Project description
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.
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 (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 sciencesclinical medicineoncologyskin cancermelanoma
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
56126 Pisa
Italy