STEM-03. SMARCA5 AS A THERAPEUTIC TARGET FOR GLIOBLASTOMA

Abstract Glioblastoma (GBM) is an aggressive form of primary brain tumor, characterized by high malignancy and genetic heterogeneity, and standard treatment for GBM has remained unchanged in the last decade. A feature of GBM that makes it particularly difficult to treat is its heterogeneity, in part created by glioma stem cells (GSCs) within the solid tumor. GSCs have high plasticity and the ability to self-renew and differentiate into various heterogeneous cancer cell populations. GSCs are kept in a ‘stem’- like state with unlimited self-replication without differentiation and maturation, which helps maintain tumor heterogeneity and growth. This state also prevents them from being targeted effectively by traditional therapeutics. Histone modifications keep late-glial genes inaccessible by transcription factors, promoting transcription of replication and early-glial genes, maintaining stem-ness. A major player in this process is the imitation switch (ISWI) family of ATP-dependent chromatin remodelers, which have been found to have widespread aberrant expression in cancers, including gliomas. The ISWI complex can change the spacing of histones on the chromatin, and is primarily involved in the repression of gene expression. It contains a catalytic subunits, SMARCA5, and our data support that inhibition of SMARCA5 reprograms GSCs to differentiate. RNA-Seq after genetic depletion and pharmacologic inhibition of SMARCA5 in GSCs leads to loss of expression of early glial lineage genes and increased expression of late glial genes. We have developed a first-in-class small molecule SMARCA5 inhibitor that passes the BBB. In pilot studies, SMARCA5 depletion through genetic and pharmacologic inhibition extended animal survival in GSC-derived xenograft models of GBM. ATAC-Seq and single-cell RNA-Seq of tumors further support that SMARCA5 inhibition facilitated transition from stem/progenitor to differentiated cell states. Additionally, the SMARCA5 pharmacological inhibitor was well tolerated in vivo, suggesting that targeting SMARCA5 may have a favorable therapeutic window and high clinical translation potential.