Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

Nguyên, Thi Lien-Anh; Abdelbary, Hesham; Arguello, Meztli; Breitbach, Caroline J.; Léveillé, Simon; Diallo, Jean-Simon; Yasmeen, Amber; Bismar, Tarek A.; Kirn, David H.; Falls, Theresa; Snoulten, Valerie; Vanderhyden, Barbara C.; Werier, Joel; Atkins, Harold L.; Vähä‐Koskela, Markus; Stojdl, David F.; Bell, John C.; Hiscott, John

doi:10.1073/pnas.0803988105

Cited by 164 publications

(181 citation statements)

References 49 publications

Supporting

Mentioning

176

Contrasting

Order By: Relevance

“…However, in addition to the fact that many cancer cells produce type I IFN (16,32), the virusinduced "systemic" type I IFN response also impedes the utility of Control and VSV ΔM51 -GFP log-rank test, P = 0.2402; control and rapamycin log-rank test, P = 0.0038; control and VSV ΔM51 -GFP plus rapamycin log-rank test, P = 0.0007; rapamycin and VSV ΔM51 -GFP plus rapamycin log-rank test, P = 0.0011. oncolytic viruses such as VSV ΔM51 as efficient therapeutic agents. Thus, the effectiveness of VSV ΔM51 oncolytic therapeutic is determined by the combination of two main factors: (i) type I IFN deficiency and (ii) tumor-specific virus replication.…”

Section: Discussionmentioning

confidence: 99%

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Alain

Lun

Martineau

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

108

View full text Add to dashboard Cite

Oncolytic viruses constitute a promising therapy against malignant gliomas (MGs). However, virus-induced type I IFN greatly limits its clinical application. The kinase mammalian target of rapamycin (mTOR) stimulates type I IFN production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Here we show that mouse embryonic fibroblasts and mice lacking S6K1 and S6K2 are more susceptible to vesicular stomatitis virus (VSV) infection than their WT counterparts as a result of an impaired type I IFN response. We used this knowledge to employ a pharmacoviral approach to treat MGs. The highly specific inhibitor of mTOR rapamycin, in combination with an IFN-sensitive VSV-mutant strain (VSV ΔM51 ), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV ΔM51 selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. These results demonstrate that reducing type I IFNs through inhibition of mTORC1 is an effective strategy to augment the therapeutic activity of VSV ΔM51 .innate antiviral immunity | malignant gliomas | mTORC1 | oncolytic viruses M alignant gliomas (MGs) are by far the most frequent, aggressive, and lethal primary brain tumor variants (1, 2). Patients with MGs have a median survival time of approximately 1 y and respond poorly to most available therapeutic modalities (3-5). Thus, more effective treatments are needed.Recent evidence implicates the PI3K/mammalian target of rapamycin (mTOR) signaling pathway as one of the main oncogenic signaling pathways whose deregulation may underlie gliomagenesis (6, 7). mTOR exists in two complexes: mTOR complex 1 (mTORC1), which is sensitive to the drug rapamycin and regulates mRNA translation, and mTORC2, which is rapamycininsensitive and regulates the organization of the actin cytoskeleton (reviewed in refs. 8-10). mTORC1 stimulates type I IFN production via phosphorylation of its target proteins 4E-BPs and S6K1/2 (11). Evidence for the critical role of the mTORC1 signaling pathway in innate immunity emerged from the findings that the mTORC1 inhibitor rapamycin suppresses type I IFN in plasmacytoid dendritic cells (pDCs), which are the major producers of systemic type I IFN (12). In addition, genetic deletion of the mTOR downstream target S6K1/2 leads to impaired type I IFN response (see Results). In contrast, we recently found that the lack of the translational repressors 4E-BP1/2 leads to enhanced type I IFN production (13).Oncogenic transformation is associated with a deficient type I IFN response, which constitutes the first line of defense against virus infection (14,15). Oncolytic viruses are studied as effective anticancer agents because they exploit this selective defect (16)(17)(18)(19). One of the best characterized oncolytic viruses, whose replication is extremely sensitive to the inhibition by IFN, is vesicular stomatitis virus (VSV) (20). However, there are several reasons that limit the use of oncolytic viruses for the treatment of MGs. First, some MGs exhibit a robust type I I...

show abstract

Section: Discussionmentioning

confidence: 99%

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Alain

Lun

Martineau

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

108

View full text Add to dashboard Cite

show abstract

“…8 Combination strategies using chemotherapeutic compounds and OVs simultaneously are designed to target and increase cancer cell killing, in part, by modulating the antiviral state of the tumor cell or by enhancing the capacity to stimulate apoptosis and/or cell cycle arrest. [9][10][11][12] Histone deacetylase inhibitors or rapamycin have demonstrated enhanced effects on oncolysis, in part, through their capacity to increase OV replication, by dampening the innate antiviral response. 9,11 Increased therapeutic effect has also been achieved under circumstances when viral replication and spreading are not enhanced.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12] Histone deacetylase inhibitors or rapamycin have demonstrated enhanced effects on oncolysis, in part, through their capacity to increase OV replication, by dampening the innate antiviral response. 9,11 Increased therapeutic effect has also been achieved under circumstances when viral replication and spreading are not enhanced. 10 Tumor cells encountering 5FU at subtoxic concentrations are altered metabolically by the drug; 34 such cellular changes could potentially affect OV permissiveness.…”

Section: Discussionmentioning

confidence: 99%

“…VSV has been used in combination with chemotherapeutic agents such as histone deacetylase inhibitors, BCL-2 inhibitors, rapamycin, doxorubicin and other compounds to enhance therapeutic activity. [9][10][11][12] Limitations arising from the use of chemotherapeutic agents include non-selective toxicity in healthy tissues and development of drug resistance. One way to circumvent these restrictions and to further utilize OV combinations is to incorporate a suicide gene strategy that allows specific gene transduction of tumor cells with nonmammalian enzymes that convert innocuous prodrugs into highly toxic chemotherapeutic compounds within the tumor.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

View full text Add to dashboard Cite

Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MD51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MD51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.

show abstract

“…For example in earlier work, we have shown that treatment of resistant tumour cells with histone deacetylase (HDAC) inhibitors that downregulate IFN-responsive genes 12 leads to increased oncolysis by VSVD51 (ref. 13). More recently, we screened a small molecule library to discover novel enhancers of VSVD51-mediated oncolysis and identified distinct chemical entities that unexpectedly share the common feature of destabilizing microtubules.…”

mentioning

confidence: 99%

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

et al. 2015

Self Cite

View full text Add to dashboard Cite

In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule-destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes.

show abstract

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

Cited by 164 publications

References 49 publications

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing

Contact Info

Product

Resources

About