AIRC IG grant 2017 - cod. 20095 - Development of a GRASP65/Aurora-A signalling network as a therapeutic target for cancer (DSB.AD001.107)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOMI)

Other structures collaborating in the research project

• Istituto di Biochimica e Biologia Cellulare (IBBC)

Project manager

ANTONINO COLANZI
Phone number: 0816132538
Email: a.colanzi@ibp.cnr.it

Abstract

Because cell cycle dysregulations are a hallmark of cancer, mitotic kinases have been the target of anti-cancer therapeutics. Despite the many progresses, clinical success has been limited to a minor group of diseases because of tumour heterogeneity and drug resistance. Consequently, there is the need for the identification of more efficacious antiproliferative strategies.
An emerging strategy to defeat tumour heterogeneity and drug resistance is drug combination. However, how to combine the existing drugs is a significant challenge. Here we propose that the targeting at suboptimal drug concentrations of key elements of the Golgi/Aurora-A signalling network can be exploited to rationally define a combinatorial strategy to block proliferation and induce cell death. A key aspect of the proposal is the development of a quantitative and rapid phenotypic assay for optimization of drug combinations. Moreover, many elements of the network have been investigated in clinical trials for drug development, indicating that these drugs can be easily repurposed. An additional value of our approach is that it can be also applied to the targeting of cell migration and invasion.

Goals

We plan to: a) optimize membrane-permeant GRASP65-mimetic peptides as specific "research drugs" to block Golgi unlinking and cause G2-arrest; b) validate a drug-based targeting of the GRASP65/Aurora-A signalling network as a novel therapeutic approach to block cell proliferation and induce cell death; c) investigate the regulation of GRASP65 in Golgi organization; d) apply the targeting of the "Golgi unlinking" to models of cell migration and invasion; and e) validate selected drug-based approaches in in vivo animal models.

Start date of activity

01/01/2018

Keywords

Cell cycle checkpoint, Combination therapy, Golgi complex

Last update: 03/01/2025