Group Leader…………………………………………………… Dr. Gabriella Zupi Director of Experimental Chemotherapy Laboratory Regina Elena Cancer Institute via delle Messi d'Oro 156 00158 Rome - Italy Phone: +39 06 5266 2537 Fax: +39 06 5266 2592 E-mail: zupi@ifo.it Group Members..……………………………………………… Dr. Annamaria Biroccio Researcher, permanent position Phone: +39 06 5266 2569 E-mail: biroccio@ifo.it Dr. Carlo Leonetti Researcher, permanent position Phone: +39 06 5266 2534 E-mail: leonetti@ifo.itDr. Angela Rizzo fellow Phone: +39 06 5266 2545 E-mail: angela.rizzo@ifo.itDr. Erica Salvati fellowship Phone: +39 06 5266 2545 Dr. Manuela Porru fellow Phone: +39 06 5266 2545 Key words (max 5).…………………………………………… Telomeres, senescence, apoptosis Research projects.……………………………………………

• Meccanismo d'azione ed efficacia di molecole biologiche e farmaci citotossici di ultima generazione e loro interazione

• Studio del ruolo fisiopatologico dei recettori chemiotattici CXCR1-2 e CXCR4 e dei loro agonisti naturali nello sviluppo e nella progressione di patologie neoplastiche: meccanismi e potenziale farmacologico

• Study of telomere maintenance on melanoma apoptosis and senescence to identify new therapeutic strategies

• Identification and characterization of novel human telomere-related biomarkers that aid cancer management by improving patient diagnosis, treatment selection, response monitoring, and drug development

• Novel approaches to improve ErbB targeting therapies Collaborations…...…………………………………………… Prof. Paola Caiafa, University La Sapienza, Rome Publications (last 5 years)…..………………………………

1. Trisciuoglio D, Iervolino A, Candiloro A, Fibbi G, Fanciulli M, Zangemeister-Wittke U, Zupi G, Del Bufalo D. bcl-2 induction of urokinase plasminogen activator receptor expression in human cancer cells through Sp1 activation: involvement of ERK1/ERK2 activity. J Biol Chem 279:6737-45, 2004.

2. Giavazzi R, Aglietta M, Astolfi A, Falanga A, Fusco A, Labianca R, Lollini PL, Lombardo C, Natali PG, Pierotti MA, Presta M, Santoro M, Taraboletti G, Zupi G, Vecchio G. 45th annual meeting of the Italian Cancer Society. Bergamo, 9-12 November 2003. Tumori 90: 356-62, 2004.

3. Biroccio A, Benassi B, Fiorentino F, Zupi G. Glutathione depletion induced by c-Myc downregulation triggers apoptosis on treatment with alkylating agents. Neoplasia 6:195-206, 2004.

4. D'Alessio S, Margheri F, Pucci M, Del Rosso A, Monia BP, Bologna M, Leonetti C, Scarsella M, Zupi G, Fibbi G, Del Rosso M. Antisense oligodeoxynucleotides for urokinase-plasminogen activator receptor have anti-invasive and anti-proliferative effects in vitro and inhibit spontaneous metastases of human melanoma in mice. Int J Cancer 110:125-33, 2004.

5. Leonetti C, Scarsella M, Semple SC, Molinari A, D'Angelo C, Stoppacciaro A, Biroccio A, Zupi G. In vivo administration of liposomal vincristine sensitizes drug-resistant human solid tumors. Int J Cancer 110: 767-74, 2004.

6. Messina S, Leonetti C, De Gregorio G, Affatigato V, Ragona G, Frati L, Zupi G, Santoni A, Porcellini A. Ras inhibition amplifies cisplatin sensitivity of human glioblastoma. Biochem Biophys Res Commun 320:493-500, 2004.

7. Del Bufalo D, Trisciuoglio D, Scarsella M, D’Amati G, Candiloro, A Iervolino A, Leonetti C, Zupi G. Lonidamine causes inhibition of angiogenesis-related endothelial cell functions. Neoplasia 6:513-22, 2004.

8. Leonetti C, Amodei S, D'Angelo C, Rizzo A, Benassi B, Antonelli A, Elli R, Stevens MF, D'Incalci M, Zupi G, Biroccio A. Biological activity of the G-quadruplex ligand RHPS4 is associated with telomere capping alteration. Mol Pharmacol 66:1138-46, 2004.

9. Milella M, Trisciuoglio D, Bruno T, Ciuffreda L, Mottolese M, Cianciulli A, Cognetti F, Zangemeister-Wittke U, Del Bufalo D, Zupi G. Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene--amplified breast cancer cells. Clin Cancer Res 10:7747-56, 2004.

10. Tonini T, Gabellini C, Bagella L, D'Andrilli G, Masciullo V, Romano G, Scambia G, Zupi G, Giordano A. pRb2/p130 decreases sensitivity to apoptosis induced by camptothecin and doxorubicin but not by taxol. Clin Cancer Res 10: 8085-93, 2004.

11. Tesei A, Ulivi P, Fabbri F, Rosetti M, Leonetti C, Scarsella M, Zupi G, Amadori D, Bolla M, Zoli W. In vitro and in vivo evaluation of NCX 4040 cytotoxic activity in human colon cancer cell lines. J Transl Med 3:7, 2005.

12. Zupi G, Scarsella M, Semple SC, Mottolese M, Natali PG, Leonetti C. Antitumor efficacy of bcl-2 and c-myc antisense oligonucleotides in combination with cisplatin in human melanoma xenografts: relevance of the administration sequence. Clin Cancer Res 11:1990-8, 2005.

13. D’Incalci M, Zupi G. Are we close to the clinical development of novel drugs targeting telomeres and telomerase? Eur J Cancer 41:970, 2005.

14. De Cesare M, Perego P, Righetti SC, Pratesi G, Carenini N, Rivoltini L, Zupi G, Del Bufalo D, Balsari A, Zunino F. Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts. Eur J Cancer 41:1213-22, 2005.

15. Biroccio A, D’Angelo C, Jansen B, Gleave ME, Zupi G. Antisense clusterin oligodeoxynucleotides increase the response of HER-2 gene amplified breast cancer cell to trastuzumab. J Cell Physiol 204:463-9, 2005.

16. Zupi G, Scarsella M, D'Angelo C, Biroccio A, Paoletti G, Lopez M, Leonetti C. Potentiation of the antitumoral activity of gemcitabine and paclitaxel in combination on human breast cancer cells. Cancer Biol Ther 4:866-71, 2005.

17. Trisciuoglio D, Iervolino A, Zupi G, Del Bufalo D. Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells. Mol Biol Cell 16:4153-62, 2005.

18. Del Bufalo D, Rizzo A, Trisciuoglio D, Cardinali G, Torrisi MR, Zangemeister-Wittke U, Zupi G, Biroccio A. Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function. Cell Death Differ 12:1429-38, 2005.

19. Trisciuoglio D, Desideri M, Ciuffreda L, Mottolese M, Ribatti D, Vacca A, Del Rosso M, Marcocci L, Zupi G, Del Bufalo D. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth. J Cell Physiol 205:414-21, 2005.

20. Benassi B, Fanciulli M, Fiorentino F, Porrello A, Chiorino G, Loda M, Zupi G, Biroccio A. c-Myc phosphorylation is required for cellular response to oxidative stress. Mol Cell 21:509-19, 2006.

21. Leonetti C, Scarsella M, Zupi G, Zoli W, Amadori D, Medri L, Fabbri F, Rosetti M, Ulivi P, Cecconetto L, Bolla M, Tesei A. Efficacy of a nitric oxide-releasing nonsteroidal anti-inflammatory drug and cytotoxic drugs in human colon cancer cell lines in vitro and xenografts. Mol Cancer Ther 5:919-26, 2006.

22. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66:5549-54, 2006.

23. Biroccio A, Rizzo A, Elli R, Koering CE, Belleville A, Benassi B, Leonetti C, Stevens MF, D'Incalci M, Zupi G, Gilson E. TRF2 inhibition triggers apoptosis and reduces tumorigenicity of human melanoma cells. Eur J Cancer 42:1881-8, 2006.

24. Gabellini C, Del Bufalo D, Zupi G. Involvement of RB gene family in tumor angiogenesis. Oncogene 25:5326-32, 2006.

25. Hugo H, Cures A, Suraweera N, Drabsch Y, Purcell D, Mantamadiotis T, Phillips W, Dobrovic A, Zupi G, Gonda TJ, Iacopetta B, Ramsay RG. Mutations in the MYB intron I regulatory sequence increase transcription in colon cancers. Genes Chromosomes Cancer 45:1143-54, 2006.

26. Leonetti C, Zupi G. Targeting different signaling pathways with antisense oligonucleotides combination for cancer therapy. Curr Pharm Des 13:463-70, 2007.

27. Caraglia M, Marra M, Leonetti C, Meo G, D'Alessandro AM, Baldi A, Santini D, Tonini G, Bertieri R, Zupi G, Budillon A, Abbruzzese A. R115777 (Zarnestra)/Zoledronic acid (Zometa) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation. J Cell Physiol 211:533-43, 2007.

28. Giorgini S, Trisciuoglio D, Gabellini C, Desideri M, Castellini L, Colarossi C, Zangemeister-Wittke U, Zupi G, Del Bufalo D. Modulation of bcl-xL in tumor cells regulates angiogenesis through CXCL8 expression. Mol Cancer Res 5:761-71, 2007.

29. Leonetti C, Biroccio A, D'Angelo C, Semple SC, Scarsella M, Zupi G. Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer. Prostate 67:1475-85, 2007.

30. Benassi B, Zupi G, Biroccio A. Gamma-glutamylcysteine synthetase mediates the c-Myc-dependent response to antineoplastic agents in melanoma cells. Mol Pharmacol 72:1015-23, 2007.

31. Salvati E, Leonetti C, Rizzo A, Scarsella M, Mottolese M, Galati R, Sperduti I, Stevens MF, D'Incalci M, Blasco M, Chiorino G, Bauwens S, Horard B, Gilson E, Stoppacciaro A, Zupi G, Biroccio A. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J Clin Invest 117:3236-47, 2007.

32. Guastafierro T, Cecchinelli B, Zampieri M, Reale A, Riggio G, Sthandier O, Zupi G, Calabrese L, Caiafa P. CCCTC-binding factor activates PARP-1 affecting DNA methylation machinery. J Biol Chem 283:21873-80, 2008.

33. Gabellini C, Castellini L, Trisciuoglio D, Kracht M, Zupi G, Del Bufalo D. Involvement of Nuclear Factor-kappa B in bcl-xL-induced interleukin 8 expression in glioblastoma. J Neurochem 107:871-82,2008.

34. Leonetti C, Scarsella M, Riggio G, Rizzo A, Salvati E, D'Incalci M, Staszewsky L, Frapolli R, Stevens MF, Stoppacciaro A, Mottolese M, Antoniani B, Gilson E, Zupi G, Biroccio A. G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors. Clin Cancer Res 14:7284-91, 2008.