Metabolic effects of anti-VEGF therapy in tumors
Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (TN) - Room B103
at 11:30 a.m.
- Stefano Indraccolo, M.D. - Group Leader, Istituto Oncologico Veneto - IRCCS, Padova, Italy
Background: My research team was the first to show that anti-VEGF therapy causes metabolic perturbations in tumors, including severe impairment of glucose and ATP levels. Recently, we investigated therapeutic effects of anti-VEGF therapy in experimental tumors with different glycolytic phenotypes as well as the possible modulation of metabolic features of tumor cells by anti-VEGF therapy.
Methods: Tumor xenografts and spontaneous tumors were treated with anti-VEGF antibodies. In situ markers, induced metabolic bioluminescence imaging and extracellular flux analysis were used to characterize metabolic changes in tumors treated with anti-VEGF therapy or ex vivo cultures of tumor cells. [18F]FLT and [18F]FAZA PET were used to track proliferation and hypoxia in tumor xenografts, respectively.
Results: We found that protracted anti-VEGF therapy induced both necrosis and vascular regression in all tumors; however, whereas highly glycolytic tumors became rapidly resistant, poorly glycolytic tumors displayed an initial regression, followed by acquisition of a resistant phenotype. Resistance of tumors chronically treated with anti-VEGF therapy was associated with increased hypoxic and highly proliferative tumor areas. We also observed that protracted anti-VEGF therapy selects for highly glycolytic cells and that this metabolic switch is stable and associated with decreased expression of the mitochondrial complex NDUFS1 and increased tumor aggressiveness.
Conclusions: Our results support the hypothesis that in xenograft models the highly glycolytic phenotype of tumor cells - either primary or secondary - confers resistance to VEGF blockade. Moreover, the observation that some metabolic traits of tumors can be stably modulated by anti-angiogenic therapy suggests evolutionary dynamics of tumor metabolism.
