New prECision thErapieS for uveal melanoma (targeting the Gαq/GNAQ oncogenic Signaling cIrcuiTrY)

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 Gqregulated 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 Gq-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