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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.

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

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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