Measles virus selectively blind to signaling lymphocyte activity molecule has oncolytic efficacy against nectin‐4‐expressing pancreatic cancer cells

Awano, Mutsumi; Fujiyuki, Tomoko; Shoji, Koichiro; Amagai, Yosuke; Murakami, Yoshinori; Furukawa, Yoichi; Sato, Hiroki; Yoneda, Misako; Kai, Chieko

doi:10.1111/cas.13064

Cited by 35 publications

(23 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently Nectin-4 has been reported to be up-regulated in a variety of cancer cells [ 37 , 38 ]. SLAM-blind MV with only R533A substitution has shown oncologic efficacy on lung and pancreatic cancer cells implanted in severe combined immune deficiency (SCID) mice [ 39 , 40 , 41 ]. Table 3 above shows that five amino acid residues in MVH, Asp507, Asp505, Arg533, Arg556, and Asp530, play pivotal roles in binding to SLAM.…”

Section: Resultsmentioning

confidence: 99%

Computational Analysis of the Interaction Energies between Amino Acid Residues of the Measles Virus Hemagglutinin and Its Receptors

Tanaka

Watanabe

et al. 2018

Viruses

View full text Add to dashboard Cite

Measles virus (MV) causes an acute and highly devastating contagious disease in humans. Employing the crystal structures of three human receptors, signaling lymphocyte-activation molecule (SLAM), CD46, and Nectin-4, in complex with the measles virus hemagglutinin (MVH), we elucidated computationally the details of binding energies between the amino acid residues of MVH and those of the receptors with an ab initio fragment molecular orbital (FMO) method. The calculated inter-fragment interaction energies (IFIEs) revealed a number of significantly interacting amino acid residues of MVH that played essential roles in binding to the receptors. As predicted from previously reported experiments, some important amino-acid residues of MVH were shown to be common but others were specific to interactions with the three receptors. Particularly, some of the (non-polar) hydrophobic residues of MVH were found to be attractively interacting with multiple receptors, thus indicating the importance of the hydrophobic pocket for intermolecular interactions (especially in the case of Nectin-4). In contrast, the electrostatic interactions tended to be used for specific molecular recognition. Furthermore, we carried out FMO calculations for in silico experiments of amino acid mutations, finding reasonable agreements with virological experiments concerning the substitution effect of residues. Thus, the present study demonstrates that the electron-correlated FMO method is a powerful tool to search exhaustively for amino acid residues that contribute to interactions with receptor molecules. It is also applicable for designing inhibitors of MVH and engineered MVs for cancer therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Computational Analysis of the Interaction Energies between Amino Acid Residues of the Measles Virus Hemagglutinin and Its Receptors

Tanaka

Watanabe

et al. 2018

Viruses

View full text Add to dashboard Cite

show abstract

“…The increasing anti-tumour activity of MV-Edm in human adenocarcinoma cells with up-regulated levels of nectin-4 suggested that its expression is correlated with MV-mediated oncolysis [34,35]. …”

Section: Mechanisms Of Specificitymentioning

confidence: 99%

“…In this manner, a miRNA-sensitive measles virus was engineered to target miRNA-7, which is reportedly downregulated in gliomas. While the potency of the oncolytic virus was retained in glioblastoma multiforme xenografts, viral replication was repressed in normal brain tissue, where miRNA-7 is ubiquitously expressed [35]. Moreover, to achieve “detargeting” of multiple vital organs during the systemic administration of oncolytic MV, a triple-miRNA-sensitive virus was developed targeting miRNA-7, miRNA-122 and miRNA148a, commonly expressed in brain tissues, liver and gastrointestinal organs, respectively [57].…”

Section: Engineering Oncolytic Measles Virusmentioning

confidence: 99%

Measles to the Rescue: A Review of Oncolytic Measles Virus

Aref

Bailey

Fielding

2016

Viruses

109

View full text Add to dashboard Cite

Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and “blinding” the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.

show abstract

“… 18 , 19 , 20 , 21 We expected that rMV-SLAMblind selectively targets and kills nectin-4 positive tumor cells and demonstrated that rMV-SLAMblind shows anti-tumor effects against various cell lines expressing nectin-4 derived from breast, lung, pancreas, and colorectal cancer. 16 , 22 , 23 , 24 …”

Section: Introductionmentioning

confidence: 99%

Recombinant SLAMblind Measles Virus Is a Promising Candidate for Nectin-4-Positive Triple Negative Breast Cancer Therapy

Fujiyuki

Amagai

Shoji

et al. 2020

Molecular Therapy - Oncolytics

Self Cite

View full text Add to dashboard Cite

One of the most refractory breast cancer types is triple negative (TN) breast cancer, in which cells are resistant to both hormone and Herceptin treatments and, thus, often cause recurrence and metastasis. Effective treatments are needed to treat TN breast cancer. We previously demonstrated that rMV-SLAMblind, a recombinant measles virus, showed anti-tumor activity against breast cancer cells. Here, we examined whether rMV-SLAMblind is effective for treating TN breast cancer. Nectin-4, a receptor for rMV-SLAMblind, was expressed on the surface of 75% of the analyzed TN breast cancer cell lines. rMV-SLAMblind infected the nectin-4-expressing TN breast cancer cell lines, and significantly decreased the viability in half of the analyzed cell lines in vitro . Additionally, intratumoral injection of rMV-SLAMblind suppressed tumor growth in xenografts of MDA-MB-468 and HCC70 cells. To assess treatment for metastatic breast cancer, we performed intravenous administration of the luciferase-expressing-rMV-SLAMblind to MDA xenografted mice. Virus replicated in the tumor and resulted in significant suppression of the tumor growth. The safety of the virus was tested by its intravenous injection into healthy cynomolgus monkeys, which did not cause any measles-like symptoms. These results suggest that rMV-SLAMblind is a promising candidate as a therapeutic agent for treating metastatic and/or TN type breast cancer.

show abstract

Measles virus selectively blind to signaling lymphocyte activity molecule has oncolytic efficacy against nectin‐4‐expressing pancreatic cancer cells

Cited by 35 publications

References 27 publications

Computational Analysis of the Interaction Energies between Amino Acid Residues of the Measles Virus Hemagglutinin and Its Receptors

Computational Analysis of the Interaction Energies between Amino Acid Residues of the Measles Virus Hemagglutinin and Its Receptors

Measles to the Rescue: A Review of Oncolytic Measles Virus

Recombinant SLAMblind Measles Virus Is a Promising Candidate for Nectin-4-Positive Triple Negative Breast Cancer Therapy

Contact Info

Product

Resources

About