Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Stewart, Roxana M Rodríguez; Berry, Jameson T L; Berger, Angela K.; Yoon, Sung Bo; Guberman, Jaime A; Patel, Nirav; Tharp, Gregory K.; Bosinger, Steven E.; Mainou, Bernardo A.

doi:10.1101/644815

Cited by 3 publications

(8 citation statements)

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“…2A). Similar to that observed previously (69), r2Reovirus impaired cell viability with faster kinetics than T1L and T3D did not impact cell viability. Treatment of cells with U0126 alone resulted in a dose-dependent cytostatic effect on cell viability, with cell viability leveling at 2 dpi when treated with 10 µM U0126 (red line).…”

Section: Results R2reovirus Impairs Mapk/erk Signalingsupporting

confidence: 88%

“…We previously generated a reassortant reovirus with enhanced infective and cytotoxic properties in TNBC cells (69). The mechanisms through which this virus promotes TNBC cell death is not known.…”

Section: Results R2reovirus Impairs Mapk/erk Signalingmentioning

confidence: 99%

“…The reassortant r2Reovirus is composed of 9 T1L gene segments and an M2 gene segment from T3D in addition to several synonymous and non-synonymous point mutations (69). To determine the contribution of the M2 gene segment to r2Reovirus oncolysis in TNBC cells, reoviruses were engineered by reverse genetics with T1L and T3D M2 gene segment swaps in otherwise isogenic backgrounds (55,70,104,105).…”

Section: Enhanced R2reovirus Oncolysis Maps To the T3d M2 Gene Segmentmentioning

confidence: 99%

“…We previously engineered an oncolytic reovirus with enhanced infective and cytotoxic properties in TNBC (r2Reovirus) (69). Oncolytic r2Reovirus is a reassortant virus with 9 gene segments from serotype 1 Lang (T1L) reovirus and a serotype 3 Dearing (T3D) M2 gene segment, as well as several synonymous and non-synonymous point mutations.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Results R2reovirus Impairs Mapk/erk Signalingsupporting

confidence: 88%

Section: Results R2reovirus Impairs Mapk/erk Signalingmentioning

confidence: 99%

Section: Enhanced R2reovirus Oncolysis Maps To the T3d M2 Gene Segmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Non-canonical cell death by reassortant reovirus

Stewart

Raghuram

Berry³

et al. 2020

Preprint

Self Cite

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“…Bourgeois-Daigneault et al have shown that the Maraba virus exerts an oncolytic effect against BrCa and the anti-tumor efficacy of the virus can be further enhanced by combination with paclitaxel or immune checkpoint inhibitors (ICIs) [61,62]. Also, NDV [63] and reovirus [64] have also shown oncolytic properties in preclinical models of BrCa.…”

Section: Replicating Viruses For Breast Cancer Therapymentioning

confidence: 99%

Viroimmunotherapy for breast cancer: promises, problems and future directions

Chaurasiya

Fong

2020

Cancer Gene Ther

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Virotherapy, a strategy to use live viruses as therapeutics, is a relatively novel field in the treatment of cancer. With the advancements in molecular biology and virology, there has been a huge increase in research on cancer virotherapy. For the treatment of cancer, viruses could be used either as vectors in gene therapy or as oncolytic agents. A variety of viruses have been studied for their potential usage in gene therapy or oncolytic therapy. In this review, we discuss virotherapy with a special focus on breast cancer. Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women worldwide. Current treatments are insufficient to cure metastatic breast cancer and are often associated with severe side effects that further deteriorates patients' quality of life. Therefore, novel therapeutic approaches such as virotherapy need to be developed for the treatment of breast cancer. Here we summarize the current treatments for breast cancer and the potential use of virotherapy in the treatment of the disease. Furthermore, we discuss the use of oncolytic viruses as immunotherapeutics and the rational combination of oncolytic viruses with other therapeutics for optimal treatment of breast cancer. Finally, we outline the progress made in virotherapy for breast cancer and the shortcomings that need to be addressed for this novel therapy to move to the clinic for better treatment of breast cancer.

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Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Stewart

Berry

Berger

et al. 2019

J Virol

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Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule inhibitors, we identified topoisomerase inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with topoisomerase inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells. IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

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Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

Cited by 3 publications

References 85 publications

Non-canonical cell death by reassortant reovirus

Non-canonical cell death by reassortant reovirus

Viroimmunotherapy for breast cancer: promises, problems and future directions

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors

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