Childhood Cancer

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Dissecting Functional uORFs as a Source of Cancer Genes in High-Risk Medulloblastoma

Dana-Farber Cancer Institute
John Prensner, MD/PhD
Grant Type: 
Young Investigator Grants
Year Awarded: 
Type of Childhood Cancer: 
Brain Tumors, Medulloblastoma
Project Description: 

Medulloblastoma is a highly deadly form of brain cancer that almost exclusively impacts children, especially young children. The most fatal type of medulloblastoma is known as the “Group 3” type, which affects toddlers and results in death in around 50% of patients despite intensive chemotherapy, surgery, and potentially radiation therapy. The full biological basis of Group 3 medulloblastoma has remained elusive despite significant research efforts in the past. These cancers often rely upon a gene named MYC, which is a powerful cancer gene that makes the medulloblastoma cells grow too rapidly and spread to distant regions of the brain and spine. MYC achieves these effects by dramatically affecting the activity levels of other genes.

I have recently described an uncharacterized aspect of gene activity, which may operate downstream of MYC in medulloblastoma. Specifically, I have found that the human genome produces thousands of unstudied proteins from the regions of gene regulation where MYC operates. These unstudied proteins, which are called upstream open reading frames (uORFs), may have unique roles in medulloblastoma. I have worked to study these proteins in medulloblastoma and define their functions in this terrible childhood cancer.

Project Goal
The first goal of this project is to understand how these unstudied proteins that reside in areas of gene regulation – termed upstream open reading frames (uORFs) – contribute to the aggressive nature of medulloblastoma. In particular, I have found that a set of these uORFs are required for the proper growth and survival of medulloblastoma cells. Among these, I have identified a single top candidate, called ASNSD1 uORF, whose expression is controlled by MYC and whose role in medulloblastoma cells is to operate with a group of proteins that modulate cancer cell functions, termed the prefoldin complex. This project will probe the ways in which Group 3 medulloblastoma cells rely on ASNSD1 uORF and its associated prefoldin complex proteins for survival and growth. I have proposed two project aims that focus on the importance of ASNSD1 uORF in medulloblastoma growth and its biological consequences – with the prefoldin proteins – in medulloblastoma.
The long-term aspiration of this project is to catalyze this line of research for medulloblastoma, in order to open up a new vanguard of cancer target genes in this disease, which may themselves become future clinical tools or drug targets. uORFs are a numerous population of uncharacterized proteins. Their importance in diseases, including medulloblastoma, is only beginning to be understood. My hope is that this project will provide the initial evidence that this class of proteins is critical in medulloblastoma, and thereby spur increasing interest in their ability serve as clinically-important genes. By doing so, this work may inspire new efforts to develop cancer biomarkers, clinical cancer subtypes, or drug targets for children with aggressive medulloblastoma.