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. 2024 Jun 8;32(3):200826.
doi: 10.1016/j.omton.2024.200826. eCollection 2024 Sep 19.

Oncolytic vesicular stomatitis virus alone or in combination with JAK inhibitors is effective against ovarian cancer

Affiliations

Oncolytic vesicular stomatitis virus alone or in combination with JAK inhibitors is effective against ovarian cancer

Karen Geoffroy et al. Mol Ther Oncol. .

Abstract

Therapy-resistant ovarian cancers have a poor prognosis and novel effective treatment options are urgently needed. In this study, we evaluated the therapeutic efficacy of the oncolytic vesicular stomatitis virus (VSV) against a panel of patient-derived ovarian cancer cell lines of all epithelial subtypes. Notably, we found that most of the cell lines were sensitive to VSV virotherapy. With the objective of improving treatment efficacy for the oncolytic virus-resistant cell lines, we tested various combinations with ovarian cancer standard of care drugs: olaparib, carboplatin, paclitaxel, doxorubicin, cyclophosphamide, and gemcitabine. While none of these combinations revealed to be beneficial, further experiments demonstrated that the antiviral interferon pathway was functional in VSV-resistant cell lines. Given that interferons signal through Janus kinase (JAK)-STAT to mediate their antiviral function, we tested combinations of oncolytic VSV with clinically relevant JAK inhibitors. Our results show that combining VSV with various JAK inhibitors, including ruxolitinib, enhances VSV virotherapy and treatment efficacy. Altogether, we show that VSV, either as a stand-alone treatment or in combination with JAK inhibitors provides an effective therapeutic option for ovarian cancer patients.

Keywords: JAK inhibitors; VSV; oncolytic virus; ovarian cancer; ruxolitinib.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Ovarian cancer cells are sensitive to oncolytic VSV infection (A) Fluorescence imaging of ovarian cancer cell lines infected with VSVΔ51-YFP at the indicated MOIs for 24 h. Scale bar, 100 μm. (B) Viral outputs from cells in (A) infected at an MOI of 0.1 as measured by plaque assays (n = 3). The dotted line indicates virus input. (C) Representative fluorescence microscopy images of TOV112D xenografts infected ex vivo with 1.5 × 106 PFU/mL of VSVΔ51-YFP for 24 h. The images show nucleus in blue (DAPI), VSV G in red, cleaved caspase-3 (CC3) in yellow, and epithelial (tumor) cells (CKs 8/18) in green. NV, no virus. Whole core scale bar, 50 μm, close-up scale bar, 10 μm.
Figure 2
Figure 2
Combinations of VSV with various anticancer drugs do not enhance VSV Relative fluorescence signal (infection) of ovarian cancer cell lines infected with VSVΔ51-YFP 4 h post-carboplatin, -paclitaxel, -doxorubicin, -cyclophosphamide, -gemcitabine, or -olaparib treatment at the indicated concentrations compared with no drug controls. MOIs used: 0.01 for TOV1946 and OV866(2), 1 for TOV3041G and OV3331 and 10 for TOV1369TR and TOV2414. The fluorescence was measured 24 h post-infection using an Ensight multimode plate reader. Two-way ANOVA test (n = 3), ns: p > 0.05, ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗∗∗p ≤ 0.0001.
Figure 3
Figure 3
Ovarian cancer cell lines are IFN competent (A) Viral outputs from ovarian cancer cell lines pre-treated with human IFNβ for 4 h prior to infection with VSVΔ51-YFP at an MOI of 10 for 24 h were measured by plaque assay. (B) IFNβ and (C) IFNα production from the same samples as in (A) were quantified by ELISA. (D) Viral outputs from ovarian cancer cells treated with type I IFN neutralizing antibodies and infected 4 h later with VSVΔ51-YFP at an MOI of 10. Dotted lines represent viral inputs. Multiple t test (n = 3), ns: p > 0.05, ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗∗∗p ≤ 0.0001.
Figure 4
Figure 4
Ruxolitinib increases VSV replication and cancer cell death (A) Fluorescence imaging pictures of ovarian cancer cell lines treated with ruxolitinib (10 μM) for 4 h prior to infection with VSVΔ51-YFP at various MOIs (0.01 for OV866(2), 0.1 for TOV3041G, 1 for OV3331, and 10 for TOV2414). Scale bar, 100 μm. (B) Quantification of the fluorescent signal from cells pre-treated with a range of ruxolitinib concentrations 4 h prior to infection with VSVΔ51-YFP at the indicated MOIs. (C) Viral replication and (D) Coomassie blue stain from cells infected with VSVΔ51-YFP and treated with ruxolitinib (5 μM) after 48 h post-infection were measured. Two-way ANOVA test (n = 3), ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗∗∗p ≤ 0.0001. Dotted lines indicate the fluorescent signal detected in non-treated control conditions (B), viral inputs (C), or viability of non-infected and non-treated control conditions (D).
Figure 5
Figure 5
Combination of VSV and ruxolitinib led to better viral replication ex vivo (A) Virus titers from TOV3041G, OV3331, and OV3133 xenografts pre-treated with ruxolitinib (5 μM) for 4 h prior to infection with VSVΔ51-YFP (1.5 × 106 PFU/mL). Virus outputs were measured 24 h post-infection by plaque assay (n = 4). (B) Representative IF images of OV3133 samples stained for nuclei (DAPI in blue), VSV G (red), apoptotic cells (CC3 in yellow), and epithelial tumor cells (CKs 8/18 in green). Scale bar, 50 μm, close-up scale bar, 10 μm. (C) Number of positive cells for VSV per sample were counted manually (n ≥ 12). Multiple t test, ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗∗p ≤ 0.0001.
Figure 6
Figure 6
Combination of VSV and ruxolitinib enhances VSV efficacy Tumor growth curves of OV866(2) xenograft-bearing mice treated with ruxolitinib (5 μM) or vehicle (PBS) i.p. 4 h before intratumoral injection of VSV (10e8 PFU) or PBS. Control (n = 5), ruxolitinib (n = 4), VSVΔ51 (n = 8), and ruxolitinib+VSVΔ51 (n = 8). Multiple t test, ∗p ≤ 0.05, ∗∗p ≤ 0.01, ∗∗∗p ≤ 0.001, ∗∗∗∗p ≤ 0.0001.

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References

    1. Siegel R.L., Miller K.D., Fuchs H.E., Jemal A. Cancer statistics. CA Cancer J. Clin. 2022;72:7–33. doi: 10.3322/caac.21708. - DOI - PubMed
    1. Gogineni V., Morand S., Staats H., Royfman R., Devanaboyina M., Einloth K., Dever D., Stanbery L., Aaron P., Manning L., et al. Current Ovarian Cancer Maintenance Strategies and Promising New Developments. J. Cancer. 2021;12:38–53. doi: 10.7150/JCA.49406. - DOI - PMC - PubMed
    1. Cheung-Ong K., Giaever G., Nislow C. DNA-damaging agents in cancer chemotherapy: Serendipity and chemical biology. Chem. Biol. 2013;20:648–659. doi: 10.1016/j.chembiol.2013.04.007. - DOI - PubMed
    1. Luvero D., Milani A., Ledermann J.A. Treatment options in recurrent ovarian cancer: latest evidence and clinical potential. Ther. Adv. Med. Oncol. 2014;6:229–239. doi: 10.1177/1758834014544121. - DOI - PMC - PubMed
    1. Aitken A.S., Roy D.G., Bourgeois-Daigneault M.C. Taking a Stab at Cancer; Oncolytic Virus-Mediated Anti-Cancer Vaccination Strategies. Biomedicines. 2017;5 doi: 10.3390/BIOMEDICINES5010003. - DOI - PMC - PubMed

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