Novel approach for personalized cancer treatment: UNbiasing signaling at Receptor Tyrosine Kinase (RTK)/G protein-coupled receptors (GPCR) interface

The overall objective of this proposal is to investigate the function and to use the generated knowledge of the βarr/GRKs signaling complexes involved in the GPCR/RTK crosstalk to develop novel strategies for improved management of cancer patients.

The specific aims are: (i) Further investigate the mechanisms controlling the βarr/GRK-biased signaling at the IGF1R leading to resistance to cancer therapy(II).

Evaluate the coding and ncRNA expression profiles as indicators of non-canonical signaling activation downstream IGF1R and explore their potential utility as biomarkers or molecular targets in cancer.(iii).

Develop strategies for targeting non-canonical βarr/GRK signaling at the IGF-1R for cancer treatment, with focus on clinical applicability.Preliminary results demonstrate the validity of the working model: GRKs/βarrs systems are essential for malignant transformation and their inhibition reverses the malignant phenotype.The program includes a range of experimental systems using biochemistry, pathology and molecular biology techniques to determine the contribution of this group of previously unstudied proteins to cancer progression.

Experiments are formulated to investigate the detailed composition and function of the βarr/GRKs signaling complex, both in normal and malignant cells.

The results generated will extend the possible ways of treating cancers and potentially identify new biomarkers and targets associated with different types of cancer.