Experimental oncology
Tumor biology and vascular targeting
Long-term commitment of Tumor biology and vascular targeting Unit is to understand the role of inflammatory cytokines and chromogranin A in cancer biology, and to develop new strategies for cancer therapy based on the manipulation of the tumor vasculature with targeted cytokines and anti-angiogenic agents, in order to improve the penetration of chemotherapeutic drugs and the infiltration of cells of the immune system in tumor tissues.
Research activity
The Unit has demonstrated that peptides containing the NGR or isoDGR motives (capable of recognizing tumor-vasculature-associated CD13 and integrins, respectively) can be exploited as ligands for the targeted delivery of cytokines, drugs and therapeutic nanoparticles to tumors. One therapeutic strategy originally developed by this group, based on vascular targeting with NGR-TNF (a genetically engineered tumor necrosis factor-alpha derivative) is being tested in clinical studies.
The Unit is also currently testing the hypothesis that gold nanoparticles tagged with tumor-homing peptides may work as multifunctional platforms for delivering synergistic cytokines to the tumor vasculature.
Another area of research regards investigations on chromogranin A, a protein released in circulation by the neuroendocrine system, and its regulatory role on vascular physiology, angiogenesis, and cancer metastatization. Group studies led to discover that chromogranin A is an important regulator of the tumor vascular biology, vascular permeability, angiogenesis, tumor growth, and tumor cell trafficking, and that chromogranin A-fragmentation represents an important mechanism for the activation of angiogenesis. The potential diagnostic/prognostic values of CgA fragmentation in cancer patients represent others important areas of research, based on the observation that chromogranin A cleavage, and consequent activation of an angiogenic switch, is associated with increased tumor microvascular density and disease progression.
The Unit is also currently testing the hypothesis that gold nanoparticles tagged with tumor-homing peptides may work as multifunctional platforms for delivering synergistic cytokines to the tumor vasculature.
Another area of research regards investigations on chromogranin A, a protein released in circulation by the neuroendocrine system, and its regulatory role on vascular physiology, angiogenesis, and cancer metastatization. Group studies led to discover that chromogranin A is an important regulator of the tumor vascular biology, vascular permeability, angiogenesis, tumor growth, and tumor cell trafficking, and that chromogranin A-fragmentation represents an important mechanism for the activation of angiogenesis. The potential diagnostic/prognostic values of CgA fragmentation in cancer patients represent others important areas of research, based on the observation that chromogranin A cleavage, and consequent activation of an angiogenic switch, is associated with increased tumor microvascular density and disease progression.
Alice Dellatomasina, Anna Maria Gasparri, Barbara Colombo, Angelina Sacchi, Mimma Bianco, Tiziana Daniele, Antonio Esposito, Fabio Pastorino, Mirco Ponzoni, Fabrizio Marcucci, Flavio Curnis and Angelo Corti. Spatio-Temporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement. Cancer Research, February 22, 2019. Doi: 10.1158/0008-5472.CAN-18-0289
Corti A, Gasparri AM, Ghitti M, Sacchi A, Sudati F, Fiocchi M, Buttiglione V, Perani L, Gori A, Valtorta S, Moresco RM, Pastorino F, Ponzoni M, Musco G, Curnis F. Glycine N-methylation in NGR-tagged nanocarriers revents Isoaspartate formation and integrin binding without impairing CD13 recognition and tumor homing. Adv Funct Mater. 2017; 27, 1701245.
Bianco M, Gasparri AM, Colombo B, Curnis F, Girlanda S, Ponzoni M, Bertilaccio MTS, Calcinotto A, Sacchi A, Ferrero E, Ferrarini M, Chesi M, Bergsagel PL, Bellone M, Tonon M, Ciceri F, Marcatti M, Caligaris-Cappio F, Corti A. Chromogranin A is preferentially cleaved into pro-angiogenic peptides in the bone marrow of multiple myeloma patients. Cancer Res. 2016; 76(7):1781-91.
Curnis F, Fiocchi M, Sacchi A, Gori A, Gasparri A, Corti A. NGR-tagged nano-gold: a new CD13-selective carrier for cytokine delivery to tumors. Nano Research 2016; 9(5): 1393-1948.
Crippa L, Bianco M, Colombo B, Gasparri AM, Ferrero E, Loh YP, Curnis F, Corti A. A new chromogranin A-dependent angiogenic switch activated by thrombin. Blood 2013 Jan 10;121(2):392-402.
Dondossola E, Crippa L, Colombo B, Ferrero E, Corti A. Chromogranin A regulates tumor self-seeding and dissemination. Cancer Res. 2012 Jan 15;72(2):449-59.
Dondossola E, Gasparri A, Colombo B, Sacchi A, Curnis F, Corti A. Chromogranin A restricts drug penetration and limits the ability of NGR-TNF to enhance chemotherapy efficacy. Cancer Res. 2011 Sep 1;71(17):5881-90.
Curnis F, Sacchi A, Gasparri A, Longhi R, Bachi A, Doglioni C, Bordignon C, Traversari C, Rizzardi GP, Corti A. Isoaspartate-glycine-arginine: a new tumor vasculature targeting motif. Cancer Res 2008 Sep 1;68(17):7073-82.
Ceconi C, Ferrari R, Bachetti T, Opasich C, Volterrani M, Colombo B, Parinnello G, Corti A. Chromogranin A in heart failure. A novel neurohumoral factor and a predictor for mortality. Eur Heart J. 2002 Jun;23(12):967-74.
Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest. 2002 Aug;110(4):475-82.
Curnis F, Sacchi A, Borgna L, Magni F, Gasparri A, Corti A. Enhancement of tumor necrosis factor-alpha anti-tumor immunotherapeutic properties by targeted delivery to aminopeptidase N (CD13). Nat Biotechnol. 2000 Nov;18(11):1185-90.
