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Although improvements in the past 40 years have led to markedly improved survival rates of approximately 80% overall for pediatric cancers, patients with relapsed,rare and advanced stage tumors still have a very poor prognosis. Neuroblastoma is the most common extra cranial solid tumor in children, with 700 new diagnoses projected for 2011. It accounts for 7% to 10% of childhood cancers. Whereas the prognosis for infants with neuroblastoma is generally good, currently only 30% of children diagnosed after 12-15 months of age survive despite aggressive multimodal therapies. Even with high-dose chemotherapy (HDC) followed by hematopoietic stem cell transplantation (HSCT) and maintenance therapy with retinoic acid the 5-year event-free survival remains below 50%. Long-term survival of patients who are treated with conventional therapies following relapse is <5%. As such, neuroblastoma accounts for 15% of all pediatric cancer deaths in the United States. Consequently, the evaluation of new drugs is strongly needed in this disease. Recent evidence has established the genetic heterogeneity of the disease and revealed the existence of several major molecular subsets that collectively may provide prognostic value for future disease management.
While the poor prognosis for older neuroblastoma patients underscores the need for new treatment strategies, the elucidation of specific biologic subsets of neuroblastoma suggests a way to improve disease management. The current standard-of-care treatments for relapsed neuroblastoma include a variety of Phase II or Phase I studies that generally have only modest response rates (10%-35%). Even in responding patients, tumors often go on to further rapid relapses and novel strategies to treat this patient population are urgently needed.
There are currently few treatment options from which pediatric oncologists can select with any degree of confidence to improve the management of multiply recurrent neuroblastoma patients. The current strategy is to add salvage therapies based on the anecdotal experience of the treating physician, which often leads to drug-related toxicity but may or may not extend life. The identification of agents that target specific molecular pathways associated with the development and/or progression of neoplastic diseases holds promise. Improved approaches that identify in a more rational (data-driven) fashion combinations of existing agents that are likely to be effective should result in a survival benefit in the clinical setting, while avoiding the toxicity associated with agents that are unlikely to be beneficial.
Our proposal outlines an approach by which we can utilize our expanding knowledge of molecular networks and the mechanisms of action of medications in conjunction with standardized biomarker development to create individualized predictions of effective targeted combinations for children with neuroblastoma.
Goals: Identification of predictive genomic profiles for patients with neuroblastoma of 5 targeted agents from Novartis (BKM120, LBH589, LCL161, LDE225, LEE011). We hypothesize that the in vitro and in vivo response data of these agents in neuroblastoma patient cells and tumor-bearing mice will correlate closely with patient’s genomic profiling predictions based on RNA expression profiles and DNA mutation panels.
We expect that we will find a close correlation of the in vitro and in vivo data with the patient’s genomic profiling resulting in the creation of molecular signatures of sensitivity to each of the drugs tested. Since each of these are Novartis agents, it will then be possible to translate this into the first targeted Phase I study of testing multiple new agents in one study aimed at pairing the patient with the best medication for them in the best chemotherapeutic combination shown in studies. As shown previously in targeted clinical trials, this would allow for improvement in response rates and outcomes for our patients.