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The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF)

Raffaella Soldi1, Tithi Ghosh Halder1, Alexis Weston1

  • 1Applied Cancer Research and Drug Discovery Division, Translational Genomics Research Institute (TGen) of City of Hope, Phoenix, Arizona, United States of America.

Plos One
|July 11, 2020
PubMed

Insights

SWI/SNF-mutated ovarian cancers, like SCCOHT and OCCC, are sensitive to LSD1 inhibition. SP-2577 treatment boosts anti-tumor immunity and PD-L1 expression, suggesting combination therapy potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • SWI/SNF chromatin remodeling complex mutations are prevalent in 20% of human cancers, notably ovarian cancers.
  • Ovarian clear cell carcinoma (OCCC) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) exhibit distinct SWI/SNF subunit mutations (ARID1A, SMARCA4/SMARCA2).
  • LSD1 (lysine-specific histone demethylase 1) is a histone-modifying enzyme highly expressed in SWI/SNF-mutated tumors and linked to chromatin regulation.

Purpose of the Study:

  • To investigate the therapeutic potential of the LSD1 inhibitor SP-2577 (Seclidemstat) in SWI/SNF-deficient ovarian cancers.
  • To evaluate SP-2577's ability to enhance anti-tumor immunity and T-cell infiltration in SCCOHT and OCCC models.
  • To explore the combination therapy of SP-2577 with checkpoint inhibitors for SWI/SNF-mutated ovarian cancers.

Main Methods:

  • Utilized SCCOHT and OCCC cell lines for in vitro studies.
  • Administered the reversible LSD1 inhibitor SP-2577.
  • Assessed interferon (IFN)-dependent anti-tumor immunity, T-cell infiltration, and PD-L1 expression.

Main Results:

  • SP-2577 demonstrated sensitivity in SCCOHT and OCCC cell lines, indicating dependence on LSD1 activity.
  • SP-2577 treatment stimulated IFN-dependent anti-tumor immunity in SCCOHT.
  • SP-2577 promoted PD-L1 expression in both SCCOHT and OCCC cell lines.

Conclusions:

  • LSD1 inhibition by SP-2577 shows promise for treating SWI/SNF-mutated ovarian cancers.
  • SP-2577 enhances anti-tumor immunity and PD-L1 expression, key factors for immunotherapy.
  • Combination therapy with SP-2577 and checkpoint inhibitors may represent a novel strategy for SWI/SNF-mutated ovarian cancers.

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