Role of SMARCA5 in Glioblastoma

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

Investigators

Abstract

Glioblastoma is an incurable primary brain tumor. Glioma cells lie along a continuum, with glioma stem cells (GSCs) at one end and differentiated glioma cells (DGCs) at the other end. GSCs have a high capacity for self-renewal and are highly resistant to standard treatments. They therefore play critical roles in disease progression. DGCs, on the other hand, comprise the bulk of tumor cells and are more sensitive to treatments. Forcing GSCs to differentiate may therefore render GBM less aggressive, resulting in improved patient survival. While differentiation therapy is used for some cancers, it has not yet worked successfully in GBM. Obstacles lie in finding suitable targets to force GSCs to differentiate yet not impact normal stem/progenitor cells. The stem cell state is maintained through the expression of stem-cell lineage genes and repression of genes involved in differentiation. In GSCs, chromatin is locked in a conformation such that expression of genes that specify the stem cell state are open and accessible to transcription factors, whereas expression of genes involved in differentiation are in a closed conformation and inaccessible. Chromatin remodeling complexes play key roles in regulating the chromatin landscape and expression of genes involved in cell state. Our strategy is to tip the balance between co-activator (e.g. SWI/SNF) and co-repressor (e.g. ISWI/CHD) complex activity. As a result, chromatin accessibility and conformation are altered to facilitate expression of pro-differentiation genes and reduce expression of stem cell maintenance genes. The result is the conversion of highly malignant GSCs into less aggressive DGCs. In this proposal, we identify the ISWI complex component SMARCA5 as a therapeutic target. Our pilot studies support that inhibition of SMARCA5 forces GSCs to differentiate. Further, we have developed a first-in-class and brain- penetrant inhibitor of SMARCA5 that extends animal survival in GSC-derived orthotopic models of GBM. This inhibitor appears safe for normal but not malignant cells. We hypothesize that SMARCA5 regulates GSC cell state, and that its targeting in GSCs will facilitate their differentiation to improve tumor control. We will assess the role of SMARCA5 in regulating GSC maintenance and tumorigenic potential. We will also determine its role in shaping the chromatin landscape and the expression of genes that regulate cell state. These studies will provide mechanistic understanding of cell state regulation and offer a strategy of differentiation therapy to improve GBM control. Preclinical studies with our first-in-class SMARCA5 inhibitor will facilitate its clinical translation.