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Oncogenic reprogramming of protein translation by DDX3 inact

Institution: University of California, San Francisco
Investigator(s): Stephen Floor, Ph. D.
Award Cycle: 2018 (Cycle 27) Grant #: 27KT-0003 Award: $748,146
Subject Area: Cancer
Award Type: New Investigator Awards

Initial Award Abstract

Cancer is often caused by changes to the DNA sequence of genes. These changes cause cells to grow uncontrollably, producing a tumor. Different tumors within the same cancer type can be caused by different DNA changes. It is important to understand how the DNA changes in cells lead to cancer formation, because treatments may work for individuals with some DNA changes but not others. This project aims to understand how DNA changes in the brain tumor medulloblastoma lead to cancer formation by modeling cancer in the lab.

The focus of this project is on changes to a gene called DDX3, which is altered in half of patients with specific types of medulloblastoma. DDX3 is a protein machine that changes the shape of RNA molecules in cells, leading to changes in which proteins are produced. The changes to DDX3 break the protein so it can no longer perform its normal function. This means that drugs that inhibit the activity of DDX3 are not likely to help medulloblastoma patients. However, if we knew how breaking the activity of DDX3 changed the production of other proteins in cells, we would have a better idea of other drugs to try for patients with DDX3 changes.

A new technology has emerged in the last five years called CRISPR–Cas9, which allows researchers to make precise changes to DNA in cells. We will use this technology to introduce changes identical to those found in medulloblastoma patients into cells. We will then use techniques we developed to measure how changes to DDX3 affect production of other proteins in cells. We will also perform experiments to understand why some RNA molecules require DDX3 activity while others do not. Together, these experiments will explain how changes to DDX3 can promote cancer formation.

We anticipate the results of this research will impact cancer patients in multiple ways. First, a better understanding of how DDX3 changes lead to cancer, we may propose new targets for drugs. Second, there may be FDA-approved drugs that target proteins that are affected by changes to DDX3 that patients could take. Third, patients within the same cancer type sometimes respond differently to treatments, and understanding the effects of DDX3 changes may explain this. Lastly, there are children with brain disorders involving similar changes to DDX3 but without other DNA changes that are found in medulloblastoma, and our research will predict whether these patients are likely to develop cancer. In summary, our proposed cancer research program will impact the development of medulloblastoma treatments, patient therapeutic strategies, and individuals with other DDX3-related disorders.