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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- medical and health sciences clinical medicine oncology skin cancer melanoma
- medical and health sciences basic medicine pharmacology and pharmacy drug resistance
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics genomes
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2013-IEF
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Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
CB10 1SA SAFFRON WALDEN
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.