Combination Therapy with Reovirus and ATM Inhibitor Enhances Cell Death and Virus Replication in Canine Melanoma

Igase, Masaya; Shibutani, Shusaku; Kurogouchi, Yosuke; Fujiki, Noriyuki; Hwang, Chung Chew; Coffey, Matt; Noguchi, Shunsuke; Nemoto, Yasuhiro; Mizuno, Takuya

doi:10.1016/j.omto.2019.08.003

Cited by 12 publications

(11 citation statements)

References 61 publications

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“…Combination treatment with SMAC mimetics and oncolytic VSVs enhanced tumor regression via a CD8 + T cell-dependent mechanism [ 94 ]. Moreover, anticancer activity was heightened when OVs were used in combination with either rapamycin [ 95 ], a small molecule inhibitor of ataxia telangiectasia mutated protein (ATM) [ 96 ], or an agonistic antibody targeting immunostimulant 4-1BB [ 97 ].…”

Section: Enhancing the Antitumor Effect By Combination Strategies Incmentioning

confidence: 99%

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

Zhang

Cheng

2020

Mol Cancer

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As a promising therapeutic strategy, oncolytic virotherapy has shown potent anticancer efficacy in numerous pre-clinical and clinical trials. Oncolytic viruses have the capacity for conditional-replication within carcinoma cells leading to cell death via multiple mechanisms, including direct lysis of neoplasms, induction of immunogenic cell death, and elicitation of innate and adaptive immunity. In addition, these viruses can be engineered to express cytokines or chemokines to alter tumor microenvironments. Combination of oncolytic virotherapy with other antitumor therapeutic modalities, such as chemotherapy and radiation therapy as well as cancer immunotherapy can be used to target a wider range of tumors and promote therapeutic efficacy. In this review, we outline the basic biological characteristics of oncolytic viruses and the underlying mechanisms that support their use as promising antitumor drugs. We also describe the enhanced efficacy attributed to virotherapy combined with other drugs for the treatment of cancer.

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Section: Enhancing the Antitumor Effect By Combination Strategies Incmentioning

confidence: 99%

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

Zhang

Cheng

2020

Mol Cancer

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“…programmed cell death by intrinsic and extrinsic apoptosis or necroptosis (36,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57). We did not observe an effect on r2Reovirus-induced cell death in the presence of a RIPK3 inhibitor (data not shown), suggesting that reovirus does not promote TNBC cell death by necroptosis.…”

Section: Downregulation Of Mapk/erk Signaling Can Lead To Apoptosis and Reovirus Can Inducementioning

confidence: 68%

“…Reovirus can induce cell death by apoptosis, necroptosis, cell cycle arrest or autophagy (36,(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Reovirus can trigger apoptosis through recognition of viral nucleic acid by cellular pattern recognition receptors and subsequent activation of caspase 8, Bid cleavage, and disruption of the mitochondrial membrane.…”

Section: Introductionmentioning

confidence: 99%

Non-canonical cell death by reassortant reovirus

Stewart

Raghuram

Berry³

et al. 2020

Preprint

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17Triple-negative breast cancer (TNBC) constitutes 12% of all breast cancer and is 18 associated with worse prognosis compared to other subtypes of breast cancer. Current therapies 19 are limited to cytotoxic chemotherapy, radiation, and surgery, leaving a need for targeted 20 therapeutics to improve outcomes for TNBC patients. Mammalian orthoreovirus (reovirus) is a 21 nonenveloped, segmented, dsRNA virus in the Reoviridae family. Reovirus preferentially kills 22 Importance 38Triple negative breast cancer (TNBC) is unresponsive to hormone therapies, leaving 39 patients afflicted with this disease with limited treatment options. We previously engineered an 40 oncolytic reovirus (r2Reovirus) with enhanced infective and cytotoxic properties in TNBC cells. 41However, how r2Reovirus promotes TNBC cell death is not known. In this study, we show that 42 reassortant r2Reovirus can promote non-conventional caspase-dependent but caspase 3-43 independent cell death and that the mechanism of cell death depends on the genetic composition 44 of the host cell. We also map the enhanced oncolytic properties of r2Reovirus in TNBC to 45 interactions between a Type 3 M2 gene segment and Type 1 genes. Our data show that 46 understanding the interplay between the host cell environment and the genetic composition of 47 49Breast cancer is the leading cause of cancer in women and second leading cause of death 50 by cancer in women in the United States (https://seer.cancer.gov/). Triple-negative breast cancer 51 (TNBC) constitutes 10-15% of breast cancer diagnoses, has a higher rate of relapse, and lower 52 survival after metastasis than other types of breast cancer (1). TNBC is characterized by its lack 53 of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal 54 growth factor receptor 2 (HER-2). These characteristics render TNBC cells unresponsive to 55 hormone therapies that have been efficacious in treating other types of breast cancer (2, 3). 56

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“…When cells receive DNA damage, ATM is phosphorylated by the meiotic recombination 11/DNA repair protein Rad50/Nijmegen breakage syndrome 1 protein (MRN) complex, which is the upstream of ATM, and the phosphorylated ATM activates downstream Chk and p53 cascades [73][74][75][76][77]. Previous reports have shown that, in canine MM cell lines, ATM is phosphorylated via endogenous DNA damage [78]. In this study, p-ATM expression was increased in the dPDPN-knocked-down Mi cell line compared to the control siRNA-treated cells.…”

Section: Discussionmentioning

confidence: 99%

PDPN Is Expressed in Various Types of Canine Tumors and Its Silencing Induces Apoptosis and Cell Cycle Arrest in Canine Malignant Melanoma

Shinada

Kato

Kamoto

et al. 2020

Cells

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Podoplanin (PDPN), a small transmembrane mucin-like glycoprotein, is ectopically expressed. It is also known to be linked with several aspects of tumor malignancy in some types of human tumors, including invasion, metastasis, and cancer stemness. However, there are few reports on the expression of dog PDPN (dPDPN) in canine tumors, and the association between dPDPN and tumor malignancy has not been elucidated. We identified that 11 out of 18 types of canine tumors expressed dPDPN. Furthermore, 80% of canine malignant melanoma (MM), squamous cell carcinoma, and meningioma expressed dPDPN. Moreover, the expression density of dPDPN was positively associated with the expression of the Ki67 proliferation marker. The silencing of dPDPN by siRNAs resulted in the suppression of cell migration, invasion, stem cell-like characteristics, and cell viability in canine MM cell lines. The suppression of cell viability was caused by the induction of apoptosis and G2/M phase cell cycle arrest. Overall, this study demonstrates that dPDPN is expressed in various types of canine tumors and that dPDPN silencing suppresses cell viability through apoptosis and cell cycle arrest, thus providing a novel biological role for PDPN in tumor progression.

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Combination Therapy with Reovirus and ATM Inhibitor Enhances Cell Death and Virus Replication in Canine Melanoma

Cited by 12 publications

References 61 publications

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy

Non-canonical cell death by reassortant reovirus

PDPN Is Expressed in Various Types of Canine Tumors and Its Silencing Induces Apoptosis and Cell Cycle Arrest in Canine Malignant Melanoma

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