About > INNB Experimental Neuro-Oncology and Gene Therapy


Istituto Nazionale Neurologico Besta  http://www.istituto-besta.it

Unit of Experimental Neuro-Oncology and Gene Therapy
via Celoria 11, 20133 Milano, Italy
phone +39-02-2394-453 or -454
fax +39-02-26681688

The laboratory of Experimental Neuro-Oncology developed its activity in the Istituto Nazionale Neurologico Besta (INNB) starting in 1992 and working on two areas: the molecular genetics of brain tumors and the experimental treatment of malignant gliomas.

 



Previous and Current Research

The laboratory contributed data on the most relevant tumor suppressor genes involved in gliomagenesis (p53, p16, PTEN) and on patterns of chromosomal losses in gliomas. 
It is providing genetic exams of relevance for the definition of prognosis/diagnosis and for decisions on the treatment of gliomas. 

More recently a genetic characterization of pediatric and adult medulloblastomas has been started with the identification of gene expression patterns that may identify different subsets of tumors. The laboratory is developing DNA microarray and loss of heterozygosity (LOH) studies on meningiomas with the goal of identifying genetic markers helping to select tumors that are more prone to relapse.

The PI and the laboratory have been active in the field of gene therapy. The PI was the main investigator in Italy of the phase III clinical trial for GBM based on retroviral transfer of HSV-tk: the laboratory includes a BL2 facility that was approved for the preparation of retroviral producer cells for clinical use. The group developed preclinical experiments of immuno-gene therapy based on viral transfer of IL-4 and IL-12 and on IL-4 expression by neural stem progenitor cells grafted in the tumor.

 



Future Projects

Skin-derived stem cells are and will be used to evaluate their fate after grafting into murine brain and their potential for the expression of therapeutic molecules in the context of a brain tumor.

Another project under development is based on the use of mesenchymal stem cells for the expression of therapeutic molecules in experimental gliomas.

On 2003 the laboratory started the study of cancer stem-like cells (CSC) in different brain tumors, with special emphasis on the genetic characterization of CSC and CSC-derived tumors. This project will be developed in the near future on a larger number of cases and using the techniques of immune separation by magnetic beads and DNA microarray.

The Unit has also started a project on manipulation of murine Dendritic Cells (DC) to be used for the vaccination of experimental gliomas. Different approaches for DC maturation, pulsing and administration will be tested in experimental models.

In the INNB all the critical structures for the treatment of neuro-oncological patients are located in the same building: neurosurgery, neuroradiology, neuropathology, clinical neuro-oncology, radiotherapy, and experimental neuro-oncology. 
At the clinical level the Lab plan to apply for a phase I project of DC vaccination in patients with relapsing glioblastomas. The functional department of Neuro-Oncology in the INNB is the frame for such study. This functional department is directed by Dr. Amerigo Boiardi. 

The INNB has renovated the animal facility. A new structure for GMP-GLP storage of biological material in liquid nitrogen has been prepared. A new Production Unit for Cell Therapy, organized by Dr. Eugenio Parati, has been completed and should be active during year 2005. 
In the department of Experimental Neurology and Diagnostics (director Dr. Stefano Di Donato) two FACS are available as well as all the facilities for the molecular genetic analysis (including qPCR, automated sequencing, DNA fragment analysis, DHPLC). 
The INNB is part of Genopolis, a public, non-profit Consortium, located at the University of Milano-Bicocca  (
www.genopolis.it) and is linked in an administrative consortium with the Ospedale Policlinico and the Istituto Nazionale Tumori, both in Milano.

 



Last Publications
Tiziana Piepoli, Cemile Jakupoglu, Wenli Gu, Elena Lualdi, Blanca Suarez-Merino, Pietro L. Poliani, Maria Grazia Cattaneo, Barbara Ortino, Dorota Goplen, Jian Wang, Rosa Mola, Francesca Inverardi, Carolina Frassoni, Rolf Bjerkvig, Ortrud Steinlein, Lucia M. Vicentini, Oliver Brüstle and Gaetano Finocchiaro
Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI1
Supplemental Items. Figures 1S-4S and Tables 1S and 2S
Neuro-oncol 2006; 8(2): 96-108; first published on March 2, 2006 as DOI: 10.1215/15228517-2005-006


Boiardi A, Eoli M, Salmaggi A, Lamperti E, Botturi A, Broggi G, Bissola L, Finocchiaro G, Silvani A.
Systemic Temozolomide Combined with Loco-regional Mitoxantrone in Treating Recurrent Glioblastoma.
J Neurooncol. 2005 Nov;75(2):215-20.
PMID: 16283445 [PubMed - in process]

Pellegatta S, Tunici P, Poliani PL, Dolcetta D, Cajola L, Colombelli C, Ciusani E, Di Donato S, Finocchiaro G.
The therapeutic potential of neural stem/progenitor cells in murine globoid cell leukodystrophy is conditioned by macrophage/microglia activation.
Neurobiol Dis. 2005 Sep 28; [Epub ahead of print]
PMID: 16199167 [PubMed - as supplied by publisher]

Montanini L, Regna-Gladin C, Eoli M, Albarosa R, Carrara F, Zeviani M, Bruzzone MG, Broggi G, Boiardi A, Finocchiaro G.
Instability of mitochondrial DNA and MRI and clinical correlations in malignant gliomas.
J Neurooncol. 2005 Aug;74(1):87-9.
PMID: 16078113 [PubMed - indexed for MEDLINE]


Pellegatta S, Finocchiaro G.
Cell therapies in neuro-oncology.
Neurol Sci. 2005 May;26 Suppl 1:S43-5.
PMID: 15883693 [PubMed - indexed for MEDLINE]

Gu W, Brodtkorb E, Piepoli T, Finocchiaro G, Steinlein OK.
LGI1: a gene involved in epileptogenesis and glioma progression?
Neurogenetics. 2005 May;6(2):59-66. Epub 2005 Apr 13. Review.
PMID: 15827762 [PubMed - indexed for MEDLINE]

Salsano E, Pollo B, Eoli M, Giordana MT, Finocchiaro G.
Expression of MATH1, a marker of cerebellar granule cell progenitors, identifies different medulloblastoma sub-types.
Neurosci Lett. 2004 Nov 11;370(2-3):180-5.
PMID: 15488319 [PubMed - in process]

Tunici P, Bissola L, Lualdi E, Pollo B, Cajola L, Broggi G, Sozzi G, Finocchiaro G.
Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma.
Mol Cancer. 2004 Oct 06;3(1):25.
PMID: 15469606 [PubMed - in process]

Montanini L, Bissola L, Finocchiaro G.
KLF6 is not the major target of chromosome 10p losses in glioblastomas.
Int J Cancer. 2004 Sep 10;111(4):640-1. No abstract available.
PMID: 15239145 [PubMed - indexed for MEDLINE]

Moroni I, Bugiani M, D'Incerti L, Maccagnano C, Rimoldi M, Bissola L, Pollo B, Finocchiaro G, Uziel G.
L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition?
Neurology. 2004 May 25;62(10):1882-4. Review.
PMID: 15159502 [PubMed - indexed for MEDLINE]

Magrassi L, Finocchiaro G, Milanesi G, Benvenuto F, Spadari S, Focher F.
Lack of enantioselectivity of herpes virus thymidine kinase allows safer imaging of gene delivery.
Gene Ther. 2003 Dec;10(25):2052-8.
PMID: 14595377 [PubMed - indexed for MEDLINE]

Beghini A, Magnani I, Roversi G, Piepoli T, Di Terlizzi S, Moroni RF, Pollo B, Fuhrman Conti AM, Cowell JK, Finocchiaro G, Larizza L.
The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines.
Oncogene. 2003 May 1;22(17):2581-91.
PMID: 12735302 [PubMed - indexed for MEDLINE]

Gariboldi MB, Ravizza R, Petterino C, Castagnaro M, Finocchiaro G, Monti E.
Study of in vitro and in vivo effects of the piperidine nitroxide Tempol--a potential new therapeutic agent for gliomas.
Eur J Cancer. 2003 Apr;39(6):829-37.
PMID: 12651210 [PubMed - indexed for MEDLINE]

Benedetti S, Pirola B, Poliani PL, Cajola L, Pollo B, Bagnati R, Magrassi L, Tunici P, Finocchiaro G.
Dexamethasone inhibits the anti-tumor effect of interleukin 4 on rat experimental gliomas.
Gene Ther. 2003 Jan;10(2):188-92.
PMID: 12571648 [PubMed - indexed for MEDLINE]

Bissola L, Eoli M, Pollo B, Merciai BM, Silvani A, Salsano E, Maccagnano C, Bruzzone MG, Fuhrman Conti AM, Solero CL, Giombini S, Broggi G, Boiardi A, Finocchiaro G.
Association of chromosome 10 losses and negative prognosis in oligoastrocytomas.
Ann Neurol. 2002 Dec;52(6):842-5.
PMID: 12447941 [PubMed - indexed for MEDLINE]

Martini F, Lazzarin L, Iaccheri L, Vignocchi B, Finocchiaro G, Magnani I, Serra M, Scotlandi K, Barbanti-Brodano G, Tognon M.
Different simian virus 40 genomic regions and sequences homologous with SV40 large T antigen in DNA of human brain and bone tumors and of leukocytes from blood donors.
Cancer. 2002 Feb 15;94(4):1037-48.
PMID: 11920474 [PubMed - indexed for MEDLINE]

Manni I, Tunici P, Cirenei N, Albarosa R, Colombo BM, Roz L, Sacchi A, Piaggio G, Finocchiaro G.
Mxi1 inhibits the proliferation of U87 glioma cells through down-regulation of cyclin B1 gene expression.
Br J Cancer. 2002 Feb 1;86(3):477-84.
PMID: 11875718 [PubMed - indexed for MEDLINE]

Tunici P, Gianni D, Finocchiaro G.
Gene therapy of glioblastomas: from suicide to homicide.
Prog Brain Res. 2001;132:711-9. Review. No abstract available.
PMID: 11545030 [PubMed - indexed for MEDLINE]

Martinez di Montemuros F, Tavazzi D, Salsano E, Piepoli T, Pollo B, Fiorelli G, Finocchiaro G.
High frequency of the H63D mutation of the hemochromatosis gene (HFE) in malignant gliomas.
Neurology. 2001 Oct 9;57(7):1342. No abstract available.
PMID: 11591868 [PubMed - indexed for MEDLINE]

Negri DR, Mezzanzanica D, Sacco S, Gadina M, Benigni F, Cajola L, Finocchiaro G, Ghezzi P, Canevari S.
Role of cytokines in cancer cachexia in a murine model of intracerebral injection of human tumours.
Cytokine. 2001 Jul 7;15(1):27-38.
PMID: 11509006 [PubMed - indexed for MEDLINE]

Lualdi E, Chiariello E, Finocchiaro G.
Identification of regulatory regions of the putative tumor suppressor gene DMBT1.
Biochem Biophys Res Commun. 2000 Apr 13;270(2):673-5.
PMID: 10753682 [PubMed - indexed for MEDLINE]

Selleri S, Torchiana E, Pareyson D, Lulli L, Bertagnolio B, Savoiardo M, Farina L, Carrara F, Filocamo M, Gatti R, Sghirlanzoni A, Uziel G, Finocchiaro G.
Deletion of exons 11-17 and novel mutations of the galactocerebrosidase gene in adult- and early-onset patients with Krabbe disease.
J Neurol. 2000 Nov;247(11):875-7. No abstract available.
PMID: 11151421 [PubMed - indexed for MEDLINE]

Farina L, Bizzi A, Finocchiaro G, Pareyson D, Sghirlanzoni A, Bertagnolio B, Savoiardo M, Naidu S, Singhal BS, Wenger DA.
MR imaging and proton MR spectroscopy in adult Krabbe disease.
AJNR Am J Neuroradiol. 2000 Sep;21(8):1478-82.
PMID: 11003282 [PubMed - indexed for MEDLINE]

Benedetti S, Pirola B, Pollo B, Magrassi L, Bruzzone MG, Rigamonti D, Galli R, Selleri S, Di Meco F, De Fraja C, Vescovi A, Cattaneo E, Finocchiaro G.
Gene therapy of experimental brain tumors using neural progenitor cells.
Nat Med. 2000 Apr;6(4):447-50.
PMID: 10742153 [PubMed - indexed for MEDLINE]

DiMeco F, Rhines LD, Hanes J, Tyler BM, Brat D, Torchiana E, Guarnieri M, Colombo MP, Pardoll DM, Finocchiaro G, Brem H, Olivi A.
Paracrine delivery of IL-12 against intracranial 9L gliosarcoma in rats.
J Neurosurg. 2000 Mar;92(3):419-27.
PMID: 10701528 [PubMed - indexed for MEDLINE]

Sacco M, Benedetti S, Cato EM, Caniatti M, Ceruti R, Scanziani E, Pirola B, Villa A, Finocchiaro G, Vezzoni P.
Retrovirus-mediated IL-4 gene therapy in spontaneous adenocarcinomas from MMTV-neu transgenic mice.
Gene Ther. 1999 Nov;6(11):1893-7.
PMID: 10602385 [PubMed - indexed for MEDLINE]

Chiariello E, Roz L, Albarosa R, Magnani I, Finocchiaro G.
Identification of PTEN-related sequences in glioma cells and in non-neoplastic cell lines.
Cancer Lett. 1999 Apr 26;138(1-2):1-4.
PMID: 10378766 [PubMed - indexed for MEDLINE]

Magnani I, Chiariello E, Conti AM, Finocchiaro G.
A recurrent 19q11-12 breakpoint suggested by cytogenetic and fluorescence in situ hybridization analysis of three glioblastoma cell lines.
Cancer Genet Cytogenet. 1999 Apr 15;110(2):82-6.
PMID: 10214354 [PubMed - indexed for MEDLINE]

Benedetti S, Bruzzone MG, Pollo B, DiMeco F, Magrassi L, Pirola B, Cirenei N, Colombo MP, Finocchiaro G.
Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin 4 gene.
Cancer Res. 1999 Feb 1;59(3):645-52.
PMID: 9973213 [PubMed - indexed for MEDLINE]




Director Gaetano Finocchiaro

Biographical Sketch
Date of Birth: Milan, October 30, 1952
Education and Training (Institution and Location, Degree, Year, Field of Study):
▪ Milan University, School of Medicine (MD, 1979, Neurology)
▪ Milan University, School of Medicine (1983, Board in Neurology)
Yale University (1984-1987, Post-doctoral fellow in Human Genetics)
▪ Milan University (1988, Board in Biochemistry and Clinical Chemistry)


Research and Professional Experience
2004-1998 Director of the Departmental Structure of Experimental Neuro-Oncology, Istituto Nazionale Neurologico Besta (INNB).
1998-1997 Director pro-tempore of the Unit of Biochemistry and Genetics, INNB.
1997-1987 Neurologist and scientist in the staff of the Unit of Biochemistry and Genetics.


GF obtained his background as a clinical neurologist at the INNB from 1980 to 1984. During the three years spent in the Department of Human Genetics at the Yale Medical School (1984-1987) he worked on the biochemistry and the molecular cloning of genes involved in the beta-oxidation of fatty acids. In 1987 he started the activity of molecular biology at INNB that was developed in collaboration with Drs. Massimo Zeviani, Massimo Pandolfo and Franco Taroni in the Unit directed by Dr. Stefano Di Donato. In 1992 he created the laboratory of Molecular Neuro-Oncology from which originated the Unit of Experimental neuro-oncology that he is directing since 1998.

GF is in the editorial Board of Neuro-Oncology, the official journal of the American Society for Neuro-Oncology, and of Neurological Sciences, the official journal of the Italian Society of Neurology. He acts as reviewer of journals specialized in oncology or molecular biology including Cancer Research, Gene Therapy, Oncogene, Human Gene Therapy and of national and international grant agencies. He wrote more than 90 papers published in peer reviewed journals.
GF is a member of the scientific board of the Italian Association for Neuro-Oncology and of the Italian Association supporting neurological research. He was a member of the consulting committee for gene therapy of the Italian Prime Minister. He was the PI of the only phase III gene therapy trial developed in Italy.


His research interests in the last decade have been focused on novel treatments for malignant gliomas and on their genetic analysis. GF developed in Italy translational and clinical studies based on the gene transfer into brain tumors and was the first to work on the therapeutic potential of neural stem cells for gliomas. Presently the Unit of Experimental Neuro-Oncology is the only Italian structure providing molecular genetic tests for tumors of the nervous system.

 



Staff Five project areas are present in the laboratory, with six people in charge.


Serena Pellegatta has a degree in Biology obtained at the University of Milan. 
She is coordinating the work on dendritic cells and mesenchymal stem cells. She is also the main investigator in a cell therapy project for a non-oncologic disease, globoid cell leukodystrophy.

Patrizia Tunici obtained her degree in Biology at the University of Milan. 
She is the senior fellow working in the area of stem cell biology. 
Her studies include neural and skin stem cells as well as cancer stem-like cells deriving from brain tumors.
Since May 2005 Patrizia Tunici is at
Los Angeles CA, Cedars-Sinai Medical Center, Maxine Dunitz Neurosurgical Institute (Dr. John Yu's Laboratory) thru a scholarhip by Arin (Fondo di Giò).

Donata Bianchessi (in the picture) and Lorella Valletta have both a degree in biology and are in charge for the clinical genetic screening of malignant gliomas. LOH studies in gliomas, methylation analysis and DHPLC screening of mutations of the neurofibromatosis gene are the main activities.

Ettore Salsano, MD, is working at the INNB as a fellow in clinical neurology and experimental neuro-oncology. He is involved in the study of the genetic profile of medulloblastomas mostly using real-time PCR.

Francesca Menghi obtained her degree in Biotechnology in the 2004 in Milan. 
She is working on the molecular genetics of meningiomas using DNA microarray and LOH analysis.

 
Melania Cusimano (degree in Biology) is working on mesenchymal stem cells. 
Luigi Poliani
, MD is supporting the morphological analysis of experimental models. 
Valentina Caldera
(junior scholarship holder), Daniela Corno (pre-doctoral student), Anna Di Stefano ( pre-doctoral student), Linda Lupo ( pre-doctoral student) and a student-technician, Rina Monasterio Munoz, are also collaborating with the research team.
Mrs. Maria Pia Cavalli is working in the Unit as administrative assistant.


 

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