Most patients with high-risk neuroblastoma have metastatic (stage 4) disease. Outcome for this group was homogenous when treated with chemotherapy, which resulted in long-term survival of 10-15 percent. However, homogeneity is becoming heterogeneity with improvements in therapy. The Children's Cancer Group study CCG-3891 showed that myeloablative chemoradiotherapy/autologous bone marrow transplant followed by 13-cis retinoic increased event-free survival to nearly 40 percent three years after diagnosis. Currently, those with different outcomes cannot be identified unless disease persists or progresses, which portends a poor outcome. Accurate risk assessment for this group will have a major impact upon developing and testing potentially more effective therapy. Hypothesis. Gene expression profiles derived from high density oligonucleotide arrays will identify significant differences among stage 4 tumors that can be used to predict outcome. Furthermore, profiles of untreated tumors will reflect intrinsic biologic differences whereas profiles of treated tumors will reflect these and differences due to selective pressure of chemotherapy.
Specific Aims. 1) Determine intra-tumor consistency of expression profiles for untreated and treated neuroblastomas. 2) Compare expression profiles of sequential pairs of neuroblastomas obtained at diagnosis/during induction chemotherapy and at diagnosis/disease progression and correlate changes with outcome. 3) Determine if expression profiles of 100 untreated and 100 treated tumors correlate with response, event-free survival, and survival. 4) Develop statistical models to predict outcome based upon expression profiles and known clinical and laboratory risk factors. Research Design. The Children's Oncology Group (COG) performs nationwide biologic and therapeutic studies. Tumors and clinical data already are available from patients enrolled in CCG studies during the 1980s and 1990s and will be obtained prospectively from patients enrolled in COG studies. Our pilot study using oligonucleotide arrays indicate that high-quality cRNA can be prepared from more than 90 percent of untreated and treated tumors. Importantly, preliminary analysis identified genes whose expression may predict outcome. Quantitative PCR and RT-PCR, histopathology, and immunohistochemistry are established in our laboratories. Statistical expertise and software are in place for analyzing the large amounts of data that will be generated and for developing predictive models. Summary. These studies should improve risk assessment and thus lead to more specific and effective therapy for patients with high-risk, stage 4 disease. They also should lead to a better understanding of aggressive neuroblastomas and to rational development of new therapeutic strategies. Discoveries made in this research may well have relevance for other childhood and adult solid tumors.
Showing the most recent 10 out of 35 publications
