Estrogen-mediated NF-κB blockade enables breast cancer sensitivity to oncolytic VSV virotherapy

Mélissa Viens1, Karen Geoffroy1, Elline Meuriot1

  • 1Cancer Axis and Institut du Cancer de Montréal, Centre Hospitalier de l'Université de Montréal (CHUM) Research Center, Montreal, QC H2X 0A9, Canada; Immunopathology Axis, CHUM Research Center, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectious Diseases, and Immunology, University of Montreal, Montreal, QC H3C 3J7, Canada.

Insights

Novel therapies for breast cancer show promise. Combining oncolytic Vesicular stomatitis virus (oVSV) with NF-κB inhibitors enhances treatment efficacy, particularly for triple-negative breast cancers (TNBC) resistant to estrogen.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Breast cancer requires novel therapies, with oncolytic viruses showing promise but yielding heterogeneous responses.
  • Triple-negative breast cancers (TNBC) are resistant to oncolytic Vesicular stomatitis virus (oVSV), unlike estrogen receptor-positive (ER+) cancers.
  • Estrogen (E2) enhances oVSV infection in ER+ cancers, while E2-antagonizing therapies reduce efficacy.

Purpose of the Study:

  • To enhance oncolytic virotherapy for breast cancer, independent of estrogen.
  • To investigate the role of NF-κB activation in estrogen-mediated oVSV enhancement.
  • To evaluate combination therapies of oVSV with NF-κB inhibitors for TNBC.

Main Methods:

  • Utilized oncolytic Vesicular stomatitis virus (oVSV) in breast cancer models.
  • Investigated the effect of estrogen (E2) and NF-κB inhibitors (IKK16, Sulfasalazine) on oVSV replication.
  • Assessed virus replication in TNBC cell lines and patient samples.

Main Results:

  • Estrogen (E2) stimulation enhanced oVSV infection, while E2-antagonizing therapies reduced it.
  • Mechanistic studies revealed E2 stimulation impairs NF-κB activation.
  • NF-κB inhibitors IKK16 and Sulfasalazine improved oVSV replication in TNBC.
  • Combination therapy showed efficacy in TNBC cell lines and patient samples.

Conclusions:

  • Estrogen significantly impacts oncolytic virotherapy efficacy in breast cancer.
  • NF-κB inhibitors can overcome E2-mediated resistance and enhance oVSV activity.
  • Combination therapy offers a promising strategy for treating all breast cancer subtypes, including TNBC.

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