Deconstruction of the CIC-DUX4 Fusion Oncoprotein Complex: Insights Into Disease Etiology and Therapeutics
Abstract
Genes instruct cells to do their jobs by making specific proteins. In our body, all cells store this instruction manual in high-order structures, called chromosomes, which are made of DNA and protein. When chromosomes duplicate during cell division, they break and re-attach at several places. If chromosomes exchange re-attachment sites during this process, they build new chromosomes that often abnormally create fusion protein products by the joining of two or more genes originally encoded for separate proteins. These errors, termed “translocations,” can have no effect on our bodies, but in many cases they can cause problems as severe as cancer. We have chosen to study a highly aggressive type of translocation-associated cancer, defined molecularly by the fusion of two unrelated genes, CIC and DUX4. The resulting CIC-DUX4 fusion protein is known to reprogram normal cells into cancer, but how this process operates in molecular terms remains unclear. Our proposed work aims to fill this gap in current knowledge by defining an essential binding partner of CIC-DUX4-activating genes that contribute to tumor growth and metastasis. By understanding how this regulation can be inhibited by existing drugs, such as histone deacetylase inhibitors (HDACi), we hope to turn the best treatment ideas into clinical care. If successful, this project will create new therapeutic strategies targeted to CIC-DUX4 fusion-positive sarcomas that most commonly afflict children and young adults, and for which truly effective, curative therapies do not yet exist. Patients both with primary and recurring CIC-DUX4 sarcomas, or even in the metastatic setting (the deadliest phase, accounting for about 60% of all cases), may gain survival benefit from HDACi treatment that can directly target CIC-DUX4 biology and would therefore suppress any stage of disease progression. Given that numerous HDACi have entered clinical trials worldwide, our study could make an immediate and broad impact on therapeutic management of CIC-DUX4 sarcomas. Collectively, the present research program not only generates new and fundamental knowledge on the molecular basis of a rare but highly lethal cancer, but also lays out a novel treatment approach to improve outcomes for an underserved group of patients who need real cures.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110632
Entities
People
- Le Su
Organizations
- HudsonAlpha Institute for Biotechnology
- United States Army