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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.

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

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

 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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