The group is focused on developing specific approaches based on the delivery of toxins for the treatment of bladder cancer. The employment of plant and bacterial toxins as effectors in cancer therapy has been evaluated in pilot pre-clinical and clinical studies with promising results. Ribosome-inactivating proteins of plant origin such as saporin (SAP) are potent protein synthesis inhibitors, promptly inducing apoptosis of target cells and SAP-based conjugates showed selective killing of tumor cells. We are developing different systems for SAP delivery and tumor targeting, improved by the parallel study of the molecular mechanisms underlying tumor occurrence and progression in order to further identify specific tumor markers as potential therapeutic targets.
2004 PhD in Genetic and Biomolecular Sciences, Università degli Studi di Milano
2000 Degree in Pharmaceutical Chemistry and Technology, Università degli Studi di Milano
2014-today Group leader, Urological Research Institute, Division of Molecular Oncology, San Raffaele Scientific Institute, Milan
2011-today Lecturer of Biochemistry, Università Vita e Salute San Raffaele, Milan
2013-2014 Project leader, Department of Biotechnology and Biosciences, Università degli Studi di Milano-Bicocca
2008-2013 Project leader, Neurogenomics Unit (former Human Molecular Genetics Unit), San Raffaele Scientific Institute, Milan
2005-2007 Postdoc, Institute of Molecular Genetics – National Research Council, Pavia
2002-2004 PhD student, Institute for Research in Biomedicine, Bellinzona, Switzerland
2001-2002 PhD student, Protein Transport and Secretion Unit, San Raffaele Scientific Institute, Milan
2000-2001 Post-Graduate fellow, Biotechnology Unit, San Raffaele Scientific Institute, Milan
2000 Visiting fellow, Southampton General Hospital, United Kingdom
Development of toxin-based targeted therapy for the treatment of bladder cancer
Bladder cancer is among the most common and expensive to manage cancers in developed countries due to a need for continuous monitoring and recurrence treatment. Despite research efforts, available therapeutic options in bladder cancer have still limited results and alternative and/or complementary strategies to state-of-art therapies are needed to limit the recurrence and improve survival. Although extensive molecular characterization of urothelial bladder carcinoma showed a plethora of alteration in a relevant number of tumors, so far no molecularly targeted agents have been approved for treatment of the disease.
Plant and bacterial toxins have been increasingly studied as effectors in cancer treatment and some of them have been used with promising results in pilot preclinical and clinical studies. Ribosome-inactivating proteins such as saporin (SAP) are potent protein synthesis inhibitors, promptly inducing apoptosis of target cells. In particular, SAP has high enzymatic activity, stability and resistance to conjugation procedures and blood proteases, thus lending itself well to be used in cancer therapy. SAP-based conjugates showed selective killing in vitro and in vivo, with only mild and transient side effects.
We have developed saporin-based chimeric fusions targeted against specific molecules over-expressed on the surface of cancer cells and demonstrated their activity and efficacy in vitro. Our research activity is based on the employment of such fusions in the treatment of bladder cancer and on the study of additional molecules as therapeutic targets to be tested in various cellular and animal models available at the Urological Research Institute. Moreover, it is of our interest to develop alternative systems for toxin delivery to the tumor to be synergistically used with other treatments.
Analysis of factors leading to bladder cancer occurrence and progression
Tumors depend on a cross talk with the surroundings to guarantee their survival (angiogenesis, immune escape), to support phenotypic changes (epithelial-to-mesenchymal transition) required to leave the primary tumor mass and to prepare the bone marrow and pre-metastatic organs allowing migrating tumor cells to settle and grow. Specific microvesicles termed exosomes are emerging as important vehicles for tumor-derived factors to modulate pre-metastatic sites, promote neo-angiogenesis and reduce immune surveillance.
Most newly diagnosed bladder cancer (around 75%) are non-muscle invasive; nevertheless, a significant percentage, ranging from 10 to 20%, of low grade superficial tumors progress to high-grade carcinomas, that are initially treated with trans urethral resection of the lesion followed by chemo- or immunotherapy. Unfortunately, chemo-resistance and side effects often limit the therapeutic efficacy and the tumors frequently recur and to some extent progress. The muscle-invasive tumors are generally treated by radical cystectomy followed by chemotherapy, but up to 50% of patients develop metastatic disease with a poor prognosis.
The activity of the research group is focused on the study of the mechanisms leading to the development and progression of bladder cancer, such as stromal reorganization, neo-angiogenesis and cell migration through the analysis of selected bioactive molecules such as enzymes and RNAs carried by tumor exosomes. A thorough dissection of the molecular and cellular pathways involved in these processes is the basis of the identification of possible therapeutic targets.
Vago R (2015), “Ribosome Inactivating Proteins: Exploiting Plant Weapons to Fight Human Cancer” J Genet Syndr Gene Ther. 6:272
Della Cristina P, Castagna M, Lombardi A, Barison E, Tagliabue G, Ceriotti A, Koutris I, Di Leandro L, Giansanti F, Vago R, Ippoliti R, Flavell SU, Flavell DJ, Colombatti M, Fabbrini MS. (2015) “Systematic comparison of single-chain Fv antibody-fusion toxin constructs containing Pseudomonas Exotoxin A or saporin produced in different microbial expression systems” Microb Cell Fact. 13;14(1):19.
Vago R, Ippoliti R, Fabbrini MS (2013) “Current status & Biomedical applications of Ribosome-inactivating proteins”. Antitumor Potential and other Emerging Medicinal Properties of Natural Compounds. Springer
Giansanti F, Giordani V, Vago R, Flavell DJ, Flavell SU, Fabbrini MS, Ippoliti R. (2013) “Dissecting the entry route of saporin-based anti-CD7 immunotoxins in human T-cell acute lymphoblastic leukaemia cells” Antibodies 2(1), 50-65
Zarovni N, Vago R, Fabbrini MS. (2009) “Saporin suicide gene therapy” Methods Mol Biol. 542:261-83.
Zarovni N., Vago R., Soldà T., Monaco L., Fabbrini M.S. (2007) “Saporin as a novel suicide gene in cancer gene therapy” Cancer Gene Ther. 14(2):165-73.
Vago R., Marsden C.J., Lord J.M., Ippoliti R., Flavell D.J., Flavell S.U., Ceriotti A. and Fabbrini M.S. (2005). “Saporin and ricin, two ribosome-inactivating proteins from plants, differ in their routes of entry into mammalian cells” FEBS J. 272(19):4983-95