Responsabile Scientifico

• CAPELLO Daniela (DiMET)

Partecipanti al progetto

• CAPELLO Daniela (DiMET)

Titolo del progetto

• Exploiting metabolic vulnerabilities to overcome resistance to targeted therapies in colorectal cancer

Ente finanziatore

• MUR - Ministero dell'Università e Ricerca

Programma di finanziamento

• PRIN - Progetti di Ricerca di Rilevante Interesse Nazionale (dal 2020)

Bando di riferimento

• PRIN 2022 PNRR

Anno di presentazione del progetto

• 2022

Anno di approvazione del progetto

• 2023

Project ID / numero contratto

• P2022E3BTH_002

Durata del progetto

• 24 mesi

Inizio del progetto

• 30/11/2023

Fine del progetto

• 29/11/2025

Ente capofila

• UNITO - Università degli studi di Torino

Altri partner del progetto

• UNIROMA1 - Università di Roma La Sapienza

Progetto approvato - Contributo unità di ricerca del Dipartimento

• €57.744,00

Sustainable Development Goals - Agenda 2030

Keyword

• Metabolism
• Oncology
• colorectal cancer
• biomarker discovery
• molecular medicine
• preclinical models

Stato del progetto

• Approvato

Abstract

• Colorectal cancer (CRC) is the third most frequent type of solid tumor worldwide (1). Despite great advances in the knowledge of the genetic bases of CRC, a more comprehensive understanding of the mechanisms accounting for tumor initiation, progression and resistance to therapy is still needed. Recently, the deregulation of cellular metabolism has emerged as a key hallmark of cancer (2, 3). Metabolic reprogramming represents indeed a key process to provide CRC cells with the energy substrates, anaplerotic precursors and reducing equivalents required to fuel tumor growth and survival in stressing settings. In addition, treatment with targeted therapies can further trigger a metabolic rewiring to adapt to the novel growth conditions and to allow CRC to cope with the downregulation of oncogenes that supports cell growth. In this regard, metabolism direct impact on epigenetics (4) needs to be considered in CRC studies as an additional mechanism of stress condition adaptation. In this research proposal, we aim at providing key evidence regarding the metabolic makeup of colorectal tumors displaying representative types of genomic profiles and their corresponding pairs with acquired resistance to commonly used targeted therapies. The project is divided in five main work packages (WPs) with the following objectives: WP1, WP2 and WP3 will respectively identify metabolic, proteomic and epigenetic vulnerabilities of CRC preclinical models; WP4 will exploit findings gathered from the previous WPs to devise novel therapeutic strategies. Finally, the integration of WPs will take place by translationally validating data in a platform of patient-derived organoids (PDOs) already available or de novo generated in WP5. The elucidation of pathways underlying metabolic reprogramming will have a tremendous impact by shedding light on therapeutic targets useful for developing new translational clinical approaches and overcoming resistance to currently employed targeted therapies. A PDO biobank will represent a valuable tool for predicting patient responses to therapy and identifying alternative treatment regimens for resistant patients. The results are expected to improve our knowledge of the CRC metabolic landscape, unveiling diverse pathways and new vulnerabilities for treating patients.