EU H2020 Project "ONCOMBINE (Towards evidence-based combinations of approved and novel cancer drugs)": description, partecipants, costs and EC-fundings

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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

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

WEIZMANN INSTITUTE OF SCIENCE

IL (REHOVOT)

coordinator

2˙488˙306.00

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

List of publications.
year	authors and title	journal	last update
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, NadÃ¨ge 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 thirdâ€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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