PRIN 2017 - 2017SA5837 - Giovanni Maga (DSB.AD007.192)

Area tematica

Scienze biomediche

Area progettuale

Struttura responsabile del progetto di ricerca

Istituto di genetica molecolare "Luigi Luca Cavalli Sforza" (IGM)

Responsabile di progetto

GIOVANNI MAGA
Telefono: 0382546322
E-mail: giovanni.maga@igm.cnr.it

Abstract

Alterations in the metabolism of tumor cells are hallmarks of cancer. Cancer cell metabolism connects different biochemical pathways creating an altered metabolic network, which stimulates high proliferation rates and drives malignant transformation. Exploiting the metabolic differences between normal and tumor cells seems an effective way for achieving selective toxicities in anticancer chemotherapy. In addition, selecting targets belonging to different converging pathways within the cancer metabolome can achieve synergy among the components of the combination.
Based on these considerations, the rationale of the project is the exploitation of the high level of cross-talk among upstream signal transduction pathways promoting cell proliferation, cell migration and metastasis, with downstream glucose and lipid metabolic pathways, which are deregulated in cancer cells and essential for tumor proliferation. By targeting essential components of these pathways, we aim at developing synergic drug combinations endowed with high antiproliferative activity and high selectivity for tumor vs. healthy cells.

Obiettivi

We will focus on a set of already validated anticancer targets, namely: glucose transporter 1 (GLUT1), which regulates the uptake of glucose inside the cell; lactate dehydrogenase 5 (LDH5), which is responsible of the final step in the glycolytic cascade; monoacylglycerol lipase (MAGL) a cytosolic serine hydrolase that preferentially cleaves monoacylglycerols into fatty acids and glycerol; cannabinoid receptor type 2 (CB2R) involved in the regulation of various cell survival signaling pathways, cellular sphingolipids metabolism and glycolysis; serum and glucocorticoid kinase 1 (SGK1), which regulates amino acid, peptide, and glucose transport; Src-family kinases (SFKs), which are upstream activators of cell proliferation, regulating diverse aspects of cell metabolism including glucose uptake and lipid homeostasis. Novel chemical entities will be both rationally designed/optimized on the targets, using computational approaches (top-down approach), and identified through screening of existing libraries against the relevant targets in biological assays (bottom-up approach). The most promising candidates tested on relevant in vitro and in vivo models for the diseases.

Data inizio attività

29/08/2019

Parole chiave

cancer, protein kinase, metabolism

Ultimo aggiornamento: 02/12/2024