UOSD of Preclinical Models and New Therapeutic Agents Unit - Translational Research Functional Departmental Area

Foto (piccola)

Anna Teresa Bagnato


 The aim of the Unit is to develop patient-derived models that will set the scene for target identification and for efficacious combination therapy in oncology. Results from the preclinical studies conducted in these models are expected to identify new targeted approaches, able to hamper the malfunctioning signaling network. In particular, the resistance to targeted therapy highlights the need to discover drivers of an early non-mutational drug-tolerance state, before resistance occurs, providing an opportunity for more effective therapeutic approaches. The research topic concerns:

- the role of growth factor and receptors (i.e. endothelin (ET-1), estrogen) or anti-      apoptotic proteins (i.e.bcl-2) in invasion, metastasis, and response to anti-cancer therapy
- the mechanism of tumor angiogenesis and lymphangiogenesis. Special attention is given to the relation with the microenvironment (hypoxia).
- the membrane protrusions in cell migration and invasiveness
- preclinical models to evaluate new combinatorial therapies

The development of preclinical models “patient-derived” (PD), including primary cultures, tumoroids, circulating tumor cells, PD-xenografts, represents an important platform for the evaluation of new therapeutic agents and for the identification of new biomarkers. This platform (ovarian, lung, colon cancer, melanoma, sarcoma) can represent an opportunity of integration among inter-and intra-department that can reliably disclose the prospective results of clinical practice based on a strong pre-clinical rationale. 


Phone. +390652662575
e-mail: donatella.delbufalo@ifo.gov.it 

Phone. +390652662605
Phone. +390652662565
Phone. +3906526625
Phone. +390652662579
Phone. +390652662590

Phone. +390652662570
e-mail: piera.tocci@ifo.gov.it

Phone. +390652662570
e-mail: roberta.cianfrocca@ifo.gov.it

Phone. +390652662979
Phone. +390652662570
Phone. +390652666891
Phone. +390652666891
Phone. +390652666891
Phone. +390652666891
Phone. +390652662570
Phone. +390652666891
Phone. +390652662913
Phone. +390652665301
Phone. +390652662545
e-mail: adele.petricca@ifo.gov.it


Monaco G, La Rovere R, Karamanou S, Welkenhuyzen K, Ivanova H, Vandermarliere E, Di Martile M, Del Bufalo D, De Smedt H, Parys JB, Economou A and Bultynck G. A double point mutation at residues Ile14 and Val15 of Bcl-2 uncovers a role for BH4 domain in both protein stability and function. FEBS J. 2018 Jan;285(1):127-145. doi: 10.1111/febs.14324. Epub 2017 Dec 2.
Gabellini C, Gómez-Abenza E, Ibáñez-Molero S, Tupone MG3, Pérez-Oliva AB, de Oliveira S, Del Bufalo D, Mulero V. Interleukin 8 mediates bcl-xL-induced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model. Int J Cancer.2018 Feb 1;142(3):584-596. doi: 10.1002/ijc.31075. Epub 2017 Oct 12.
Ferrara M, Sessa G, Fiore M, Bernard F, Asteriti IA, Cundari E, Colotti G, Ferla S, Desideri M, Buglioni S, Trisciuoglio D, Del Bufalo D, Brancale A, Degrassi F. Small molecules targeted to the microtubule-Hec1 interaction inhibit cancer cell growth through microtubule stabilization. Oncogene. 2018 Jan 11;37(2):231-240. doi: 10.1038/onc.2017.320. Epub 2017 Sep 18.
Di Modugno F, Caprara V, Chiellini L, Tocci P, Spadaro F, Ferrandina G, Sacconi A, Blandino G, Nisticò P, Bagnato A, Rosanò L(*These authors have contributed equally to this work) hMENA is a key regulator in endothelin-1/-arrestin1-induced invadopodial function and metastatic process. Proc Natl Acad Sci USA. 2018 doi:10.1073/pnas.1715998115
Di Martile M, Desideri M, Tupone MG, Buglioni S, Antoniani B, Mastroiorio C, Falcioni R, Ferraresi V, Baldini N, Biagini R, Milella M, Trisciuoglio D, Del Bufalo D. Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma. Oncogenesis 2018 Feb 23;7(2):20. doi: 10.1038/s41389-018-0026-x.
Di Martino S, Amoreo CA, Nuvoli B, Galati R, Strano S, Facciolo F, Alessandrini G, Pass HI, Ciliberto G, Blandino G, De Maria R,,Cioce M. HSP90 inhibition alters the chemotherapy-driven rearrangement of the oncogenic secretome. Oncogene. 2018 Jan 9.doi: 10.1038/s41388-017-0044-8.
Nuvoli B, Camera E, Mastrofrancesco A, Briganti S, Galati R Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane. Free RadicBiol Med. 2018 Feb 1;115:266-277. doi: 10.1016/j.freeradbiomed.2017.12.008. Epub 2017 Dec 9.


Cianfrocca R, Rosanò L, Tocci P, Sestito R, Caprara V, Di Castro V, De Maria R, Bagnato A. Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer. Cell Death Differ. 2017 Jul 14. doi:10.1038/cdd.2017.121 

Fianco G, Mongiardi MP, Levi A, De Luca T, Desideri M, Trisciuoglio D, Del Bufalo D, Cinà I, Di Benedetto A, Mottolese M, Gentile A, Centonze D, Ferrè F, Barilà D. Caspase-8 contributes to angiogenesis and chemotherapy resistance 

Sestito R, Cianfrocca R, Rosanò L, Tocci P, Semprucci E, Di Castro V, Caprara V, Ferrandina G, Sacconi A, Blandino G, Bagnato A. miR-30a inhibits endothelin A receptor and chemoresistance in ovarian carcinoma. Oncotarget. 2016;7(4):4009-23 
Nuvoli B, Sacconi A, Cortese G, Germoni S, Murer B, Galati R. Reduction of estradiol in human malignant pleural mesothelioma tissues may prevent tumour growth, as implied by in in-vivo and in-vitro models. Oncotarget. 2016;7(30):47116-47126
Trisciuoglio D, Desideri M, Farini V, De Luca T, Di Martile M, Tupone MG, Urbani A, D'Aguanno S, Del Bufalo D. Affinity purification-mass spectrometry analysis of bcl-2 interactome identified SLIRP as a novel interacting protein. Cell Death Dis. 2016;7:e2090
Rosanò L, Cianfrocca R, Tocci P, Spinella F, Di Castro V, Caprara V, Semprucci E, Ferrandina G, Natali PG, Bagnato A. Endothelin A receptor/β-arrestin signaling to the Wnt pathway renders ovarian cancer cells resistant to chemotherapy. Cancer Res. 2014;74(24):7453-64
Buelli S, Rosanò L, Gagliardini E, Corna D, Longaretti L, Pezzotta A, Perico  L, Conti S, Rizzo P, Novelli R, Morigi M, Zoja C, Remuzzi G, Bagnato A, Benigni A. β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury. J Am Soc Nephrol. 2014;25(3):523-33
Nuvoli B, Germoni S, Morosetti C, Santoro R, Cortese G, Masi S, Cordone I, Galati R. Exemestane blocks mesothelioma growth through downregulation of cAMP, pCREB and CD44 implicating new treatment option in patients affected by thisdisease. Mol Cancer. 2014;13:69
Favia A, Desideri M, Gambara G, D'Alessio A, Ruas M, Esposito B, Del Bufalo D, Parrington J, Ziparo E, Palombi F, Galione A, Filippini A. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca2+ signaling. Proc Natl Acad Sci U S A. 2014;111(44):E4706-15
Del Bufalo D, Desideri M, De Luca T, Di Martile M, Gabellini C, Monica V, Busso S, Eramo A, De Maria R, Milella M, Trisciuoglio D. Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer. Mol Cancer. 2014;13:230
Rosanò L, Spinella F, Bagnato A. Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 201313(9):637-51
Nuvoli B, Galati R. Cyclooxygenase-2, epidermal growth factor receptor, and aromatase signaling in inflammation and mesothelioma. Mol Cancer Ther. 2013;12(6):844-52
Ragazzoni Y, Desideri M, Gabellini C, De Luca T, Carradori S, Secci D, Nescatelli R, Candiloro A, Condello M, Meschini S, Del Bufalo D, Trisciuoglio D. The thiazole derivative CPTH6 impairs autophagy. Cell Death Dis. 2013;4:e524
Trisciuoglio D, Ragazzoni Y, Pelosi A, Desideri M, Carradori S, Gabellini C, Maresca G, Nescatelli R, Secci D, Bolasco A, Bizzarri B, Cavaliere C, D'Agnano I, Filetici P, Ricci-Vitiani L, Rizzo MG, Del Bufalo D. CPTH6, a thiazole-derivative, induces histone hypoacetylation and apoptosis in human leukemia cells. Clin Cancer Res. 2012; 18(2):475-86 
Rosanò L, Cianfrocca R, Spinella F, Di Castro V, Nicotra MR, Lucidi A, Ferrandina G, Natali PG, Bagnato A. Acquisition of chemoresistance and EMT phenotype is linked with activation of the endothelin A receptor pathway in ovarian carcinoma cells. Clin Cancer Res. 2011;17(8):2350-60
16. Stoppoloni D, Salvatori L, Biroccio A, D'Angelo C, Muti P, Verdina A, Sacchi A, Vincenzi B, Baldi A, Galati R. Aromatase inhibitor exemestane has antiproliferative effects on human mesothelioma cells. J Thorac Oncol. 2011;6(3):583-91 
Trisciuoglio D, Gabellini C, Desideri M, Ragazzoni Y, De Luca T, Ziparo E, Del Bufalo D. Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells. Cell Death Differ.2011;18(6):1024-35
Stoppoloni D, Canino C, Cardillo I, Verdina A, Baldi A, Sacchi A, Galati R. Synergistic effect of gefitinib and rofecoxib in mesothelioma cells. Mol Cancer. 2010;9:27
19. Spinella F, Garrafa E, Di Castro V, Rosanò L, Nicotra MR, Caruso A, Natali PG, Bagnato A. Endothelin-1 stimulates lymphatic endothelial cells and lymphatic  vessels to grow and invade. Cancer Res. 2009;69(6):2669-76
Rosanò L, Cianfrocca R, Masi S, Spinella F, Di Castro V, Biroccio A, Salvati E, Nicotra MR, Natali PG, Bagnato A. Beta-arrestin links endothelin A receptor to beta-catenin signaling to induce ovarian cancer cell invasion and metastasis. Proc Natl Acad Sci U S A. 2009;106(8):2806-11
Gabellini C, Trisciuoglio D, Desideri M, Candiloro A, Ragazzoni Y, Orlandi A, Zupi G and Del Bufalo D. Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression. Eur J Cancer. 2009;45(14):2618-27
Stoppoloni D, Cardillo I, Verdina A, Vincenzi B, Menegozzo S, Santini M, Sacchi A, Baldi A, Galati R. Expression of the embryonic lethal abnormal vision-like protein HuR in human mesothelioma: association with cyclooxygenase-2 and prognosis. Cancer. 2008;113(10):2761-9
Rosanò L, Di Castro V, Spinella F, Tortora G, Nicotra MR, Natali PG, Bagnato  A. Combined targeting of endothelin A receptor and epidermal growth factor  receptor in ovarian cancer shows enhanced antitumor activity. Cancer Res. 2007;67(13):6351-9
Spinella F, Rosanò L, Di Castro V, Decandia S, Nicotra MR, Natali PG, Bagnato A. Endothelin-1 and endothelin-3 promote invasive behavior via hypoxia-inducible  factor-1alpha in human melanoma cells. Cancer Res. 2007;67(4):1725-34