The experimental pharmacology group is involved in the study of new strategies in cancer therapeutics following three main research lines:
i) identification of new therapeutic target in medulloblastoma resistance: medulloblastoma (MB) is the most common brain tumor in pediatric age and is a very aggressive and characterized by low survival and high incidence of relapse. Our group is actively involved in the characterization of the molecular basis of MB aggressiveness and resistance by modeling the chemotherapy-induced evolution of MB cells in vitro by applying conventional chemotherapy. The -omics characterization of MB resistant cells will provide novel therapeutic opportunities potentially able to reduce risk of relapse and to increase survival rates. Active projects in this area include:
a) the study of BAG interactome. The resistant medulloblastoma cells express high level of BAG protein family, a class of antiapoptotic proteins that possess the ability to prevent tumor cell death. Our goal is to identify the predominant BAG member that may be responsible for sustaining therapy resistance and relapse in MB, together with all its interacting proteins. In collaboration with Prof. Luchini (George Mason University, USA) and by using the innovative technique of “molecular painting”, we will identify of novel potential BAG-partner hotspots to be drugged to achieve a more efficient clearance of residual cancer cells after standard treatments.
b) Cancer metabolism and REDOX homeostasis. Recently we and others have demonstrated that cancer cells can regulate Nrf2 pathway as a pro-survival response against drug treatments. Nrf2 is the major regulator of redox homeostasis and defense against oxidative stress. So far, our results show that starting from early exposure of chemotherapy drugs, MB cells induce Nrf2 expression and its transcriptional activation, supporting the involvement of Nrf2 pathway in MB response to chemotherapic treatment. More interestingly we demonstrated that the upregulation of this detoxifying system induces a metabolic switch of MB cells and sustains resistance to chemotherapy. By study of Nrf2 involvement in the metabolic changes that occur in the onset of chemotherapy resistance, our research group aim to give further insight on the characterization of MB resistance and the identification of novel druggable targets.
ii) high-throughput drug screening: exploiting our in vitro models of MB drug resistance, we extend this approach on multiple tumors in order to perform high-throughput drug screening (HTS) on human patient-derived (PD) tumor cells, cultivated in reliable microenvironment-controlled conditions. Drug libraries composed by both clinically approved drugs and novel promising small molecule will be tested on our in vitro model, alone and in combination with standard chemotherapy. Information retrieved from HTS, will allow the identification of new compounds able to successfully integrate into the common therapeutic schedules improving tumor eradication while reducing chemotherapy-induced side effects.
iii) drug discovery: our group is actively involved in the design and development of new anticancer agents:
• New NOTCH1 ligands by computer-aided design. In collaboration with Prof. Brancale (University of Cardiff, UK), performing a virtual screening of a library of 3*106 small molecules, we identified 60 compounds potentially target two different NOTCH1 binding sites.
• New FLT3 inhibitors in collaboration with Prof. Barraja (Universitàdeglistudi di Palermo)
• Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors in collaboration with Prof. Romagnoli (Università di Ferrara).
Roberta Bortolozzi, Senior Scientist (IRP researcher)
Elena Mariotto, Post-doctoral fellow
Fatlum Rruga, PhD student
Romagnoli R., Baraldi P.G., Prencipe F., Oliva P., Baraldi S., Ortega Schiaffino S., Kimatrai Salvador M., Lopez Cara L.C., Brancale A., Ferla S., Hamel E., Ronca R., Bortolozzi R., Mariotto E., Mattiuzzo E., VIOLA G. Design, Synthesis and biological evaluation of 6-substituted Thieno[3,2-d]pyrimidine analogues as dual EGFR kinase and microtubule inhibitors J. Med. Chem. (2019), 62, 1274-1290;
Roncato F., Rruga F., Porcu E., Casarin E., Ronca R., Realdon R., Basso G., Alon R., Basso G., VIOLA G. Morpurgo M. Improvement and extension of anti-EGFR targeting in breast cancer therapy by integration with the Avidin-Nucleic-Acid-Nano Assemblies Nat. Commun. (2018) 9(1):4070;
Mariotto E., Viola G., Ronca R., Bhujwalla Z.M., Accordi B., Serafin V., Persano L., Lopez Cara L.C., Bortolozzi R. The novel choline kinase alpha inhibitor EB-3D induces cellular senescence reduce tumor growth and metatastic dissemination in breast cancer Cancers. (2018), 10, 391;
Mariotto E., Bortolozzi R., Volpin I., Carta D., Serafin V., Accordi B., Navarro Luque P., Lopez Cara L.C., Basso G., Viola G. EB-3D a novel choline kinase inhibitor induces deregulation of the AMPK-mTOR pathway and apoptosis in leukemia T-cells. Biochem. Pharmacol. (2018), 155, 213-223;
Bortolozzi R., Bresolin S., Rampazzo E., Paganin M., Maule F., Mariotto E., Boso D., Minuzzo S., VIOLA G., Indraccolo S., Cazzaniga G., Basso G., Persano L. AKR1C enzymes sustain therapy resistance in pediatric T-ALL. Br. J. Cancer. (2018), 118, 985-994;
Romagnoli R., Baraldi P.G., Prencipe F., Oliva P., Baraldi S., Kimatrai Salvador M., Lopez-Cara L.C., Bortolozzi R., Mattiuzzo E., Basso G., VIOLA G. Design, Synthesis and Biological Evaluation of 3-Substituted-2-Oxoindole Hybrid Derivatives as Novel Anticancer Agents Eur. J. Med. Chem. (2017), 134, 258-270;
Bortolozzi R., Mattiuzzo E., Trentin L., Accordi B., Basso G., VIOLA G. Ribociclib, a CDK4/CDK6 kinase inhibitor, enhance glucocorticoid sensitivity in B-acute lymphoblastic leukemia (B-ALL). Biochem Pharm. (2018), 153, 230-241;
Porcù E., Persano L., Ronca R., Mitola S., Bortolozzi R., Romagnoli R., Oliva P., Basso G., VIOLA G. The novel antitubulin agent TR-764 strongly reduce tumor vasculature and inhibitis HIF-1α activation Scientific Reports (2016) 6:27886;
Consolaro F., Ghaem-Maghami S., Bortolozzi R., Zona S., Basso G., VIOLA G., Lam E. FOXO3a is involved in glucocorticoid (GC) sensitiveness in B-ALL through post translational modifications. Mol. Canc. Res. (2015), 13, 1578-1590;
Bortolozzi R., Viola G., Porcù E., Consolaro F., Marzano C., Pellei M., Gandin V., Basso G. A novel copper(I) complex induces ER stress-mediated apoptosis and sensitizes B-acute lymphoblastic leukemia cells to chemotherapeutic agents. Oncotarget (2014), 5, 5978-5991.
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Fax: +39 049 9640101
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