Vai al contenuto| Home page|

   Ti trovi in: HOME »Programmi, progetti e risultati »I progetti »PRIN - Programmi di ricerca di Rilevante Interesse Nazionale»Programma di ricerca
INIZIO_TESTO_DA_INDICIZZARE

RESEARCH PROGRAM

italiano - inglese
Research Units
Similar research programs:
Scientific and education field classification
International Patent Classification
  • CHEMISTRY; METALLURGY
    • BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
      • MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF (biocides, pest repellants or attractants, or plant growth regulators, containing micro-organisms, viruses, microbial fungi, enzymes, fermentates or substances produced by or extracted from micro-organisms or animal material A01N63/00; food compositions A21, A23; medicinal preparations A61K; chemical aspects of, or use of materials for, bandages, dressings, absorbent pads or surgical articles A61L; fertilisers C05); PROPAGATING, PRESERVING OR MAINTAINING MICRO-ORGANISMS (preservation of living parts of humans or animals A01N1/02); MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (micro-biological testing media C12Q)
Geographical classification
Bibliografia
1.Gilbertson RJ: Medulloblastoma: signalling a change in treatment. The Lancet Oncoloy 2005; 5: 209-218
2.Gajjar A et al. Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol. 2004 22(6):984-93
3.Ruiz i Altaba A et. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002 2:361-72.
4.Giangaspero F et al.. Pathology & Genetics. Tumours of the nervous system. , IARC Press, Lyon. 2000
5.Ellison D. Classifying the medulloblastoma: insights from morphology and molecular genetics. Neuropathol Appl Neurobiol. 2002 28(4):25715.
6.Marino S. Medulloblastoma: developmental mechanisms out of control. Trends Mol Med, 11, 17-22, 2005
7.Zurawel, R. H.,. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma. Genes Chromosomes.Cancer 2000; 27, 44-51
8.Taylor MD al. Mutations in SUFU predispose to medulloblastoma Nat Genet 2002, 31 :306-10
9.Eberhart CG. Medulloblastoma in mice lacking p53 and PARP. All roads lead to Gli. Am J Pathol, 2003;162, 7-9
10.Eberhart CG et al. Nuclear localization and mutation of β-Catenin in medulloblastomas. J Neuropathol Exp Neurol, 59, 333-337, 2000
11.Ellison DW et al.beta-catenin status predicts a favorable outcome in childhood medulloblastoma: the united kingdom children’s cancer study group brain tumor committee. J Clin Oncol, 23, 7951-7957, 2005
12.Dahmen RP et al.Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 61, 7039-7043, 2001
13.van Noort M et al.WNT signaling controls the phosphorylation status of beta-catenin. J Biol Chem 277, 17901-17905, 2002
14.van Es JH et al. You WNT some, you lose some: oncogenes in the WNT signaling pathway. Curr Opin Genet Dev 13, 28-33, 2003
15.Sekiya T et al. Overexpression of Icat induces G2 arrest and cell death in tumor cell mutants for Adenomatous Polyposis Coli, β-catenin, or Axin. Cancer Res, 62, 3322-3326, 2002
16.Valizadeh A et al. Expression of E cadherin-associated molecules in colorectal polyps. Am J Pathol, 150, 1977-1984, 1997
17.Paliwal S et al. Targeting of C-terminal binding protein (CtBP) by ARF Results in p53-independent apoptosis. Mol Cell Biol, 26, 2360-2372, 2006
18.Ilyas M. Wnt signalling and the mechanistic basis of tumour development. J Pathol, 205, 130-144, 2005
19.Stea B et al. Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’). Cancer Lett, 202, 43-51, 2003
20.Ochs JS. Rationale and clinical basis for combining gefitinib (Iressa, ZD1839) with radiation therapy for solid tumors. Int J Radiat Oncol Biol Phys, 58, 941-949, 2004
21.Janmaat ML et al. Small-molecule epidermal growth factor receptor tyrosine kinase inhibitors. The Oncologist 8, 576-586, 2003
22.Chojnacka M et al. Medulloblastoma in childhood: impact of radiation technique upon the outcome of treatment. Pediatr Blood Cancer, 42, 155-60, 2004
23.Oren M. Decision making by p53: life, death and cancer. Cell Death and Differ, 10, 431-442, 2003
24.Lutolf et al. Notch1 is required for neuronal and glial differentiation in the cerebellum. Development 2002; 129:373
25.Fan X, et al. Notch1 and Notch2 have opposite effects on embryonal brain tumor growth. Cancer Res 2004; 64:7787-7793
26.Hallahan AR, et al. The SmoA1 mouse model reveals that Notch signaling is critical for the growth and survival of Sonic Hedgehog-induced medulloblastoma. Cancer Res 2004; 64:7794-7800
27.Wetmore C. Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. Curr Opin Genet Develop 2003; 13:34
28.Gutzman DH et al. Mouse model of human cancer consortium symposium on nervous system tumors. 2003 Cancer Res 63: 3001 -3004
29.Tong WM et al. Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(-/-) mice. Am J Pathol. 2003;162(1):343-52.
30.Pazzaglia S et al. High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice. Oncogene. 2002;21(49):7580-4.
31.Lee, Y.et al. A molecular fingerprint for medulloblastoma. Cancer Res 2003: 63:5428-37
32.Berman DM et al. . Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297:1559-61 (2002)
33.Romer JT et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell 2004; 6:229-40
34.Bjerkvig R, et al. Tumor cell invasion and angiogenesis in the central nervous system. Curr Opin Oncol 1997; 9: 223-229
35.Assimakopoulou M, et al. Microvessel density in brain tumors. Anticancer Res 1997; 17 4747-4753.
36.Ozer E, et al. Prongnostic significance of anaplasia and angiogenesis in childhood medulloblastoma: a pediatric oncology group study. Pathol Resercg Pract 2004; 200: 501-509
37.Huber H, et al. Angiogenic profile of childhood primitive neuroectodermal brain tumours /medulloblastoma. Eur J Cancer 2001; 37: 2064-2072.
38.Masood R, et al. Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor-positive human tumors. Blood 2001; 98:1904-1913
39.Koch A, et al. Somatic mutations of WNT/WINGLESS signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 2001; 93: 445-449
40.Easwaran V, et al. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 2003; 63: 3145-3153
41.Dahmen RP, et al. Delations of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 2001; 61: 7039-7043
42.Easwaran V, et al. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res 2003; 63: 3145-3153
43.Reya T et al.cancer stem cells. Nature 414: 105-111 (2001)
44.Hemmati HD et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 103:15178-15183 (2003)
45.Singh SK. Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821-5828 (2003)
46.Singh SK et al. Identification of human brain tumour initiating cells. Nature 432:396-401 (2004)
47.Giguere V. Retinoic acid receptors and cellular retinoid binding proteins: complex interplay in retinoid signaling. Endocr Rev 15:61-79 (1994)
48.Simeone A et al. Retinoic acid induces stage-specific antero-posterior transformation of rostral central nervous system. Mech Dev 51:83-98 (1995)
49.Hallahan AR al. BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med 9:1033-1038 (2003)
50.Gumireddy K et al. All-trans-retinoic acid-induced apoptosis in human medulloblastoma. Clin Cancer Res 9:4052-4059 (2003)
51.Boon K et al. Genomic amplification of orthodenticle homologue 2 in medulloblastomas. Cancer Res 65:703-7 (2005)
52.Di C et al. Identification of OTX2 as a medulloblastoma oncogene. Cancer Res 65:919-924 (2005)
53.Sun SY and Lotan R. Retinoids and their receptors in cancer development and chemoprevention.Crit Rev Oncol Hematol. 41:41-55 (2002)
54.Tallman MS et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 100:4298-302 (2002)
55.Garattini E et al. Retinoid related molecules an emerging class of apoptotic agents with promising therapeutic potential in oncology: pharmacological activity and mechanisms of action. Curr Pharm Des. 10:433-48 (2004)
56.Cincinelli R.et al. Novel atypical retinoid endowed with proapoptotic and antitumor activity. J. Med. Chem. 46:909-12 (2003)
57.Zuco V. et al. Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid. Cell Death Differ. Mar.11:280-9 (2004)
Keywords
MEDULLOBLASTOMA, MOLECULAR PATHWAYS, SONIC HEDGEHOG, WNT, B-CATENIN, NEOPLASTIC STEM CELLS, ANIMAL MODELS, THERAPY

Medilloblastoma: molecular pathways of neoplastic development and progression to identify novel therapeutic approaches

Università degli Studi di Roma "La Sapienza"
Abstract
Several genetic and epigenetic changes are described in MB, which affect signaling pathways involved in specific developmental steps and may be responsible for tumorigenesis. A major deregulated pathway in MB is the Sonic hedgehog (SHH) pathway. The SHH pathway promotes the proliferation of cerebellar granule progenitors. The WNT pathway is also involved and mutations of WNT proteins have been reported in MB. ). In the intercalation of WNT and EGFR networks activates several pathways that are thought to contribute to radiation resistance and enhanced proliferation. Less is known about the role of Notch. Insights for MB tumorigenesis arise also from animal models. The gene expression profiles of murine tumors from mutations in different pathways shared a common gene expression patterns presumed to be tumor specific. Complex interconnections between the different pathways are emerging and suggest that dysregulation of different pathways may cooperate in the pathogenesis of MB. A important result of these studies is that such pathways may represent potential therapeutic targets for novel treatments for MB. There is evidence that the molecular mechanisms promoting tumour growth and those regulating tumor angiogenesis are correlated. A variety of angiogenic factors have been implicated, individually and together, in the neo-angiogenesis of MB. The VEGF has an autocrine activity on the neoplastic cells and is not only a relevant factor for tumour cell proliferation, but it is also >>>

Principal Investigator
Felice Giangaspero Università degli Studi di ROMA "La Sapienza"
Research Objectives
The present research program is composed of four Research Units (RU) whose single projects will focus on different biologic aspects involved in the tumorigenesis of medulloblastoma (MB) in the effort to open new therapeutic roads to improve further the outcome for children affected by this tumor. Un important goal of the whole program is to create a network which will help the investigators to collect a relative high number of new cases of MB and to shear research tools as cell lines, murine models and, when obtained, cancer stem cells.
The principal objectives are the following:
•To evaluate the molecular pathways of SHH and NOTCH involved in MB tumorigenesis. Complex interconnections between the different pathways involved in MB tumorigenesis are emerging and all togheter suggest that dysregulation of different pathways may cooperate in the pathogenesis of MB.
•To evaluate the role of WNT pathway in ionizing radiation response and the molecular cross-talk between beta-catenin, p53 and signal transduction pathways turned on by EGFR in human MB cell lines.
•To understand the possible relationship between b-catenin (generally the WNT pathway) and the outocrine effect of VEGF in MB cell line. Assuming that the success of an oncologic therapeutic approach will depend upon a multiple and concurrent attacks to all those mechanisms promoting and sustaining tumour cell growth, it can hypothesized that those agents regulating the neoplastic >>>

Timescale
24 months
National and international background
Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Current treatment includes maximal surgical resection, whole neuroaxis irradiation, and chemotherapy. Cure rate is approximately 40% in children with metastatic/unresectable MB, and 65% in patients with average risk disease. In addition, treatment-related morbidity can be devastating in children, who may suffer severe long-term physical and cognitive deficits (1). Although the survival has improved considerably within the past two decades, however, patients with similar neoplasms and receiving identical therapies, can have widely disparate clinical outcome (1). It would be advantageous to tailor specific therapies to individual lesions so that patients are not over or under treated. Clinical, histological, and molecular factors have been proposed for such MB stratification (2) . Moreover the basic mechanisms of tumor progression which can explain the variable biologic behavior of such neoplasm is only beginning to emerge.
Most MB are thought to originates from transformed granule cell precursor (GCP) of the cerebellum (although some may arise from neuronal precursors cells in the subventricular zone). Several genetic and epigenetic changes are described in MB, which affect signaling pathways involved in specific developmental steps and may be responsible for tumorigenesis (3,4,5,6). A major deregulated pathway in MB is represented by the Sonic hedgehog (SHH) signaling pathway. Germline >>>