National Research Council of Italy

Institute of Biosciences and BioResources

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IBBR Project #110

IG11422 AIRC - CISPLATIN SENSITIVITY/TOLERANCE/RESISTANCE GENETIC PATHWAYS IN HEREDITARY CANCER PREDISPOSITION
Project ID 110
ID n/a
Acronym -
Project acronym and title IG11422 AIRC - CISPLATIN SENSITIVITY/TOLERANCE/RESISTANCE GENETIC PATHWAYS IN HEREDITARY CANCER PREDISPOSITION
Contract -
Description Objective: We intend to study gene pathways involved in sensitivity/tolerance/resistance to inter-strand crosslinking (ICL) agents using the powerful genetic model Caenorhabditis elegans.

Background and rationale: Neoplastic cells are characterized by genome instability leading to recurrent and multiple mutations; a key problem is understanding, among the mutated genes, which ones are the cause (drivers) and which are consequence (passengers) of the disease itself. An analogous and complex problem arises when neoplastic cells are treated with genotoxic drugs, for instance cisplatin (CDDP), or other ICL agents. These drugs introduce damages that activate checkpoints and lead to cell death, eliminating actively proliferating cells. However, de novo mutations are introduced in this way. In some unfortunate cases such hypermutation leads to resistance to the drug itself. Understanding of cancer-prone syndromes (such as Fanconi anemia, FA) that are inherited disorders characterized by increased cancer incidence, may help to discriminate between drivers and passengers mutations not only in these disorders but also in sporadic cancer. Some genes, conserved in the evolutionary scale, such as FANCD2 (responsible of FA), can be best studied in model systems suitable for the study of double strand breaks (DSBs) repair both in meiosis and mitosis. Recent work in our laboratory has led to relevant findings about the role of this protein in genome stability in C. elegans: FCD-2 suppresses the use of non-homologous end-joining (NHEJ) pathway and prevents DNA repair defects in mutant worms and Fanconi Anemia cell lines. Notably, mutations in fcd-2 gene confer ICL sensitivity. We now want to dissect the genetic pathways leading to ICL sensitivity/tolerance/resistance and characterize the proteins involved by in vitro studies.

Description of the project: We want to identify genes that, when mutated, bypass the checkpoints and determine ICL tolerance/resistance. We propose a forward genetic screen for the isolation of mutations in (known or unknown) genes conferring cisplatin tolerance/resistance in fcd-2 background. The proteins encoded by these genes will be purified and characterized in vitro. All the knowledge collected in these studies will contribute to the understanding of mechanisms underlying tumor cells resistance to DNA-damage based chemotherapy, and eventually to identification of new potential drug-targets.
Funding body AIRC-ASSOCIAZIONE ITALIANA RICERCA SUL CANCRO
UOS Napoli
Role Unico Beneficiario
Signatory -
Contact Person La Volpe Adriana, Ciaramella Maria
Starting of activities 2011
Ending of activities 2016
Extension -
Amount (euro) 240000.00
Technological Area -
Technological Field -
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Istituto di Bioscienze e Biorisorse (IBBR/CNR)
Via G. Amendola 165/A, I-70126 Bari (Italy)
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