Project Funding Details

Neuroblastoma is the second most common malignant childhood cancer. The majority of children with neuroblastoma present with metastatic disease and have a poor prognosis despite the use of very intensive chemotherapy-based approaches. Chemotherapy works by directly damaging the genetic information (DNA) of the tumor. However, this approach fails to cure most patients with high-risk neuroblastoma because the tumor cells are able to repair or survive the DNA damage inflicted by chemotherapy, or are able to pump chemotherapy drugs out of cells. Finding a cure for the majority of children with high-risk neuroblastoma will require development of novel approaches of killing tumor cells with new types of small molecule drugs that target other cellular processes unique to neuroblastoma cells. New small molecules anticancer drugs that target abnormal growth signaling, drug resistance or repair pathways in cancer cells have shown extraordinary promise in the treatment of otherwise fatal malignancies. The prototypic model for this type of therapy was the development of imatinib (Gleevec) for the treatment of chronic myeloid leukemia (CML). Imatinib works by targeting an abnormal growth-signaling gene (BCR/ABL fusion gene), in the leukemia cells. Imatinib was identified as a targeted treatment of CML by a screen of small molecule chemical compounds for their inability to inhibit the abnormal BCR/ABL gene and growth of CML cells. Unfortunately, neuroblastoma has not been yet screened to identify effective targeted small molecule anticancer drugs. The Genome Research Institute of the University of Cincinnati (UC-GRI) and Cincinnati Children’s Hospital Medical Center have developed a large chemically diverse “library” of 250,000 potential anticancer drugs. This library was designed by medicinal chemists to include small molecules that target and inhibit pathologic growth signaling pathways in cancer cells. It is an extraordinary and unique resource - only a very few academic institutions have similar capabilities, and they are not generally used to screen pediatric tumors. Hypothesis: We hypothesize that screening of the UC-GRI/CCHMC small molecule library will identify novel active small molecules that kill high risk neuroblastoma cell lines. A correlative of this hypothesis is that new small molecules that are found to be active against high-risk neuroblastoma cell lines will identify new and important pathways in carcinogenesis.