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A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor

Valerio Benedetti1, Federica Banfi1,2, Mattia Zaghi1

  • 1Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.

Science Advances
|August 3, 2022
PubMed

Insights

A novel synthetic repressor, SOX2 epigenetic silencer (SES), effectively targets glioblastoma multiforme (GBM) by silencing SOX2. This approach shows promise in killing cancer cells and tumors while sparing healthy brain cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Glioblastoma multiforme (GBM) recurrence leads to poor patient survival.
  • Current therapies are insufficient for preventing GBM recurrence.
  • SOX2 is a key transcription factor promoting GBM malignancy.

Purpose of the Study:

  • To engineer a synthetic repressor targeting SOX2 for GBM treatment.
  • To evaluate the efficacy and safety of the SOX2 epigenetic silencer (SES) in preclinical models.

Main Methods:

  • Rational engineering of SOX2 with Kruppel-associated box and DNA methyltransferase3A/L catalytic domains to create SES.
  • In vitro and in vivo testing of SES on glioma cell lines, cancer stem cells, and mouse xenografts.
  • Local viral delivery of SES for tumor treatment.

Main Results:

  • SES induces transcriptional silencing of SOX2 targets, leading to cell death in glioma and cancer stem cells.
  • In vivo, SES expression caused significant tumor regression and improved survival in mouse xenografts.
  • SES demonstrated safety, sparing neurons and glia due to targeted expression in mitotically active cells.

Conclusions:

  • SES effectively represses aggressive brain tumors by silencing the SOX2 network.
  • SES represents a promising therapeutic strategy for glioblastoma multiforme.
  • Targeted delivery and minimal promoter design enhance SES safety and efficacy.

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