Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. It is the third most common form of cancer in infants after leukemia and neuroblastoma. If left untreated, retinoblastoma is virtually always fatal, and even with the best treatment, the 10% survival rate for metastatic retinoblastoma is among the worst for any pediatric cancer. In the U.S., most patients survive because the cancer is detected early before it metastasizes, but saving the patient's life often requires surgical enucleation. This is particularly debilitating for children ith the most advanced form of bilateral retinoblastoma; approximately half of those patients lose at least 1 eye and are permanently vision impaired. The goal of this translational research is to identify new treatments to save the vision of children with retinoblastoma and the lives of children with metastatic progression. We have identified 3 novel, exciting molecular-targeted therapies that show promise in laboratory studies. In this application, we will perform comprehensive preclinical testing of these 3 agents. The results from these studies will be used to design the next retinoblastoma clinical trial at St. Jude Children's Research Hospital. Therefore, the successful completion of the Aims presented here will directly impact human health. One unique and innovative aspect of this application is the multidisciplinary team that we have assembled, which is made up of ocular oncologists, pediatric oncologists, developmental neurobiologists, chemists, and pharmacologists. This team has a proven record of moving basic science discoveries into clinical trials and then sharing our findings with the national and international communities to affect the greatest change in global human health. Another innovative aspect of the application is our expertise in retinoblastoma translational research and development of preclinical models, which we have optimized and characterized for these studies. No other center has the team, resources, expertise, or tools available to perform the studies presented here and move the most promising findings directly into a clinical trial.
Over the past decade, we have studied the basic mechanisms of retinal development and how those processes are perturbed in retinoblastoma. We have identified 3 essential pathways that are deregulated in retinoblastoma and we have developed novel and exciting new approaches to target those pathways in translational studies. Importantly, we have assembled a unique multidisciplinary translational research team and the necessary infrastructure and expertise to move our translational research into clinical trials to enhance the well-being and reduce the burden of retinoblastoma in children. This research application is precisely aligned with the mission of the NIH and our translational research is an important model for investigating other orphan diseases that affect 25 million Americans each year.
|Stewart, Elizabeth; McEvoy, Justina; Wang, Hong et al. (2018) Identification of Therapeutic Targets in Rhabdomyosarcoma through Integrated Genomic, Epigenomic, and Proteomic Analyses. Cancer Cell 34:411-426.e19|
|Wang, Lu; Hiler, Daniel; Xu, Beisi et al. (2018) Retinal Cell Type DNA Methylation and Histone Modifications Predict Reprogramming Efficiency and Retinogenesis in 3D Organoid Cultures. Cell Rep 22:2601-2614|
|Aldiri, Issam; Xu, Beisi; Wang, Lu et al. (2017) The Dynamic Epigenetic Landscape of the Retina During Development, Reprogramming, and Tumorigenesis. Neuron 94:550-568.e10|
|Stewart, Elizabeth; Federico, Sara M; Chen, Xiang et al. (2017) Orthotopic patient-derived xenografts of paediatric solid tumours. Nature 549:96-100|
|Bharatham, Nagakumar; Finch, Kristin E; Min, Jaeki et al. (2017) Performance of a docking/molecular dynamics protocol for virtual screening of nutlin-class inhibitors of Mdmx. J Mol Graph Model 74:54-60|
|Hiler, Daniel J; Barabas, Marie E; Griffiths, Lyra M et al. (2016) Reprogramming of mouse retinal neurons and standardized quantification of their differentiation in 3D retinal cultures. Nat Protoc 11:1955-1976|
|Stewart, Elizabeth; Federico, Sara; Karlstrom, Asa et al. (2016) The Childhood Solid Tumor Network: A new resource for the developmental biology and oncology research communities. Dev Biol 411:287-293|
|Pritchard, Eleanor M; Dyer, Michael A; Guy, R Kiplin (2016) Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma. Mini Rev Med Chem 16:430-54|
|Valle-García, David; Qadeer, Zulekha A; McHugh, Domhnall S et al. (2016) ATRX binds to atypical chromatin domains at the 3' exons of zinc finger genes to preserve H3K9me3 enrichment. Epigenetics 11:398-414|
|Dyer, Michael A (2016) Lessons from Retinoblastoma: Implications for Cancer, Development, Evolution, and Regenerative Medicine. Trends Mol Med 22:863-876|
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