Dr. Stefano Indraccolo, MD
Stefano Indraccolo is Experimental Oncologist at the Immunology and Molecular Oncology Unit of Istituto Oncologico Veneto – IRCCS, where he is leading a research group. He graduated in Medicine and specialized in Oncology at the University in Padova in 1994. During the early years of his career, he spent almost two years as post-doc at the Institute of Molecular Virology, GSF-Forschungszentrum, Munich (nowadays Helmholtz Zentrum Munich). He is active member of Società Italiana di Cancerologia (SIC) and European Association of Cancer Research (EACR). Dr. Indraccolo has been involved in several international and national projects as Principal Investigator, and his research work is currently supported by AIRC, among other sponsors. He has been invited as speaker at many international conferences. He has published >110 scientific articles in peer-reviewed journals dealing with tumor angiogenesis and metabolism, tumor dormancy, and Notch signaling in leukemia. Currently his interest is mainly focused on understanding the metabolic adaptations of tumors to anti-angiogenic therapy and the mechanisms involved in this phenomenon, with the long-term aim to identify new metabolic drugs to improve therapeutic efficacy of angiogenesis inhibitors in cancer.
Metabolic adaptation of tumors to anti-angiogenic therapy
The better understanding of the effects of angiogenesis inhibition on tumor metabolism will allow to design new strategies in order to overcome the resistance to anti-angiogenic therapy and improve therapeutic outcome in patients.
The focus of our research is to investigate the biology of metabolic heterogeneity of tumors and how this heterogeneity modulates and is itself modulated by anti-angiogenic therapy. In this conceptual framework, we are also keen to investigate the possible impact on tumor angiogenesis of therapeutic strategies targeting glycolysis and their combination with anti-angiogenic therapy.
Albeit less studied compared with genetic heterogeneity, it is increasingly recognized that tumors are metabolically heterogeneous. In general, both inter-tumor and intra-tumor metabolic heterogeneity can be observed and the biological basis of this phenomenon remains largely unexplored. Enhanced glycolytic activity, one of the best known metabolic hallmarks of cancer, is an heterogeneous trait of tumors and is inter-connected with another hallmark of cancer, namely angiogenesis. Indeed, it has been shown that soluble factors released by highly glycolytic tumor cells, such as lactic acid, modulate the stromal microenvironment, contributing to promote angiogenesis. On the other hand, it has also been observed that endothelial cells preferentially use glycolysis as energy source, especially during angiogenesis. Therefore, in the presence of highly glycolytic tumor cells a metabolic competition with endothelial cells could occur, and glucose could become a limiting substrate for angiogenesis. This provisional balance between two seemingly opposing forces could be further perturbed by anti-angiogenic therapies, which hit the microvasculature and simultaneously increase tumor glycolysis. These mechanisms could underscore modulation of the therapeutic activity of anti-angiogenic drugs by a tumor metabolic trait.
Our team pioneered investigation of metabolic effects of anti-angiogenic drugs in solid tumors. We initially established that VEGF blockade is accompanied by dramatic reduction in glucose and ATP levels in the tumor microenvironment (Nardo G. et al. Cancer Res 2011) and this metabolic change activates the LKB1/AMPK pathway, a sensor of nutrients starvation in cells. We further hypothesized that alterations affecting this pathway could modulate therapeutic response to anti-VEGF drugs, and validated this hypothesis in CRC and lung cancer patients treated with chemotherapy plus bevacizuamb (Zulato E. et al., BJC 2014 and Bonanno L. et al., under revision). In parallel, we found that anti-VEGF therapy impacts on the metabolic profile of tumors and exacerbates the Warburg phenotype of tumors. Importantly, some of these metabolic chnages are stable and are associated with resistance to bevacizumab (Curtarello M. et al. Cancer Res 2015). Additional metabolic changes occurring in tumors treated with angiogenesis inhibitors are currently under investigation in collaboration with other groups.
Conclusions and perspectives
Results of our ongoing studies will provide a multi-level representation of the connections between the glycolytic phenotype of tumors and certain genetic or epigenetic profiles, highlight the therapeutic potential of glycolysis inhibitors in combination with anti-angiogenic drugs, investigate effects of tumor glycolysis on angiogenesis, and establish the possible predictive value of metabolic markers in patients treated with anti-angiogenic drugs.
Genetic profiling of lung cancer
Decoding the cancer genome to improve personalized therapy for lung cancer patients.
The focus of this Project is to investigate dynamic changes of the cancer genome through serial analysis of tumor and plasma samples from non-small cell lung cancer (NSCLC) patients.
Among common solid tumors, NSCLC is probably the best example of successful clinical application of targeted therapies. Accordingly, genetic screening for actionable mutations or alterations in genes such as EGFR, ALK, ROS1 is current practice, as detection of such mutations enables prescription of certain targeted drugs, belonging to the family of tyrosine kinase inhibitors (TKI). In face of an increasing demand of genetic characterization of the tumor sample, in most cases there is a limiting amount of tissue available for molecular analysis. This stimulated the development of new methods, such as next generation sequencing (NGS), which enable parallel profiling of many genes of potential clinical interest starting from a minimal amount of tumor DNA. Moreover, it has been shown that tumor-specific mutations can be found in circulating tumor DNA (ctDNA) obtained from plasma, which has stimulated the development of so called “liquid biopsy” methods to track cancer-associated mutations through blood samples. This latter development has been very successful in NSCLC and enables to monitor genetic changes of cancer during treatment by minimally invasive methods.
Our team pioneered at IOV investigation of innovative methods to detect somatic mutations in NSCLC samples, including both NGS and droplet digital PCR (ddPCR) techniques. In 2017, we routinely genotyped >500 tissue samples and >150 plasma samples from NSCLC patients, being one of the leading laboratories for molecular diagnostics of lung cancer in the Veneto region. Results of our ongoing studies show the feasibility of using NGS to profile NSCLC samples and its potential to uncover mutations in actionable genes which would not be found by routine analysis. We aim to further improve application of upcoming cutting edge technologies to clinical samples with the long-term aim to increase the percentage of patients who can access to targeted therapy.
We have also started to use NGS and ddPCR technologies for quantitative measurements of the mutational load in plasma and monitor its variations during therapy. This study will investigate whether molecular variations detected in cfDNA can even precede radiologic or clinical responses. In this conceptual framework, we are also keen to investigate possible early biomarkers of resistance to targeted therapies.
- Sonia Minuzzo
- Valentina Agnusdei
- Alessandra Gasparini
- Giorgia Nardo
- Lorenza Pasqualini
- Marica Pinazza
- Elisabetta Zulato
- Andrea Boscolo Bragadin
- Martina Tognon
- Martina Verza
- Arianna Masaro
- Alleanza Contro il Cancro (ACC) – Ministero della Salute
- Fondazione Celeghin
- IOV 5×1000 Grants
- Serafin V, Capuzzo G, Milani G, Minuzzo SA, Pinazza M, Bortolozzi R, Bresolin S, Porcù E, Frasson C, Indraccolo S, Basso G, Accordi B. Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia. Blood. 2017 Dec 21;130(25):2750-2761.
- Bonanno L, De Paoli A, Zulato E, Esposito G, Calabrese F, Favaretto A, Santo A, Conte AD, Chilosi M, Oniga F, Sozzi G, Moro M, Ciccarese F, Nardo G, Bertorelle R, Candiotto C, De Salvo GL, Amadori A, Conte P, Indraccolo S. LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab. Clin Cancer Res. 2017 Jul 1;23(13):3316-3324.
- 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 RM, Indraccolo S. VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells. Cancer Res. 2015 Jan 1; 75(1):120-33.