Neuroblastoma is the most common extra cranial tumor of childhood, and cases are highly heterogenous with regard to clinical behavior. Although patient groups with different expected survivals can be identified by clinical staging at diagnosis, individual clinically defined risk groups include patients with quite different outcomes. Inter- and intra-stage diversity provides opportunities for identifying molecular genetic and biologic properties of tumors that are associated with treatment outcome. Such correlations can identify risk groups that otherwise are not recognizable, thus aiding in the interpretation of clinical studies, and they can provide new criteria for more appropriate therapy assignment. They may also suggest new approaches to therapy. The long-term goal of the proposed studies is to develop tests that improve definition of risk groups so that the most appropriate and effective therapy can be given to each patient. The hypothesis of this application is that subsets of neuroblastomas can be identified by evaluating (1) genes that are critically involved in neuroblastoma growth, differentiation, and survival and (2) the ability of tumor cells to grow continuously in vitro. Plans are to build upon previous studies of N-myc proto-oncogene expression in neuroblastoma and of the neurotrophins (nerve growth factor, NGF, and brain derived neurotrophic factor, BDNF) and their receptors (e.g., TrkAl), and of tumor cell growth in vitro, which demonstrated the potential importance of these markers in prognostication.
The specific aims are as follows: (1) determine if tumor phenotype defined by MYCN gene amplification and expression, TrkA expression, telomerase RNA expression, and growth in vitro correlates with disease progression during or after therapy; (2) develop multivariate statistical models for predicting outcome based upon clinical presentation (stage and age) and laboratory data (tumor MYCN gene amplification, TrkA expression, telomerase RNA expression, growth in vitro, and histopathology); (3) determine in a pilot study if expression of other neurotrophins and their receptors defines risk groups. If so, include these in the above analyses. The CCG performs phase III studies in which newly diagnosed patients receive therapy according to risk classification, which is currently based upon clinical stage, age, histopathology, and N-myc gene amplification status. Approximately 200 patients are registered annually in studies for low, intermediate, and high-risk neuroblastoma. Tumor tissues including (in some patients) bone marrow with tumor are obtained at diagnosis prospectively. Tumors are tested to determine their phenotype with regard to N-myc amplification, trk RNA expression level and pattern of expression, BDNF RNA expression, telomerase RNA expression and activity, chromosome 1p deletions, and tumor cell growth in vitro. The goal is to determine if these laboratory test results can identify clinically important but small subsets of patients who may benefit from different therapy. If preliminary studies indicate that specific tests are particularly important in predicting prognosis, large-scale studies will be conducted to better define the value of these new tests (e.g., their ability to identify patients who will likely fail treatment). It is anticipated that these studies will improve prognostication and that they may contribute to development of novel and possibly more effective therapies for high-risk patients, while diminishing the risks of treatment for low risk patients.
Showing the most recent 10 out of 35 publications
