Detalji

Kategorija: Blog (en-GB)

Objavljeno: 15 Studeni 2019

Project no. : uniri-Biomed-18-76 Molecular features associated with BRAFV600E-mutated versus wild type BRAF colorectal cancer

This research project represents an upgrade to the CSF project No. 2018-01 3900 Dissecting the mechanisms of therapy resistance in BRAF-mutant colon cancer using an integrated omics approach. The CSF project will illuminate processes underlying the development of resistance to BRAF inhibition by vemurafenib in BRAFV600E mutant colorectal cancer (CRC) cells via integration of results of the proteome, glycoproteome, secretome and sphingolipidome analysis. The CSF project will identify novel biomarkers and targets associated with the development of resistance to vemurafenib in BRAF mutant CRC cells and will investigate the role of bioactive sphingolipid metabolism in acquired resistance to vemurafenib. 
However, identification of molecular and cellular mechanisms specifically modulated by oncogenic BRAF mutation represents an important piece of information that adds to a better understanding of the role of BRAFV600E mutant protein in the regulation of growth, survival and response of CRC cells to chemotherapy. This project has several goals: 1. explore differences in the molecular profiles (global proteome, sphingoid bases) between BRAF mutant  vs. wild-type BRAF CRC cells to identify molecular factors associated with the aggressive phenotype of BRAF mutant CRC; 2. determine the correlation between BRAF status and the expression of the key proteins regulating metabolism and functions of bioactive sphingolipids; 3. identify proteins at the level of global proteome and the key enzymes in sphingolipid metabolism and signaling whose expression is directly controlled by BRAF mutant protein. Results obtained in this study are expected to reveal new molecular features of the aggressive phenotype of BRAFV600E mutant CRC, whose validation in tissues from CRC patients will deliver novel histopathologic biomarkers as a foundation for the development of new diagnostic and prognostic tools.

Detalji

Kategorija: Blog (en-GB)

Objavljeno: 15 Studeni 2019

BRAFCON brings together the complementary skills, resources and state-of-the-art technological platforms for mass spectrometry-based proteomics (University of Rijeka Department of Biotechnology) and sphingolipidomics (University of Graz Institute of Molecular Biosciences, Austria) supported by advanced bioinformatics tools (Ingenet. Ltd, UK) to study chemoresistance in BRAFV600-mutant colon cancer and covering the path from target discovery and validation, design of novel combinatorial therapies to their preclinical evaluation.

The project is strongly supported by the internationally recognised scientific expertise of the multidisciplinary team in the field of cancer biology, cell signalling, experimental oncology, mass spectrometry, protein isolation and separation from complex biological samples, proteomics, glycoproteomics and glycomics, cancer secretome analysis, sphingolipidomics, bioinformatics, pathway and network analysis and modelling and preclinical testing of novel anticancer agents.

Detalji

Kategorija: Blog (en-GB)

Objavljeno: 15 Studeni 2019

Project no. 2018-01 3900

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world. Owing to the improvements in systemic chemotherapy, targeted therapies and surgical techniques, the survival of patients with metastatic CRC (mCRC) has improved over the past two decades. Still, these therapeutic advances have not brought benefits to all molecular subtypes of CRC. This particularly holds true for the population of mCRC patients with BRAFV600E mutation (7–10%) which have a poor response to most systemic therapies and a very poor prognosis. Vemurafenib, a protein kinase inhibitor of BRAFV600E approved by the FDA for the treatment of metastatic melanoma with BRAFV600E mutation, has raised hopes of treatment for BRAF-mutant CRC. However, opposite to the results seen in patients with BRAFV600E mutant melanoma, single-agent vemurafenib exerted limited clinical efficacy in patients with BRAFV600E mutant CRC. In order to improve outcomes in CRC patients with BRAF mutation, there is a critical need to better understand the mechanisms of resistance to BRAF inhibitors. The BRAFCON project strives to give a new perspective on the processes governing acquired resistance to BRAF inhibition by vemurafenib in BRAFV600E mutant colon cancer cells by integrating different layers of molecular information (proteome, glycoproteome, secretome, and sphingolipidome) while taking into account an intricate interplay of molecular signals both, inside and outside of colon cancer cells that influence multiple aspects of cell behavior. Specific scientific objectives of this project are: 1) to identify and validate in vitro novel actionable pathways, biomarkers and targets associated with the development of resistance to BRAF inhibition by vemurafenib in BRAF-mutant colon cancer cells; 2) to investigate the role of bioactive sphingolipids, their metabolism and signaling in acquired resistance to vemurafenib; 3) to investigate the correlation between the BRAF gene status and the regulation of  sphingolipid metabolic pathways; and 4) to identify and validate in vitro novel combinatorial strategy to counter therapeutic resistance to vemurafenib. Findings obtained in BRAFCON are expected to advance treatment and diagnosis of BRAF-mutant colon cancer patients by contributing to the development of 1) new treatment modalities, and 2) novel potential diagnostic biomarkers for predicting resistance to vemurafenib.

 https://www.hrzz.hr/default.aspx?id=78&pid=7422&rok=2018-01