Project description DEENESFRITPL Novel targets for treating uveal melanoma Uveal melanoma is a rare yet deadly primary cancer of the eye in adults associated with mutations in two transmembrane G protein-coupled receptors. The malignancy emerges in melanocytes in the ocular region. Although surgical resection and radiation are used to treat local disease, half of the patients develop metastases and die within one year. The scope of the EU-funded NECESSITY project is to identify novel targets for therapeutic intervention. Researchers will study the signalling pathways in uveal melanoma cells and identify molecules that inhibit cell growth and initiate apoptosis. Results will provide fundamental information on an unmet medical need, hoping to improve the clinical outcome of patients with uveal melanoma. Show the project objective Hide the project objective Objective G protein-coupled receptors (GPCRs) represent the largest family of cell surface proteins involved in signal transmission. Nearly 30% of human cancers harbor mutations in GPCRs/G proteins. Activating mutations in GNAQ and GNA11 have been discovered in 90% of Uveal Melanoma (UM).UM is the most common primary cancer of the eye in adults and to date there are no effective treatments. 50% of UM patients develop metastatic disease, which is refractory to current chemotherapies leading to patient death within a year. Prolonged Gaq signaling leads to the activation of YAP, a transcriptional co-activator regulated, necessary for UM growth. GNAQ stimulates YAP through FAK. Inhibition of FAK reduces UM growth,leading FAK to be a potential therapeutic target for UM. In UM, the particular Gαq–regulated pathways that when overactive can render FAK inhibitor(FAKi) ineffective, as well as what feedback mechanisms should be targeted to optimize therapeutic responses to FAKi are still unknown. I will use a panel of GNAQ-driven UM cells and perform a genetic screen using the Cancer Signaling Toolkit to discover molecular determinants of sensitivity or resistance to FAK inhibition. Signaling candidates and screening hits discovered will be prioritized and their biological impact in UM growth and FAKi sensitivity will be evaluated. To increase FAKi activity and reduce therapy resistance, I will also investigate whether co-targeting candidate GNAQ-effector and FAKi resistance pathways will synergize with FAKi, resulting in UM cell death. Finally,I will explore the mechanism of UM cell death by co-targeting. My studies will reveal new targeted(precision) strategies for multiple Gαq-driven pathological conditions in cancer The project will be supervised by Dr. Gutikind and Dr.Martini two experts in GPRC/G proteins. Through this work, I aim to broaden my scientific expertise (including technical and transferable skills) and to establish myself as an independent researcher in cancer biology Fields of science medical and health sciencesclinical medicineoncologyskin cancermelanomanatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutation Keywords Uveal Melanoma FAK YAP Cancer Cell signaling Screening G-proteins and or GPCR Drug resistance Precision therapy Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2020 - Individual Fellowships Call for proposal H2020-MSCA-IF-2020 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator UNIVERSITA DI PISA Net EU contribution € 269 002,56 Address Lungarno pacinotti 43/44 56126 Pisa Italy See on map Region Centro (IT) Toscana Pisa Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Partners (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all Partner Partner organisations contribute to the implementation of the action, but do not sign the Grant Agreement. THE REGENTS OF THE UNIVERSITY OF CALIFORNIA United States Net EU contribution € 0,00 Address Franklin street 1111 12 floor 94607 Oakland ca See on map Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 177 265,92
