Angiogenesis is an hallmark of cancer needed to escape from the microscopic phase of tumor growth and lead to clinically relevant tumors. Anti-angiogenic therapy, which targets the tumor vasculature, tends to exacerbate both hypoxia and glucose deprivation in the tumor microenvironment, as we and others described in experimental tumor models, (1, 2). Thus angiogenesis blockade and tumor metabolism are closely intertwined and, not surprisingly, several metabolic pathways are substantially modulated in the tumor microenvironment following treatment with anti-angiogenic drugs. Under anti-angiogenic treatment, tumors become generally more dependent on host support in terms of uptake of key metabolites, such as glucose and lipids (3, 4). Despite this conceptual premise, limited evidence about the influence of tumor metabolism on outcome of anti-angiogenic therapy is available from clinical studies, although some studies indicate that certain signaling pathways involved in the adaptation to metabolic perturbations, such as LKB1/AMPK, could predict response to angiogenesis inhibitors (5). Finally, although in most clinical studies anti-angiogenic drugs have been prescribed with chemotherapy or immunotherapy, new drug combinations are needed in order to improve therapeutic outcome and metabolism-targeting drugs could be considered for future pre-clinical and clinical studies.

Aims

In this conceptual framework, our group seeks to investigate by a multi-omics approach metabolic adaptations of experimental tumors to anti-angiogenic drugs, and to subsequently validate key signatures and biomarkers in clinical samples from patients receiving anti-angiogenic therapy. Finally, we also aim to investigate genetic and epigenetic factors impacting on the metabolic plasticity of cancer cells and to leverage on this knowledge to propose new therapeutic strategies targeting metabolism and their combination with anti-angiogenic therapy.

5 Publications

Nardo, G., Favaro, E., Curtarello, M., Moserle, L., Zulato, E., Persano, L., Rossi, E., Esposito, G., Crescenzi, M., Casanovas, O., Sattler, U., Mueller-Klieser, W., Biesalski, B., Thews, O., Canese, R., Iorio, E., Zanovello, P., Amadori, A., Indraccolo, S. Glycolytic phenotype and AMP kinase modify the pathologic response of tumor xenografts to VEGF neutralization (2011) Cancer Research, 71 (12), 4214-4225.

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.

Indraccolo S, De Salvo GL, Verza M, Caccese M, Esposito G, Piga I, Del Bianco P, Pizzi M, Gardiman MP, Eoli M, Rudà R, Brandes AA, Ibrahim T, Rizzato S, Lolli I, Zagonel V, Lombardi G. Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis. (2020) Clin Cancer Res, 26(17), 4478-4484.

Funding
AIRC

People involved:
Stefano Indraccolo, Associate Professor

Group members
Sonia Minuzzo, TA, University of Padova
Valentina Serafin, RTDA, University of Padova
Chiara Trento, PhD student, University of Padova
Daniele Boso, post-doc, IOV
Federica Ferrarini, post-doc, IOV