RAD001 (Everolimus) Improves the Efficacy of Replicating Adenoviruses that Target Colon Cancer

Homicsko, Krisztian; Lukashev, Alexander N.; Iggo, Richard

doi:10.1158/0008-5472.can-05-0309

Cited by 55 publications

(66 citation statements)

References 52 publications

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“…Another recently used strategy to augment oncolytic virus therapy is to target the tumor microenvironment (Rhim and Tosato, 2007). Inhibition of angiogenesis with bevacizumab, sunitinib, cyclic arginine-glycine-aspartic (cRGD) peptide or mammalian target of rapamycin (mTOR) inhibitors has been reported to enhance the anti-tumor effects of oncolytic viruses (Homicsko et al, 2005;Kurozumi et al, 2007;Libertini et al, 2008;Kottke et al, 2010). Since bortezomib inhibits nuclear factor kB activity, reduces vascular endothelial growth factor (VEGF) levels and decreases angiogenesis (Sunwoo et al, 2001;Nawrocki et al, 2002;Roccaro et al, 2006), modulation of vascular permeability may also account for some of the promising activity observed in vivo with the Reolysin/bortezomib combination.…”

Section: Discussionmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.

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Section: Discussionmentioning

confidence: 99%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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“…Although rapamycin in conjunction with other viruses (e.g., myxoma virus, vaccinia virus, or adenovirus) augment oncolysis (23,(33)(34)(35)(36), the molecular mechanism by which this process occurs remained elusive. Autophagy and the antiangiogenic effect induced by rapamycin were postulated to promote viral oncolysis (35,37). Here we demonstrate that the inhibition of systemic type I IFN production by rapamycin is the primary mechanism by which VSV ΔM51 (and most likely the other oncolytic viruses) exhibits superior therapeutic efficacy against MGs compared with VSV ΔM51 or rapamycin alone.…”

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.

121

108

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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...

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“…One could imagine the creation of similar E4-ORF1 and E4-ORF4 adenoviral mutants that are deficient in activation of mTOR, in order to specifically treat tumors with increased mTOR activity (O'Shea et al, 2005b). Paradoxically, it should be noted that it has also been shown that the mTOR inhibitor RAD001 increases the efficacy of replicating adenoviruses used for colon cancer ablation (Homicsko et al, 2005).…”

Section: Viruses and Mtormentioning

confidence: 99%

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

2006

Oncogene

348

309

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The mammalian target of rapamycin (mTOR) is a serine/ threonine kinase that controls many aspects of cellular physiology, including transcription, translation, cell size, cytoskeletal organization and autophagy. Recent advances in the mTOR signaling field have found that mTOR exists in two heteromeric complexes, mTORC1 and mTORC2. The activity of mTORC1 is regulated by the integration of many signals, including growth factors, insulin, nutrients, energy availability and cellular stressors such as hypoxia, osmotic stress, reactive oxygen species and viral infection. In this review we highlight recent advances in the mTOR signaling field that relate to how the two mTOR complexes are regulated, and we discuss stress conditions linked to the mTOR signaling network that have not been extensively covered in other reviews. Given the diversity of signals that have been shown to impinge on mTOR, we also speculate on other signaltransduction pathways that may be linked to mTOR in the future.

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RAD001 (Everolimus) Improves the Efficacy of Replicating Adenoviruses that Target Colon Cancer

Abstract: Selectively replicating adenoviruses have the potential to cure cancer but have shown little efficacy in clinical trials. We have tested the ability of the mTOR kinase inhibitor RAD001

Cited by 55 publications

References 52 publications

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

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

Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?

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