A Novel E1B-55kD-Deleted Oncolytic Adenovirus Carrying Mutant KRAS-Regulated <i>hdm2</i> Transgene Exerts Specific Antitumor Efficacy on Colorectal Cancer Cells

Liu, Chin Cheng; Liu, Jin Hwang; Wu, Shun-Chi; Yen, Chueh Chuan; Chen, Wei Shone; Tsai, Yao‐Chou

doi:10.1158/1535-7163.mct-09-0704

Cited by 4 publications

(5 citation statements)

References 31 publications

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“…Although these CRAds are better than first-generation CRAds, such as onyx-015, they were not very effective in clinical trials when used alone [ 269 ]. To target cancer cells that harbor activating mutant KRAS (KRAS aMut ) but spare p53 wild normal cells, Liu et al [ 270 ] constructed the Δ p53RE P2 promoter with deletion of its p53-response elements. This was used to regulate the expression of the hdm2 transgene in a novel E1B-55kD-deleted CRAd, the Ad-KRhdm2.…”

Section: Strategies For Specific Targeting Of Advmentioning

confidence: 99%

Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity

Hajeri

Sharma

Yamamoto

2020

Cancers

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Cancer is a major health problem. Most of the treatments exhibit systemic toxicity, as they are not targeted or specific to cancerous cells and tumors. Adenoviruses are very promising gene delivery vectors and have immense potential to deliver targeted therapy. Here, we review a wide range of strategies that have been tried, tested, and demonstrated to enhance the specificity of oncolytic viruses towards specific cancer cells. A combination of these strategies and other conventional therapies may be more effective than any of those strategies alone.

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Section: Strategies For Specific Targeting Of Advmentioning

confidence: 99%

Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity

Hajeri

Sharma

Yamamoto

2020

Cancers

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“…Transient transfections of siRNAs and plasmid. HGC-27 cells were plated on 6-well plates at a density of 2x10 5 per well for 24h. Cells were then transiently transfected with 50 nM STAT3 siRNA (si-1:sequences of STAT3 siRNA: sense, GAUACGACUGAGGCGCCUATT; antisense, UAGGCGCAUCAGUCGUAUCTT; si-2:…”

Section: Methodsmentioning

confidence: 99%

“…A large number of preclinical studies have con rmed that OVs could effectively control tumor growth through direct oncolytic killing effect and enhancing anti-tumor immune response, including breast cancer, colorectal cancer, gastric cancer, melanoma, prostate cancer, etc. (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…T1012G studied in this project is a type I herpes simplex virus (HSV-1) which could be genetically engineered easily like T-VEC (16). NV1020, an oncolytic herpes virus (oHSV), has completed phase II clinical trials in the United States, which has shown safety and effectiveness in patients with colon cancer and liver cancer (5). T1012G studied in this project deleted the inserted HSV-2 glycoprotein based on NV1020, which could reduce the pathogenicity of virus.…”

Section: Introductionmentioning

confidence: 99%

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β-adrenergic Receptor Inhibition Enhances Oncolytic Herpes Virus Propagation Through STAT3 Activation in Gastric Cancer

et al. 2021

Preprint

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BackgroundOncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker , on the antitumor efficacy of T1012G virus in gastric cancer models.Results Cell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a 7-fold increase of virus titers compared with T1012G only group (P < 0.001). Moreover, propranolol pretreatment caused sustained tumor regression (335.3± 36.92 mm3 vs. 1118 ± 210.0 mm3, P<0.01) and enhanced the viral propagation (4-fold increase, P < 0.01) compared with T1012G only group. Propranolol pretreatment significantly enhanced the p-STAT3 (2.9-fold, P<0.05) and suppressed p-PKR (65.94% ± 10.11%, P<0.05) compared with T1012G only group. In addition, propranolol could counteract IFN-α/β-mediated inhibition of viral propagation (compared with IFNα: 5.1-fold, P<0.001; IFNβ: 4.6-fold, P<0.01) or enhancement of PKR activation (IFNα: 92.57% ± 1.77%, P<0.001, IFNβ: 99.34%± 0.13% decrease, P<0.001). Conclusions In summary, β-blocker pretreatment could improve the propagation and therapeutic efficacy of T1012G in human gastric cancer by regulating STAT3-PKR signaling cascade, even in the presence of type I IFNs . These data support new strategies of improving the efficacy of OVs in gastric cancer.

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“…OVs can selectively replicate in tumor cells and induce apoptosis without harming adjacent normal tissues (Kaufman et al, 2015). A large number of preclinical studies have confirmed that OVs have activity against a variety of solid tumors, through direct oncolytic killing effects and enhance antitumor immune responses, including against colorectal cancer (Liu et al, 2010;Amagai et al, 2016;Huang et al, 2016;Yang et al, 2016). Despite the development of novel OVs with improved efficacy and tumor selectivity, the limited efficacy of OVs as monotherapeutic agents remains a significant challenge (Kirn et al, 1998;Andtbacka et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

β-Adrenergic Receptor Inhibitor and Oncolytic Herpesvirus Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects on Colorectal Cancer

Chen

et al. 2021

Front. Pharmacol.

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Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, despite the development of novel OVs with improved efficacy and tumor selectivity, their limited efficacy as monotherapeutic agents remains a significant challenge. This study extended our previously observed combination effects of propranolol, a nonselective β-blocker, and the T1012G oncolytic virus into colorectal cancer models. A cell viability assay showed that cotreatment could induce synergistic killing effects on human and murine colorectal cell lines. Moreover, cotreatment caused sustained tumor regression compared with T1012G monotherapy or propranolol monotherapy in human HCT116 and murine MC38 tumor models. The propranolol activity was not via a direct effect on viral replication in vitro or in vivo. Western blotting showed that cotreatment significantly enhanced the expression of cleaved caspase-3 in HCT116 and MC38 cells compared with the propranolol or T1012G alone. In addition, propranolol or T1012G treatment induced a 35.06% ± 0.53% or 35.49% ± 2.68% reduction in VEGF secretion in HUVECs (p < 0.01/p < 0.01). Cotreatment further inhibited VEGF secretion compared with the monotherapies (compared with propranolol treatment: 75.06% ± 1.50% decrease, compared with T1012G treatment: 74.91% ± 0.68%; p＜0.001, p < 0.001). Consistent with the in vitro results, in vivo data showed that cotreatment could reduce Ki67 and enhance cleaved caspase 3 and CD31 expression in human HCT116 and murine MC38 xenografts. In summary, β-blockers could improve the therapeutic potential of OVs by enhancing oncolytic virus-mediated killing of colorectal cancer cells and colorectal tumors.

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A Novel E1B-55kD-Deleted Oncolytic Adenovirus Carrying Mutant KRAS-Regulated hdm2 Transgene Exerts Specific Antitumor Efficacy on Colorectal Cancer Cells

Cited by 4 publications

References 31 publications

Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity

Oncolytic Adenoviruses: Strategies for Improved Targeting and Specificity

β-adrenergic Receptor Inhibition Enhances Oncolytic Herpes Virus Propagation Through STAT3 Activation in Gastric Cancer

β-Adrenergic Receptor Inhibitor and Oncolytic Herpesvirus Combination Therapy Shows Enhanced Antitumoral and Antiangiogenic Effects on Colorectal Cancer

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