Tuthill, Matthew C

Wada, Randal K

eVols at University of Hawaii at Manoa

LIb Cancer Research Center HotlineTargeting Oncogene Expressionin a Childhood CancerMatthew C. Tuthill, PhDJunior ResearcherCancer Research Center of HawaiiRandal K. Wada, MDAssociate ResearcherCancer Research Center of HawaiiNeuroblastoma is a common solid tumor ofyoung childrenNeuroblastoma is a childhood cancer originating in pluripotentnerve cells from the neural crest that normally give rise to thepostganglionic sympathetic nervous system. It is the most commonextra-cranial tumor in infants, with 600 new cases diagnosed in theUnited States annually. In children neuroblastoma represents I 0of all tumors, hut is responsible for more than 15% of pediatriccancer deaths.One reason for this discrepancy is that in the majority of cases. thetumor has already metastasized by the time of diagnosis. Unlikeother forms of childhood cancer, advances in theraps. have onlyrecently begun to yield an increase in survivorship for neurohiastoma patients with the more aggressive forms of disease. Since mostneuroblastoma patients are infants and oung children, the need forless toxic vet more effective therapy is especially important. Someof the major challenges that are being addressed are how to balancethe effectiveness of treatment and side effects from radiation!chemotherapy with long-term patient health. Nev approaches capitalize on the emerging insights we have gained into the biolog\ oftins tumor.Neuroblastoma can regress, or mature to abenign formOne of the most remarkable and unique features of neuroblastomais the occurrence of complete spontaneous regression, or differentiation. In fact, despite its aggressive behavior in the majority ofpatients. neuroblastoma exhibits the highest rate of spontaneousregression of any human malignancy. Tumor regression is mostcomrnonl observed in infants. while tumors in older patients calldifferentiate into benign ganglionenroblastoma or ganglioneurorna.Neuroblastoma thus provides an interest ini model system for thede elopment of differentiation therap that could he less debilitating than conentional ehernotherap . et increase un ivorship.Retinoic acid turns off the N-myc oncogene, akey step in inducing differentiationExperinwntail\ . cultured neuroblastoma cells can be induced todifferentiate by a number of agents. including retinoie acid.phenylacetate, gamma interferon, and vitamin D An early. keyevent in the differentiation process. both in tumor cells exposed toretinoic acid and in normal fetal neuroblasts during neuronal des ciopment, is a decrease in N-myc oncogene expression. In turn, Nrnvc downregulation immediately precedes growth arrest, and isfollowed by morphologic and biochemical maturation (neuriteextension, neurotransmitter biosynthesis, nerve impulse conducnon). In patient tumors. actis ation of the N-myc oncogcne isassociated with aggressive disease, including tumor metastasis.resistance to chemotherapy, and rapid tumor progression. In thelaborator . if N—nivc dosvnregulation is prevented by the introduction of exogenous N-myc genes. retinoic acid-induced differentianon can he blocked. Conversely, decreasing N-rnsc expression byspecific anti—sense oligonucleotides induces tumor cell differentia—tion even in the absence of any drugs. Thus, regulation of N—myc byagents such as retinoic acid appears to he an important factor indetermining the biological behavior of this tumor.Retinoic acid improves patient survivalClinically, differentiation therapy with retinoic acid has been 5110w nto have its greatest benefit in tile setting of mmimal residual disease.following gross tumordebulking by chemotherapy. surgery, autologous stem cell transplant, and radiation therapy. Patients treatedwith retinoic acid have a significantly higher survival rate than thosereceiving the same therapy without retinoic acid. With multi—modalconventional therapy, stem cell transplant, and retinoic acid, thecuiTent 5-year disease-free survival rate has increased to approximately double that of historical controls,Retinoic acid resistance is associated withpersistent N-myc expression\\ hile new tindngs on the cluitcal usefulness of retinoie acidrepresent encouracing prouress. a cigniticant number of childrennonetheless suffer from tuntor relapse, and sursival in patients w ohdisease prcgrecston is dismal. Based on cell culture and anitrtalifiOdds, a potential cause 01’ failure may he the development ofreti note acid resistance. involv itIC loss of tile ability to dovitregulate‘s-tllve expresston.COfltifllft i UTHAWAS MED WAL JD.LH.!. A.. WA CATDEEH 20)3.224Understanding the molecular regulation ofN-myc transcriptionPart of our work at the Cancer Research Center of Hawaii has focused on gaining anunderstanding ofthe molecular switch that turns the N-mvc gene off in response to treatmentwith retinoic acid. A decrease in N-mvc expression appears to he necessar\ for differentianon to proceed. Our data cuagest that mutation in the control region, or promoter. of theN—rn c c’ene result in the recruitment of alternative transcription factors. \—mvc mRNAproduction is thusdri en by aditierent set of regulatory proteins than in the normal promoterwith wild type sequence. Unlike the usual proteins, those associating with mutant promotersmay he unaffected by retinoic acid, so that treated cells bearing these mutations can nolonger shut the N—ms c gene off and continue on ith the ditferentiation proerain. PersistentN-mc expression. even in the face of retinoic acid, would confer a gross th advantage onthese cells, and contribute to their chentotherap\ resistance. Clinically, such factors maunderlie the process ot tumor relapse and disease progression.Clinical applications of mechanism-basedresearchThrough determininc the mechanism of \—mve doss nregulation h retinoie acid we hope toderive a set of moleculardiagnostics that will allow us to examine tumor DNA lorsignificantpromoter mutations, and use this information to gauge patients’ prognoses with respect totheir potential responsiveness to retinoic acid. Rather than using retinoic acid as the defaultdrug to deal v ith minimal residual disease, patients at risk for treatment failure could betriaged to receive new nivestigatis e therapies. Identification of the alternate proteins thatmediate N—ms c transcription in retinoic acid—resistant cells may suggest agents that wouldbe effective even on N-myc genes with mutant promoters. Ultimately these drugs could beused in conjunction with retinoic acid, much like we currently combine different conventional chemotherapeutic agents. However, an important distinction would be that the goalofthiscomhinationdifferentiationtherap would he toeffectcurebv “rehahilitating”cancercells, rather than killing them.Therapy rooted in tumor cell biology, not tumor cell toxicity\llr’r’tilar. iiis’rIi,Iiti’fli liusetl il).icl1s’s silL h i’ hi .iie part ol a ness l\ enieinmgtreiitiiteltl piiidiuiit muted in a basic understiindni’ at Innini biulos . ml ‘hunld tncreaetieitnieni ellieaL\ ss hile rednemg otu\ieiI\ . Vi hile tIn’. isespeciall\ s aluable mtlietheiapat unnv Juldren. I ‘.‘.uns learned in nnrobla’.iunia ifli\ one Ll,l\ bend it adult piliL’i1t5 s ithR iiIfiicIilt’. and ‘.niaii ccii lung caiLnloiuas. sake these iunioi ‘ are iilsuclrl\ en h\ aneugenesal Iheii1\ Iaiutl\. iitJtidine \-iu laritiore ni rinati n.pkasest’.iithe( anerReseatLh(enter’s \s ebsile at 55 iv hare.ReferencesClassified NoticesTo place a classified notice:HMA members—Please send a signed and typewritten ad to the HMA office. As a benefit of membership. HMA members may place a complimentary onefme ciassifed ad in HMJ as space is available.Nonmembers,—Please call 536-7702 for a non-member form. Rates are $1.50 a word with a minimumof 20 words or $30. Not commissionable. Paymentmust accompany written order.Office EquipmentEVERYTHING FOR A BRANCH OFFICE— TO DO EXAMPROCEDURES INCL Dr. & pt. chairs, roller stools, fineadJust. table. BP rronitor. cstruments. auioc:ave. suopes.snk - The works. Ouaiity materials. Can ship. 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Targeting oncogene expression in a childhood cancer.

http://evols.library.manoa.hawaii.edu/bitstream/10524/53607/1/2003-10p224-225.pdf

Targeting oncogene expression in a childhood cancer.

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eVols at University of Hawaii at Manoa