Angiogenesis is a hallmark of cancer, essential for the transition from the microscopic phase of tumor growth to the development of clinically relevant tumors. Anti-angiogenic therapy, which targets the tumor vasculature, often exacerbates hypoxia and glucose deprivation within the tumor microenvironment, as demonstrated in our studies and those of others using experimental tumor models. Consequently, angiogenesis blockade and tumor metabolism are closely interconnected. It is not surprising, then, that several metabolic pathways undergo significant modulation in response to anti-angiogenic treatment.

Under such treatment, tumors typically become more reliant on host-derived support, particularly through the uptake of key metabolites such as glucose and lipids. Despite this conceptual foundation, pre-clinical or clinical evidence regarding the impact of tumor metabolism on the efficacy of anti-angiogenic therapy remains limited. However, some studies suggest that signaling pathways involved in the metabolic stress response—such as LKB1/AMPK—or genetic alterations in mitochondrial DNA (mtDNA), may serve as predictors of therapeutic response to angiogenesis inhibitors.

Our research focuses on two key aspects: first, how the genetic and metabolic landscape of a tumor influences its response to anti-angiogenic therapy; and second, the selective pressures exerted by hypoxia and nutrient deprivation within the tumor microenvironment. Looking forward, while anti-angiogenic agents are often combined with chemotherapy or immunotherapy in clinical practice, novel therapeutic combinations are needed to enhance treatment outcomes. In this context, metabolism-targeting drugs represent a promising avenue for future preclinical and clinical investigation.

Aims

Within this conceptual framework, our group aims to investigate the metabolic adaptations of experimental tumors to glucose deprivation and anti-angiogenic therapy using a multi-omics approach. We then seek to validate key metabolic signatures and potential biomarkers in clinical samples from cancer patients undergoing anti-angiogenic treatment. In parallel, we aim to explore the genetic and epigenetic factors that influence the metabolic plasticity of cancer cells. By leveraging this knowledge, our goal is to identify and propose novel therapeutic strategies that target tumor metabolism, including their potential combination with anti-angiogenic therapies.

Selected Publications

Pastò A, Bellio C, Pilotto G, Ciminale V, Silic-Benussi M, Guzzo G, Rasola A, Frasson C, Nardo G, Zulato E, Nicoletto MO, Manicone M, Indraccolo S, Amadori A: Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation. Oncotarget 2014 Jun 30;5(12):4305-19155.

Curtarello, M., Zulato, E., Nardo, G., Valtorta, S., Guzzo, G., Rossi, E., Esposito, G., Msaki, A., Pastò, A., Rasola, A., Persano, L., Ciccarese, F., Bertorelle, R., Todde, S., Plebani, M., Schroer, H., Walenta, S., Mueller-Klieser, W., Amadori, A., Moresco, R.M., Indraccolo, S. VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells (2015) Cancer Research, 75 (1), 120-133.

Curtarello M, Tognon M, Venturoli C, Silic-Benussi M, Grassi A, Verza M, Minuzzo S, Pinazza M, Brillo V, Tosi G, Ferrazza R, Guella G, Iorio E, Godfroid A, Sounni NE, Amadori A, Indraccolo S. Rewiring of Lipid Metabolism and Storage in Ovarian Cancer Cells after Anti-VEGF Therapy. Cells. 2019 Dec 9;8(12):1601.

Boso D, Tognon M, Curtarello M, Minuzzo S, Piga I, Brillo V, Lazzarini E, Carlet J, Marra L, Trento C, Rasola A, Masgras I, Caporali L, Del Ben F, Brisotto G, Turetta M, Pastorelli R, Brunelli L, Navaglia F, Esposito G, Grassi A, Indraccolo S. Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts. J Exp Clin Cancer Res. 2023 Aug 7;42(1):196. doi: 10.1186/s13046-023-02779-x. PMID: 37550722

Boso D, Piga I, Trento C, Minuzzo S, Angi E, Iommarini L, Lazzarini E, Caporali L, Fiorini C, D'Angelo L, De Luise M, Kurelac I, Fassan M, Porcelli AM, Navaglia F, Billato I, Esposito G, Gasparre G, Romualdi C, Indraccolo S. Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models. J Exp Clin Cancer Res. 2024 Dec 19;43(1):325. doi: 10.1186/s13046-024-03239-w. PMID: 39702370

Funding
AIRC (IG25179)
PRIN 2022 (PNRR)

People involved:
Stefano Indraccolo, Associate Professor

Group members
Sonia Minuzzo, PTA, University of Padova
Giulia Pigato, assegnista di ricerca, University of Padova
Chiara Trento, PhD student, University of Padova
Eleonora Angi, PhD student, University of Padova
Melina Albano, borsista, IOV
Matteo Mauceri, post-doc, IOV
Federica Ferrarini, post-doc, IOV