Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy

Abstract

Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.

Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor

“…Combinations of HDAC and mTOR inhibitors drive embryonal cell differentiation in rhabdoid tumors [74] . Treatment of mice bearing BT12 orthotopic xenografts with daily low dose panobinostat for 28 days led to decreased tumor growth as measured by bioluminescent imaging and statistically significant extension of overall survival [73] . Interestingly, when panobinostat treatment stopped after 28 days, the tumors rapidly progressed, underscoring the epigenetic plasticity inherent in AT/RT and other epigenetically driven tumors.…”

“…The histone deaceytlase inhibitor (HDAC) panobinostat suppressed the growth of AT/RT cell lines at nanomolar concentrations and induced the differentiation of these cell lines along a neuronal lineage [73] . Combinations of HDAC and mTOR inhibitors drive embryonal cell differentiation in rhabdoid tumors [74] .…”

Single-Cell Sequencing Identifies Master Regulators Affected by Panobinostat in Neuroblastoma Cells

“…Kelly cells were treated with panobinostat (10 nM) and DMSO as a vehicle control for 12 h prior to single-cell sequencing. The dosage was identical to that previously used for panobinostat treatment of neuroblastoma cells [ 10 ] and similar to that normally used in the literature for cell cultures [ 23 , 24 ].…”

Focal glioneuronal differentiation in an atypical teratoid/rhabdoid tumor after chemoradiotherapy

“…Atsuro Saito 2 Daiichiro Hasegawa 2 Yoshiyuki Kosaka 2 Junji Koyama 3 Atsufumi Kawamura 3 Yoshinobu Akasaka 4 Toshinori Soejima…”

“…Few reports have revealed tumoral differentiation of AT/RT after chemoradiotherapy, although there are a few reports that low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multilineage differentiation of malignant rhabdoid tumors in vitro. 2,3 A few autopsy reports demonstrate that embryonal tumors with abundant neuropil and true rosettes show glial and neuronal maturation after therapy. 4,5 This case suggests the possibility that chemoradiotherapy may lead to stable disease through glioneuronal differentiation of AT/RT.…”