MELANOMA DRUG RESIST

Identification of drug-resistance genes for the development of effective combined therapies for melanoma

Coordinatore	GENOME RESEARCH LIMITED    more  Organization address address: THE GIBBS BUILDING, EUSTON ROAD 215 city: LONDON postcode: NW1 2BE contact info Titolo: Mr. Nome: David Cognome: Davison Email: send email Telefono: +44 01223494937 Fax: +44 01223494919
Nazionalità Coordinatore	United Kingdom [UK]
Totale costo	221˙606 €
EC contributo	221˙606 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-IEF
Funding Scheme	MC-IEF
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-07-01   -   2016-06-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	GENOME RESEARCH LIMITED  Organization address address: THE GIBBS BUILDING, EUSTON ROAD 215 city: LONDON postcode: NW1 2BE contact info Titolo: Mr. Nome: David Cognome: Davison Email: send email Telefono: +44 01223494937 Fax: +44 01223494919	UK (LONDON)	coordinator	221˙606.40

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 Obiettivo del progetto (Objective)

'Malignant melanoma is a highly aggressive form of skin cancer with a poor outcome following metastatic spread. Chemotherapies for metastatic melanoma are rarely curative because of the emergence of clones from within the tumor that carry lesions in genes that confer therapeutic resistance. Understanding the genetic culprits of drug resistance will allow the rationale development of combination therapies that may circumvent the occurrence of resistance. Here I propose to combine different cutting-edge technologies and functional screenings in human early-passage melanoma cell cultures (EMCCs) to identify clinically relevant melanoma drug-resistance genes and consequently to develop new effective combination therapies by a data-driven approach. I will screen a library of drugs across a collection of EMCCs and in concert analyze the genome of each EMCC for mutations, epimutations and chromosomal aberrations. EMCCs found to be intrinsically resistant to a given drug will be screened with a short-hairpin-RNA library to identify genes whose knockdown reverts resistance. Those EMCCs sensitive to a given drug will be infected with lentiviral-vector based insertional mutagens to screen for genes whose upregulation mediates drug resistance, thus identifying mechanisms that may be associated with relapse in patients treated with these compounds. These 2 approaches will provide a collection of drug-resistance and -sensitivity genes that will be then validated in vitro, in vivo and in clinical samples. The knowledge of drug-resistance genes and genomic lesions carried by each EMCC will guide the design of new therapies based on the combination of multiple compounds targeting both the mutated gene and the EMCC-specific drug-resistance gene. The new combination regimens will be tested in vitro on EMCCs and in vivo in xenotransplant models. These results will pave the way to preclinical and clinical development of new combined therapies for the efficient eradication of melanoma.'