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.

Project Update 2024:

Our project focuses on the biological basis for the most aggressive type of medulloblastoma, a childhood brain cancer. Children with this aggressive type -- termed Group 3 – have a 50% chance of relapse, and once relapsed cure is very difficult to achieve. We have found that the central biological driver of this disease, a gene called MYC, has a new form of activity that has not been investigated before. We observe that MYC causes changes in the way in which these cancer cells convert genetic material (RNA) into functional proteins. This process is called RNA translation. We find that MYC creates distinct patterns of RNA translation in medulloblastoma. Moreover, MYC causes medulloblastoma cells to produce unusual or new types of proteins as well. We call these non-canonical open reading frames. We have found that these new types of genes can be critical to the survival of medulloblastoma cells, and that targeting them may be a new therapeutic approach for patients. We have focused on a compelling candidate that we call ASNSD1-uORF. This is a new gene that makes a new protein. It is required for medulloblastoma cells to survival. We find that this ASNSD1-uORF coordinates a complex network of biological activity that is rooted in regulating how medulloblastoma cells grow and divide. We can verify this in patient samples as well, where we find the same associations that we see in model systems. This work has lead to a manuscript that has been accepted for publication in 2024. We are very excited to continue to work on this project and delve more deeply into the ability to target ASNSD1-uORF and understand its role in promoting medulloblastoma cell growth.