Atypical teratoid/rhabdoid tumors-current concepts, advances in biology, and potential future therapies

Abstract

Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant CNS tumor of children below 6 months of age. The majority of AT/RTs demonstrate genomic alterations in SMARCB1 (INI1, SNF5, BAF47) or, to a lesser extent, SMARCA4 (BRG1) of the SWItch/sucrose nonfermentable chromatin remodeling complex. Recent transcription and methylation profiling studies suggest the existence of molecular subgroups. Thus, at the root of these seemingly enigmatic tumors lies a network of factors related to epigenetic regulation, which is not yet completely understood. While conventional-type chemotherapy may have significant survival benefit for certain patients, it remains to be determined which patients will eventually prove resistant to chemotherapy and thus need novel therapeutic strategies. Elucidation of the molecular consequences of a disturbed epigenome has led to the identification of a series of transduction cascades, which may be targeted for therapy. Among these are the pathways of cyclin D1/cyclin-dependent kinases 4 and 6, Hedgehog/GLI1, Wnt/ß-catenin, enhancer of zeste homolog 2, and aurora kinase A, among others. Compounds specifically targeting these pathways or agents that alter the epigenetic state of the cell are currently being evaluated in preclinical settings and in experimental clinical trials for AT/RT.

Keywords: AT/RT; BAF47; INI1; SMARCB1; SNF5; SWI/SNF; epigenetics; rhabdoid tumor.

Fig. 1.

Epigenetic roles of SMARCB1 in promoter activation, occupancy, and enhancer modification, including potential therapeutic targeting. The SWI/SNF complex modulates gene transcription including by (i) regulation of nucleosome positioning at promoters and consequently transcription factor binding and accessibility to the transcription machinery (Pol), (ii) antagonism of the Polycomb repressive complex 2 (PRC2), thus opposing the repressive H3k27Me3 mark written by PRC2 and favoring an active H3k4Me3 modified promoter, and (iii) localization at enhancers where the complex may contribute to transcription regulation, although the mechanism remains poorly understood. The SWI/SNF complex is bound at most active genes and the transcription of many genes are affected by SMARCB1 loss. Among others these include CCND1, GLI1, and AURKA, which may be therapeutically targeted by ribociclib, arsenic trioxide, and alisertib, respectively. The chromatin antagonizing effects of EZH2 may be therapeutically targeted by tazemetostat.