zitvogel L, Rusakiewicz S, Routy B, Ayyoub M,
Kroemer G. Nat Rev Clin Oncol. 2016 Jul;13(7):431-46.
Review. Immunological off-target effects of imatinib.
[70]
Awards in 2016
Professor Michel Attal received the Griffuel Award from the Fondation ARC in 2016 for his
work on the myeloma.
Scientific events
International symposium : Toulouse Onco Week 2016 (TOW 2016) The scientific Symposium was part of a week programme – TOW 2016 - centered around the World Cancer Day, and was held in Toulouse on February 3-5, 2016. It included 6 sessions : Genetic instability & Cell cycle Thomas Helleday (KI, Stockholm)
Targeting DNA repair in cancer treatment Marcos Malumbres (CNIO, Madrid)
Targeting mitosis and mitotic exit in cancer Oscar Fernandez-Capetillo (CNIO, Madrid)
Targeting oncogene-induced replication stress for cancer therapy
Gene expression & Epigenetics Mario Fraga Fernandez (CINN-CSIC, Oviedo) The role of 5-hydroxymethylcytosine in the aberrant DNA methylation in cancer François Fuks (ULB, Bruxelles)
Epigenetics and Epigenomics in Cancer Eric Solary (IGR, Villejuif)
Genetic and epigenetic insights in chronic myelomonocytic leukemia
Metabolism Jordan Virgil Craig (MD Anderson, Houston)
Sex Steroid - Induced apoptosis in steroid deprived breast cancer : a general principal for breast, prostate and ovarian cancer treatment strategies Lewis Cantley (S&E Meyer Cancer Center)
Targeting PI 3-kinase for cancer therapy Stéphane De Botton (IGR, Villejuif)
Targeting isocitrate dehydrogenase (idh)1 and idh2 mutations : clinical results in advanced hematologic malignancies
Tumor biology & Stem cells Mariano Barbacid (CNIO, Madrid)
Targeting k-ras driven lung and pancreatic tumors Craig Logsdon (MD Anderson, Houston)
Oncogenic ras and inflammation form a pathological partnership that transforms normal cells into cancer Dominik Rüttinger (Roche, Munich)
Tumor-associated macrophages as therapeutic target in oncology
Immunity Jules Hoffmann (USIAS, Strasbourg)
Innate Immunity : from flies to humans Eric Vivier (CIML, Marseille)
Towards the manipulation of innate lymphoid cells in cancer Benoit van den Eynde (Ludwig CR, Bruxelles) Restoring immune control of cancer progresses and challenges of cancer immunotherapy
Health technologies Gerd Binning (LMU, Munich)
Tissue Phenomics – Characterizing the Immuno-Tumor Ecosystem by a New Method Peter Campbell (CRUK, Cambridge)
Interrogating the architecture of cancer genomes Mickael Tanter (Institut Langevin, Paris)
Breaking of Space and Time resolution Limits in Biomedical Ultrasound
The next international Symposium will be held on February 5-7, 2018 (Toulouse Onco Week 2018).
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Seminars held in the CRCT
Thanks to its Scientific Committee, the CRCT organises many in-doors seminars. In 2016, 27 speakers were invited : Françoise Pflumio (CEA, Paris)
Investigating normal and leukemic hematopoiesis in humans with the SCL/TAL1 transcription factor as a model of hematopoietic (dys)regulation
Serge Plaza (CBD– CBI, Toulouse) Deciphering the molecular Function of Pro small peptides encoded by a putative non coding RNA. Lessons from Drosophila studies
Juan Iovana (CRCM Marseille) "Vendredis de l'Oncopole" : Towards an individualized treatment for patients with a pancreatic adenocarcinoma
Toshiro Okazaki (Kanazawa University, Japan)
Role of ceramide in ataxia telangiectasia mutated (ATM)-related cell death in leukemia cells
Vincent Cavaillès (IRCM Montpellier)
Transcriptional regulation of intestinal tumorigenesis by RIP140/NRIP1
François-Xavier Mahon (Institut Bergonié,
Bordeaux)
« Les vendredis de l’oncopole » : Peut-on guérir la leucémie myéloïde chronique : données cliniques et biologiques ?
Matthew Collin (Newcastle University) Haematopoietic and immune defects associated with GATA2 mutation
Frédéric Chibon (Institut Bergonié, Bordeaux)
Hétérogénéïté intra-tumorale et instabilité chromosomique des sarcomes pléomorphes : le couple moteur de l'oncogenèse ? Patrick Mehlen (Léon Bérard, Lyon) The Dependance Receptor Notion : From a Cell Death Paradigm to Alternative Anti-Cancer Therapies
Thomas Pradeu (CIRID Bordeaux)
"Les Vendredis de l'Oncopole" : Cancer & Therapeutics : A Philosophical Approach
Erik Sahai (Francis Crick Institute, London)
Cellular origin and mechanisms of pancreatic cancer
Marie Cargnello (McGill University, Montreal)
Dysregulation of mRNA translation and energy metabolism in neoplasia
Loïc Dupré (CPTP, Toulouse)
Multi-scale exploration of migration in normal and tumoral lymphoid cells Raffaella Santoro (IVBMV, Zurich)
The epigenetics of prostate cancer : from molecular mechanisms to biomarker signature of disease recurrence
Laurent Nguyen (GIGA-Neurosciences, Liège)
A dynamic unfolded protein response controls cortical neurogenesis
Massimo Lopes (IMCR, Zurich)
Replication fork remodelling upon replication stress in cancer and stem cells
Patrick Jacquemin (Université de Duve)
Molecular mechanisms involved in pancreatic cell plasticity and cancer
Lionel Larue (Institut Curie, Paris)
β-catenin in the melanocyte lineage Mario Tschan (Institute of Pathology, Bern)
Autophagy in retinoic acid therapy of acute myeloid leukemia
Antonio Maraver (IRCM, Montpellier)
Role of the Notch pathway in lung adenocarcinoma : beyond the KrasG12V mouse model
Cyrille Delpierre (UMR1027, Toulouse) Stress chronique depuis l'enfance et cancer à l'âge adulte : quelles évidences ?
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Arnaud Vigneron (CRCL, Lyon)
A glucocorticoid-dependent metabolic program supports cancer stem cell properties in breast cancer
Fatima Mami-Chouaib (IGR, Villejuif)
Rôle des cellules T mémoires résidentes dans le tissu (Trm) dans la réponse immunitaire antitumorale : implication de l'intégrine CD103 Daniel Fisher (IG2M, Montpellier)
The cell proliferation antigen Ki-67 controls heterochromatin organisation and tumorigenesis but not cell proliferation Ulf Nehrbass (Ksilink & FGTAC, Strasbourg)
From Drugs to Genes : implementing target free approaches in Cancer drug discovery
Esther Castellano (Barts Cancer Institute, London)
The many functions of RAS-PI3K signaling in lung cancer development Els Verhoyen (CIRI, ENS Lyon)
New lentiviral vector pseudotypes for gene of human hematopoietic healthy and cancer target cells
Gareth Veal (University of Newcastle)
Therapeutic Drug Monitoring and Clinical Pharmacology Studies in Paediatric Oncology - a UK Experience
CRCT Retreat, November 3-4, 2016
In 2016, the retreat was held at the Institut Universitaire du Cancer de Toulouse-Oncopole (IUCT-Oncopole). Following the introduction by the former Director, Jean-Jacques Fournié, and the current one, Gilles Favre, the published results and the work in progress were presented by the different teams. This event provided an opportunity to highlight the translational projects from the CRCT with the Comprehensive Cancer Center IUCT-Oncopole. In 2017, the retreat will be held outside of Toulouse, as every other year.
Cancer Research Center of Toulouse (CRCT)
UMR 1037 Inserm – Université Toulouse III Paul Sabatier
ERL 5294 CNRS
2 avenue Hubert Curien
31037 Toulouse Cedex 1
France
Telephone : +33 (0)5 82 74 15 75
www.crct-inserm.fr
