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Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor

Maggie H Chasse1, Benjamin K Johnson1, Elissa A Boguslawski1

  • 1Van Andel Research Institute, Grand Rapids, MI, USA.

EMBO Molecular Medicine
|December 17, 2020
PubMed

Insights

Pediatric rhabdoid tumors with SMARCB1 deletion show sensitivity to mithramycin and EC8042. These drugs restore cellular differentiation by targeting SWI/SNF activity, offering a promising new therapeutic avenue.

Area of Science:

  • Oncology
  • Epigenetics
  • Chromatin Biology

Background:

  • Rhabdoid tumors (RT) are aggressive pediatric cancers driven by SMARCB1 inactivation.
  • Current therapeutic options for RT are limited, highlighting the need for novel treatments.

Purpose of the Study:

  • To identify novel therapeutic agents for rhabdoid tumors.
  • To investigate the mechanism of action of identified drugs in SMARCB1-deficient cancers.

Main Methods:

  • Unbiased screening of cell line panels to identify drug sensitivities.
  • In vitro assays to assess drug effects on chromatin remodeling and gene expression.
  • In vivo studies using RT xenografts to evaluate therapeutic efficacy.

Main Results:

  • Rhabdoid tumors exhibit heightened sensitivity to mithramycin and EC8042.
  • These drugs block SMARCB1-deficient SWI/SNF activity, increasing H3K27me3 and restoring differentiation.
  • EC8042 treatment led to significant tumor regression and complete cure in a subset of mice with RT xenografts.

Conclusions:

  • Mithramycin and EC8042 represent a promising therapeutic strategy for rhabdoid tumors.
  • The mechanism involves targeting SWI/SNF activity and restoring epigenetic regulation for cellular differentiation.
  • EC8042 demonstrates significant in vivo efficacy, warranting further clinical investigation.
Keywords:
EC8042SWI/SNFepigeneticsmithramycinpediatric cancer

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