Investigation préclinique


Année de publication : 2018

Philippe De La Rochere, Silvia Guil-Luna, Didier Decaudin, Georges Azar, Sukhvinder S Sidhu, Eliane Piaggio (2018 Aug 6)

Humanized Mice for the Study of Immuno-Oncology.

Trends in immunology : 748-763 : DOI : S1471-4906(18)30125-X En savoir plus

Immunotherapy is revolutionizing cancer treatment; however, complete responses are achieved in only a small fraction of patients and tumor types. Thus, there is an urgent need for predictive preclinical models to drive rational immunotherapeutic drug development, treatment combinations, and to minimize failures in clinical trials. Humanized mouse models (HIS) have been developed to study and modulate the interactions between immune components and tumors of human origin. In this review, we discuss recent advances in the ‘humanization’ of mouse models to improve the quality of human immune cell reconstitution. We also highlight new insights into the basic mechanisms, and provide a preclinical evaluation of onco-immunotherapies, as well as the limitations thereof, which constitute drivers for the improvement of the models to increase their translational power.

Rania El Botty, Florence Coussy, Rana Hatem, Franck Assayag, Sophie Chateau-Joubert, Jean-Luc Servely, Sophie Leboucher, Charles Fouillade, Sophie Vacher, Bérengère Ouine, Aurélie Cartier, Leanne de Koning, Paul Cottu, Ivan Bièche, Elisabetta Marangoni (2018 Jul 25)

Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition.

Oncotarget : 29587-29600 : DOI : 10.18632/oncotarget.25640 En savoir plus

Breast cancer is a complex disease in which each patient could present several genetic alterations that are therapeutically relevant in cancers. Here we explored the therapeutic benefit of combining PARP and mTOR inhibitors in a context of DNA repair deficiency and PI3K pathway activation. The combination of everolimus and olaparib was tested in BRCA2-mutated patient-derived xenografts (PDX) carrying alterations in the PI3K/AKT/mTOR pathway. An RPPA analysis of different signalling pathways was performed in untreated and treated xenografts. Everolimus and olaparib showed marked anti-tumor activities in the monotherapy setting and high efficacy when given in combination with 100% of mice showing tumor regressions. The fraction of P-H2AX positive cells was increased in both monotherapy arms and strongly increased in the combination setting. Everolimus given as monotherapy resulted in downregulation of different proteins involved in DNA damage repair, including FANCD2, RAD50 and SUV39H1. In the combination setting, expression of these proteins was almost completely abolished, suggesting convergence of PARP and mTOR in downregulation of DNA damage repair components. In conclusion, our results suggest that combining mTOR and DNA repair inhibition could be a successful strategy to treat a subset of breast cancer with BRCA2 mutation and alterations in the PI3K/AKT/mTOR pathway.

Caroline Spasojevic, Elisabetta Marangoni, Sophie Vacher, Franck Assayag, Didier Meseure, Sophie Château-Joubert, Martine Humbert, Manale Karam, Jean Marc Ricort, Christian Auclair, Marie Regairaz, Ivan Bièche (2018 May 26)

PKD1 is a potential biomarker and therapeutic target in triple-negative breast cancer.

Oncotarget : 23208-23219 : DOI : 10.18632/oncotarget.25292 En savoir plus

Protein Kinase D1 (PKD1) is a serine/threonine kinase encoded by the gene. PKD1 has been previously shown to be a prognostic factor in ERα+ tamoxifen-resistant breast tumors and PKD1 overexpression confers estrogen independence to ERα+ MCF7 cells. In the present study, our goal was to determine whether PKD1 is a prognostic factor and/or a relevant therapeutic target in breast cancer. We analyzed mRNA levels in 527 primary breast tumors. We found that high mRNA levels were significantly and independently associated with a low metastasis-free survival in the whole breast cancer population and in the triple-negative breast cancer (TNBC) subtype specifically. High mRNA levels were also associated with a low overall survival in TNBC. We identified novel PKD1 inhibitors and assessed their antitumor activity in TNBC cell lines and in a TNBC patient-derived xenograft (PDX) model. Pharmacological inhibition and siRNA-mediated depletion of PKD1 reduced colony formation in MDA-MB-436 TNBC cells. PKD1 inhibition also reduced tumor growth in a TNBC PDX model. Together, these results establish PKD1 as a poor prognostic factor and a potential therapeutic target in TNBC.

Didier Decaudin, Rania El Botty, Béré Diallo, Gerald Massonnet, Justine Fleury, Adnan Naguez, Chloé Raymondie, Emma Davies, Aaron Smith, Joanne Wilson, Colin Howes, Paul D Smith, Nathalie Cassoux, Sophie Piperno-Neumann, Sergio Roman-Roman, Fariba Némati (2018 May 19)

Selumetinib-based therapy in uveal melanoma patient-derived xenografts.

Oncotarget : 21674-21686 : DOI : 10.18632/oncotarget.24670 En savoir plus

The prognosis of metastatic uveal melanoma (UM) is among the worst of all human cancers. The identification of near-ubiquitous GNAQ/GNA11 mutations and the activation of MAPK signaling in UM have raised hopes of more effective, targeted therapies, based on MEK inhibition, for example. We evaluated the potential of drug combinations to increase the efficacy of the MEK inhibitor selumetinib (AZD6244, ARRY-142886), in UM cell lines and Patient-Derived Xenografts. We first evaluated the combination of selumetinib and DTIC. We found that DTIC did not improve the or antitumor efficacy of selumetinib, consistent with the outcome of the SUMIT clinical trial assessing the efficacy of this combination in UM. We then tested additional selumetinib combinations with the chemotherapy agent docetaxel, the ERK inhibitor AZ6197, and the mTORC1/2 inhibitor, vistusertib (AZD2014). Combinations of selumetinib with ERK and mTORC1/2 inhibitors appeared to be the most effective in UM PDX models.