This Mentored Clinical Scientist Development Award (K08) is designed to enable the candidate to become an independent physician-scientist, by augmenting her molecular and clinical background in neuroblastoma research, with training in neurodevelopmental biology. The goal of this application is to use the genetic and embryonic advantages of the zebrafish model system to isolate genes that could function as tumor suppressors in neuroblastoma, an enigmatic tumor of the sympathetic nervous system (SNS) whose spontaneous regression in infants and relentless progression in older children pose daunting problems to therapists and experimental oncologists alike. Despite major modifications of therapy over the past two decades, the long-term cure rate in patients with advanced disease is still far from satisfactory. The central hypothesis of this research is that neuroblastoma development is initiated by the loss of function of several types of suppressor genes that regulate normal embryologic development of the SNS. The identification and delineation of the genetic programs they regulate will yield important insights into normal SNS development and the molecular pathways that become dysregulated in NB. The applicant has isolated two SNS mutations; CC1, defined by the absence of tyrosine hydroxylase (TH) expressing cells in the cervical complex, and CC2, associated with increased numbers of TH expressing cells in the same structure. The CC1 mutation has been characterized and identified as a point mutation in the FoxD3 gene. The phenotypic consequences of the CC2 mutation in the SNS of developing zebrafish embryos will be determined in Aim 1, while the genes responsible for the CC2 mutant phenotype will be determined in Aim 2.
In Aim 3, the mutagenesis screen will be expanded to identify more mutants and two that specifically relate to neural development will be picked for further study. Dr A. Thomas Look, the candidate's mentor, has an exemplary track record in NB research and has committed major resources at the Dana-Farber Cancer Institute to the study of human peripheral SNS development and neuroblastoma pathobiology in the zebrafish model. In addition, an advisory committee of highly regarded medical scientists will provide scientific and career advice. Didactic course work in neuroscience and developmental neurobiology will complement this training program. The goal of this K08 proposal is to obtain the necessary scientific training in developmental neurobiology and zebrafish models to allow the candidate to test the above hypothesis, and in doing so, to allow her to develop into a successful and independent physician scientist. Her career development plan, world-class training environment, and commitment from her Department will allow the realization of this goal. Furthermore, successful completion of these aims will provide a base for her long-term goal of establishing zebrafish models of neuroblastoma, which she will use as a starting point for modifier screens to identify genetic suppressors of particular defects in SNS development. Insight into the proteins encoded by such modifier genes may lead to the discovery of genes that could serve as novel drug targets for the treatment of older children with advanced disease. ? ?
|Pei, Desheng; Luther, William; Wang, Wenchao et al. (2013) Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLoS Genet 9:e1003533|
|George, Rani E; Lahti, Jill M; Adamson, Peter C et al. (2010) Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer 55:629-38|
|George, Rani E; Sanda, Takaomi; Hanna, Megan et al. (2008) Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 455:975-8|
|Moreau, Lisa A; McGrady, Patrick; London, Wendy B et al. (2006) Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children's Oncology Group study. Clin Cancer Res 12:5693-7|
|George, Rani E; London, Wendy B; Cohn, Susan L et al. (2005) Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23:6466-73|