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Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
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.
Abstract:
Novel therapies are urgently needed for breast cancer. While our previous work investigating the use of oncolytic viruses against the disease demonstrated its promise, heterogeneous responses were observed. Interestingly, breast cancer is classified into subtypes based on the expression of hormone receptors. We noted that triple-negative breast cancers (TNBCs), which lack the expression of the estrogen (E2) receptor (ER) were resistant to the oncolytic vesicular stomatitis virus (oVSV), whereas ER+ cancers were particularly sensitive. We found that E2 stimulation enhanced virus infection, while E2-antagonizing endocrine therapies counteract the virus. Further mechanistic studies revealed a defect of nuclear factor (NF)-κB activation with E2 stimulation. With the goal of enhancing oncolytic virotherapy independently of E2, we designed a treatment strategy that combines oVSV with the NF-κB inhibitors IKK16 and sulfasalazine and found that both drugs improved virus replication in TNBC cell lines and patient samples. Our data uncover a novel impact of E2 on oncolytic virotherapy and demonstrate that combining virus treatment with NF-κB inhibitors recapitulates the E2-mediated virus enhancement. Importantly, our treatment combinations could be beneficial to all breast cancers, including TNBCs, as well as other breast cancers that do not respond to E2.
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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