Institut National De La Sante Et De La Recherche Medicale

Institut Gustave Roussy

Centre National De La Recherche Scientifique

Institut Pasteur

Assistance Publique - Hopitaux De Paris (aphp)

Sorbonne Université

Universite Paris Cité

Université De Technologie De Compiègne

Other

Amgen Inc.

UniversitÉ Paris Descartes

Université Paris—sud

Université Pierre Et Marie Curie

Instituto Nazionale Per Le Malattie Infettie Irccs Lazzaro Spallanzani

Inserm

Guido Kroemer

Laurence Zitvogel

Jean-Luc Perfettini

Bernard P Roques

Eric Deutsch

Johan Hoebeke

Santos A Susin

Josef Martin Penninger

David Peter Siderovski

Lena Edelman

Anne-Sophie Belzacq

Naoufal Zamzami

Bryan E L Snow

Catherine Brenner-Jean

José Manuel Bravo San Pedro

Etienne Daniel Francois Jacotot

Marie-Lise Gougeon

Nicolas Delahaye

Mauro Piacentini

Awatef Allouch

Guillermo Marino

Yuting Ma

Tamara Hirsch

Oliver Kepp

Didier Decaudin

Lionel Apetoh

Federico Pietrocola

Theocharis Panaretakis

Autophagy is typically activated by starvation, allowing cells and organisms to mobilize their energy reserves. It is known that pharmacological modulation of autophagy represents a therapeutic potential. Here the inventors report that a protein that is released from cells in an unconventional, autophagy-dependent manner, namely, diazepam binding inhibitor (DBI), regulates autophagy. In particular, the inventors demonstrate that DBI inhibits autophagy and that the supply of recombinant DBI to mice enhanced glycolysis, enhanced lipogenesis, and inhibited fatty acid oxidation. The inventors show that neutralisation of DBI by a monoclonal antibody and an active immunization by means of an immunogenic DBI derivative eliciting autoantibodies induce autophagy and lead to metabolic changes that increase starvation-induced weight loss, reduce food intake upon refeeding, and reduce weight gain in response to hypercaloric diets. Accordingly, the present invention relates to methods and pharmaceutical compositions for modulating autophagy based on the modulation of the activity or expression of DBI.

Methods for inhibiting diazepam binding protein

Methods for weight reduction

The present invention provides novel methods for the modulation of autophagy and the treatment of autophagy-related diseases, including cancer, neurodegenerative diseases, liver diseases, muscle diseases and pancreatitis.

Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof

The present inventors show that cannibal cells can undergo senescence after entosis in vivo and that the tumor suppressive protein p53 act as a repressor of this phenomenon. They therefore propose new tools to study the molecular pathways involved in the cannibalism process, for example by measuring the expression levels of p53 or splice variants thereof (such as &#x394;133TP53, TP53&#x3b2;, TP53&#x3b3; or &#x394;40TP53), the release of extracellular ATP or purinergic P2Y2 receptor activity. The present inventors also demonstrated that the detection of senescent cannibal cells in breast adenocarcinoma obtained from patients treated with neo-adjuvant therapy positively correlates with good patient's response to treatment. Altogether, these results provide the first evidence that detection of cellular cannibalism and senescence simultaneously in tumors helps for the diagnosis of disease outcomes and for the prediction of treatment efficiency against cancer diseases.

Simultaneous detection of cannibalism and senescence as prognostic marker for cancer

The present invention provides methods and pharmaceutical compositions for treating human immunodeficiency virus type 1 (HIV-1) infections. In particular, the present invention relates to a method for treating HIV-1 infection in a subject in need thereof comprising administering the subject with a therapeutically effective amount of an inhibitor of SGT1 activity or expression.

Methods and pharmaceutical compositions for treating human immunodeficiency virus type 1 (HIV-1) infections

The present invention relates to the fields of genetics, immunology and medicine. The present invention more specifically relates to in vitro or ex vivo methods for determining the susceptibility to a cancer treatment of a subject having a tumor. These methods comprise a step of determining the ability of the treatment, of the subject and/or of the tumor to induce an anticancer immune response, the inability of at least one of the treatment, the subject and the tumor to induce an anticancer immune response being indicative of a resistance of the subject to the therapeutic treatment of cancer. Inventors in particular identify genes specific of a human subject or of cancerous cells which can be used to predict or assess the sensitivity of a subject to a treatment of cancer. The invention also relates to particular compounds capable of activating or enhancing the immune system of a particular subject, when the subject is exposed to a therapeutic treatment of cancer or before such an exposition. It further relates to uses of such compounds, in particular to prepare a pharmaceutical composition to allow or improve the efficiency of a therapy of cancer in a subject in need thereof. The present invention in addition provides kits, methods for selecting a compound of interest, as well as pharmaceutical compositions and uses thereof.

Method of treatment for immunogenic treatment resistant cancer

Compounds and uses thereof to induce an immunogenic cancer cell death in a subject

The present invention relates to an in vitro method of assessing the sensitivity of a subject to a treatment of cancer, which method comprises detecting the presence of a mutated Toll Like Receptor 4 (TLR4) nucleic acid or an abnormal TLR4 protein expression or activity in a sample from the subject, the presence of said mutated TLR4 nucleic acid or abnormal TLR4 expression or activity being indicative of a resistance to said treatment. The invention further provides compounds for treating or preventing a cancer in a subject having a mutated TLR4 nucleic acid or an abnormal TLR4 protein expression or activity.

Toll like receptor 4 dysfunction and the biological applications thereof

The present invention relates to a method for determining the susceptibility of a patient tumor cell to a cancer treatment, which method comprises the detection or measure of CRT, KDEL receptor and/or ERp57 on the surface of a tumor cell.

Compounds regulating calreticulin, KDEL receptor and/or Erp-57 cell surface exposure and uses thereof to evaluate the efficiency of a cancer treatment

The present invention relates to the use of a protein phosphatase inhibitor selected from an inhibitor of the catalytic subunit of the protein phosphatase 1 (PP1), an inhibitor of GADD34 and an inhibitor of the PP1/GADD34 complex to prepare a pharmaceutical composition to prevent or treat a cancer in a mammal, wherein the pharmaceutical composition is intended for administration in combination with a product used in a treatment of a cancer.

Inhibitors of protein phosphatase 1, GADD34 and protein phosphatase 1/GADD34 complex, preparation and uses thereof

The invention is directed to the induction of mitochondrial membrane permeabilization via the physical and functional interaction of the HIV-1 Vpr protein with the mitochondrial inner membrane protein ANT (adenine nucleotide translocator, also called adenine nucleotide translocase or ADP/ATP carrier). Reagents and methods for inducing and/or inhibiting the binding of Vpr to ANT, mitochondrial membrane permeabilization, and apoptosis are provided.

Screening methods for the identification of inhibitors of human immunodeficiency virus (HIV) viral protein R (Vpr) binding to the adenine nucleotide translocator (ANT)

The present invention related generally novel mammalian apoptosis-inducing factors, polynucleotides encoding such factors and methods related thereto.

Apoptosis-inducing factor

Mimetics and inhibitors of the interaction between Vpr (HIV viral protein of regulation) and ANT (Mitochondrial adenine nucleotide translocator)

Growing community of inventors

Paris, France

Guido Kroemer