Research And Grants

SUMOylation as a novel therapeutic target in DIPG

This grant was funded in cooperation with the Aubreigh’s Army and Reflections of Grace foundations.

Post-translational protein modification (PTM) is one of the important  mechanisms by which the function of cellular proteins are modulated.  SUMOylation is a  reversible PTM which has emerged as a crucial molecular  mechanism, involved in the control of DNA damage repair, immune responses, carcinogenesis, cell  division and cell death (1).  During the process, SUMO (Small Ubiquitin-like Modifier) proteins, which are a family of small proteins, are attached to target proteins.  There are several SUMO proteins that may be conjugated including SUMO1, SUMO2 and SUMO3.  The greatest impact of SUMOylation has been demonstrated around gene regulation (2-8).  As the importance of SUMOylation in human tumorigenesis has gradually emerged, there has been an effort to develop SUMOylation inhibitors as therapeutic agents. Subasumstat (TAK-981) is a first in-class SUMOylation inhibitor that disrupts SUMOylation (9). TAK-981 is now in multiple oncology clinical trials in patients with advanced cancers allowing for clinical evaluation of SUMOylation inhibition as a tractable pathway in cancer. Nothing is known about the importance of SUMOylation in DIPG. We discovered that SUMOylation genes are elevated specifically in DIPG compared to normal brain and other pediatric brain tumors that do not have the DIPG-specific mutations. When tested in several DIPG cell lines, the SUMOylation inhibitor TAK-981 killed 70-90% DIPG cells in the Petri dish. Given the hypersensitivity of all DIPG lines to an existing  drug already in multiple oncology clinical trials, in this grant we will test the efficacy of the drug in our well-established mouse models of DIPG in combination with radiation.