Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

The Department of Cancer BiologyIdentification of N-myc Regulated GenesOpens Paths for Targeted Therapyof NeuroblastomasTHE RAWWASLABORATORYLEAD TECHNOLOGISTKarrie Trevarthen, B.S.Neuroblastoma is the most commonextracranial solid tumor of childhood,accounting for 8-10% of all tumors inchildren. It is a heterogeneous disease thatdisplays a spectrum of clinical behaviorsdepending on the biology of the tumor and theage of presentation. Older children usuallypresent with advanced stage progressive diseasethat has poor outcome. According to the NationalCancer Institute statistics, the five-year survivalof US children with neuroblastoma above 5 yearsof age was still around 40% during the period1985-1994. Surgery, intensive chemotherapy,radiation therapy and stem cell transplant appearto be insufficient or too toxic to achieve thedesired goal of significant improvement inoutcome. Therefore, understanding the mechanismsof neuroblastoma proliferation anddifferentiation and the genes involved is a keyelement in understanding disease developmentand the factors that determine the clinical courseand patient outcome.Patients with aggressive advanced stageneuroblastoma usually have a high rate of N-myconcogene amplification. N-myc is a nuclearphosphoprotein transcription factor that bindsDNA and affects gene regulation. Its in vitrooverexpression results in malignant transformationand increased proliferation and suppressionof differentiation. Overexpression of N-myccauses neuroblastoma in transgenic mice. We havepreviously identified nucleotide diphosphatekinase-A as a gene associated with advanced stageneuroblastoma tumors. We have also correlatedN-myc amplification with high levels of CellularRetinoic Acid Binding Protein-II in neuroblastomatumors using 2-dimensional PAGE. Morerecently, we have utilized cDNA microarraytechnology to examine global patterns of geneexpression between different types of tissues andcell lines (ex. N-myc amplified tumor or cell linevs. normal N-myc copy number tumor or cell line).My lab is interested in identifying the genesthat are directly or indirectly activated by N-mycand to understand their potential role in thedevelopment and progression of neuroblastoma.Dissection of the biologic pathways involved willhelp identify novel targets for therapeuticintervention in neuroblastoma patients.Jawhar Rawwas, M.D.Chang, C.L., Zhu, X.X., Thoraval, D.H., Ungar, D., Rawwas, J., Hora, N., Strahler, J.R., Hanash, S.M.,and E. Radany (1994) Nm23-H1 mutation in neuroblastoma. Nature 370:335-336.Shulkin, B.L., Wieland, D.M., Baro, M.E., Ungar, D.R., Mitchell, D.S., Dole, M.G., Rawwas, J.B., Castle,V.P., Sisson, J.C., and R.J. Hutchinson (1996) PET hydroxyephedrine imaging of neuroblastoma. J. Nucl.Med. 37:16-21.Chen, C.L., Rawwas, J., Sorrell, A., Eddy, L., and F.M. Uckun (2001) Bioavailability and pharmacokineticfeatures of etoposide in childhood acute lymphoblastic leukemia patients. Leuk. Lymphoma 42:317-327.58