Treatment of Neuroblastoma by Inhibition of Sphingosine Kinase

PROJECT ABSTRACTNeuroblastomaNBis the most common extracranial solid tumor in childrenwith only approximatelyof children with high risk disease surviving foryears in spite of intense chemotherapyClearlynew and more effective therapies are desperately needed for NB patientsHigh risk NB is often associated with MYCN gene amplificationof casesand so N Myc has been considered as a prime target for new NB drugsSphingolipid metabolism is being increasingly recognized as a key pathway in cancer biologyExtensive research demonstrates the roles of ceramidesdihydroceramidessphingosine and sphingosinephosphateS Pin regulating tumor cell proliferationdeath and drug resistanceas well as host angiogenesisinflammation and immune responseIn particularsphingosine kinasesSKand SKare validated sites for manipulation of the ceramide S P rheostat that regulates the balance between tumor cell proliferation and deathas well as tumor sensitivity to radiation and chemotherapyDihydroceramide desaturaseDEScontrols the balance between saturated and unsaturated ceramidessphinganine and sphingosine coresrespectivelyand this regulates proliferative and autophagic signalingWe have identified orally available SK inhibitors with activity in vitro and in vivoand our clinical phase II dual SKDESinhibitorABCalso known as opaganib and YELIVAhas antitumor and anti inflammatory activities in several in vivo preclinical modelsABChas excellent safety and pharmacologic profiles in nonclinicalincludingmonth GLP high dose toxicology studies in rats and dogsand ongoing clinical studiesMechanisticallyABCattenuates Akt signaling and the expression of c Myc and Mclin multiple cancer cell linesOur new studies demonstrate that ABCalso down regulates N Myc mRNA and protein expression in NB cells and has therapeutic activity in NB xenograftsThereforewe hypothesize that SKs and DESare key regulators of NB tumor growthand that ABCin particular has excellent potential for use in NB patientsTo determine the potential for targeting SKs and DESto treat NBwe will conduct the following Specific Aims in this phaseSBIR projectTo define the functional and biochemical effects of SK and DESinhibitors on NB cells in vitroandTo evaluate the antitumor activity of ABCin orthotopic xenografts of murine NB cells in immunocompetent miceThese studies are designed to provide proof of concept for treating NB patients with an SK DESinhibitorand more specificallywill provide the efficacy data needed to support a clinical trial of ABCin NB patientsBecause ABCis already in phase II clinical testing in adult cancer patientsdemonstration of efficacy against NB xenografts in the proposed studies could be rapidly translated into clinical trials in children having this disease PROJECT NARRATIVENeuroblastoma is the most common cancer in infants and the most common solid tumor outside the brain in childrenand responds poorly to current therapiesWe have identified a new drug that blocks a key pathway required for cancer growthand our data indicate that it has excellent potential for use against neuroblastomaThe proposed studies will determine the potential therapeutic activity of this drug in cell culture and in animal models of neuroblastomaand may lead to new clinical trials in children with this disease