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onCOMBINE SIGNED

Towards evidence-based combinations of approved and novel cancer drugs

Total Cost €

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EC-Contrib. €

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Partnership

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 onCOMBINE project word cloud

Explore the words cloud of the onCOMBINE project. It provides you a very rough idea of what is the project "onCOMBINE" about.

met    disease    awaited    cocktails    myeloid    adaptations    driver    receptors    homo    signalling    senescence    cells    antibodies    employ    recognising    effectors    poly    drug    once    axl    apoptosis    synergies    persistently    harness    therapy    evoked    generalizing    mapping    inhibit    unlike    oncology    rna    examined    her2    bases    underlying    conceptualize    pkis    primary    transcriptomics    lymphoid    monoclonal    interference    interface    hypothesis    action    kinase    establishing    mutations    approved    cytotoxicity    protein    mechanisms    significance    background    resistance    cancer    mabs    conferring    inducing    molecular    drugs    tt    monotherapies    guide    route    epitopes    optimising    combinations    granularity    inhibitors    maps    gt    chemotherapy    oncogene    intercepts    25    toxicities    addictions    pharmacology    hetero    interactions    lung    receptor    immunological    immune    interceptors    deeper    mutant    models    tumours    egfr    employs    offers    loops    compensatory    phosphoproteomics    animal    fatalities    rarely    limited   

Project "onCOMBINE" data sheet

The following table provides information about the project.

Coordinator
WEIZMANN INSTITUTE OF SCIENCE 

Organization address
address: HERZL STREET 234
city: REHOVOT
postcode: 7610001
website: www.weizmann.ac.il

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Israel [IL]
 Total cost 2˙488˙306 €
 EC max contribution 2˙488˙306 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2016-ADG
 Funding Scheme ERC-ADG
 Starting year 2017
 Duration (year-month-day) from 2017-10-01   to  2022-09-30

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    WEIZMANN INSTITUTE OF SCIENCE IL (REHOVOT) coordinator 2˙488˙306.00

Map

Leaflet | Map data © OpenStreetMap contributors, CC-BY-SA, Imagery © Mapbox

 Project objective

Background: Molecular targeted therapy (TT; e.g., monoclonal antibodies, mAbs, and protein kinase inhibitors, PKIs) intercepts oncogene and other addictions of tumours. However, unlike chemotherapy, which employs cocktails of drugs, only rarely does TT harness poly-pharmacology. Because lung cancer is the major cause of oncology related fatalities and many driver mutations are known, this disease offers opportunities for establishing and generalizing novel TT combinations and their interface with the immune system. Working hypothesis: High granularity maps of compensatory loops evoked by TT, along with deeper understanding of mechanisms underlying drug action, resistance and interactions with lymphoid/myeloid cells, will conceptualize drug combinations able to persistently inhibit tumours, while inducing only limited toxicities. Goal and specific aims: Addressing resistance to TT, potential synergies and the immune system, we will employ lung cancer models driven by mutant EGFR, HER2, MET or AXL. Phosphoproteomics, transcriptomics and RNA interference, will enable mapping adaptations evoked by specific drugs. Once identified, we will test combinations of interceptors able to inhibit the primary target as well as the emerging, resistance-conferring route(s). Next, we will determine the mechanisms of action of selected interceptors (e.g., apoptosis, immunological cytotoxicity and senescence) as bases for optimising effective combinations. Homo-combinations of antibodies (i.e., antibodies recognising distinct epitopes of a receptor), hetero-combinations targeting distinct signalling and immune receptors, and combinations with PKIs will be examined in animal models. Significance: More than 30 PKIs and >25 mAbs are approved in oncology, but most are used as monotherapies. Detailed knowledge of adaptation-driven resistance, mechanisms of drug action and immune effectors, will guide the long awaited application of TT combinations in oncology, including lung cancer.

 Publications

year authors and title journal last update
List of publications.
2018 D. Romaniello, L. Mazzeo, M. Mancini, I. Marrocco, A. Noronha, M. Kreitman, S. Srivastava, S. Ghosh, M. Lindzen, T.M. Salame, A. Onn, J. Barr, Y. Yarden
A Combination of Approved Antibodies Overcomes Resistance of Lung Cancer to Osimertinib by Blocking Bypass Pathways
published pages: 5610-5621, ISSN: 1557-3265, DOI: 10.1158/1078-0432.ccr-18-0450
Clinical Cancer Research Mpvember 15, 2018 2019-06-05
2018 Maicol Mancini, Hilah Gal, Nadège Gaborit, Luigi Mazzeo, Donatella Romaniello, Tomer Meir Salame, Moshit Lindzen, Georg Mahlknecht, Yehoshua Enuka, Dominick GA Burton, Lee Roth, Ashish Noronha, Ilaria Marrocco, Dan Adreka, Raya Eilam Altstadter, Emilie Bousquet, Julian Downward, Antonio Maraver, Valery Krizhanovsky, Yosef Yarden
An oligoclonal antibody durably overcomes resistance of lung cancer to third‐generation EGFR inhibitors
published pages: 294-308, ISSN: 1757-4676, DOI: 10.15252/emmm.201708076
EMBO Molecular Medicine 10/2 2019-06-05

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