Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples

Nuovo, Gerard J.; Garofalo, Michela; Valeri, Nicola; Roulstone, Vicki; Volinia, Stefano; Cohn, David E.; Phelps, Mitch A.; Harrington, Kevin; Vile, Richard G.; Melcher, Alan; Galanis, Evanthia; Sehl, Sarah; Adair, R.; Scott, Karen J.; Rose, Ailsa; Toogood, Giles J.; Coffey, Matthew

doi:10.1038/modpathol.2012.95

Cited by 48 publications

(45 citation statements)

References 25 publications

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“…19 We grew SiHa (1 HPV DNA copy/cell), HeLa (20 HPV DNA copies/cell), and Caski (hundreds of HPV DNA copies/cell) in DMEM media until 75% confluent, then fixed the cells in 10% buffered formalin overnight, washed the cells several times, then processed them for immunohistochemistry and in situ hybridization analyses.…”

Section: Cell Culturementioning

confidence: 99%

“…18,19 In brief, after using a standard optimization protocol, that included positive controls known to have the target of interest, we tested each tissue for CD8 (Ventana Medical System), PD L1 and PD1 (each from ABCAM). Selected cases that showed strong PD L1 expression and that had sufficient remaining tissue were also tested for CD3, CD68, CD45, CD 117, Ki67, CD45RO, and CD20 (each from Ventana Medical System) as well as RANTES and granyzme B (Enzo Life Sciences).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…19 In brief, a given tissue was tested for two different antigens using fast red as the chromogen for one target followed by immunohistochemistry using DAB (brown) as the second chromogen with hematoxylin as the counterstain. The results were then analyzed by the Nuance and InForm systems in which each chromogenic signal is separated and converted to a fluorescence based signal, then mixed to determine what percentage of cells were expressing the two proteins of interest.…”

Section: Co-expression Analysismentioning

confidence: 99%

“…18,19 The presence of HPV was determined using the PathoGene Alkaline Phosphatase NBT/BCIP human papillomavirus in situ typing assay for tissue sections (Enzo Life Sciences, Farmingdale, NY).…”

Section: In Situ Hybridizationmentioning

confidence: 99%

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Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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Programmed death ligand 1 (PD L1) expression can reduce the immune response in both infectious diseases and cancers. We thus examined PD L1 expression in cervical intraepithelial neoplasias (CINs) and cancers since they each reflect infection by human papillomavirus (HPV). PD L1 protein was not evident by immunohistochemistry in histologically normal cervical epithelia (0/55) even when adjacent to CIN or cancer. PD L1 expression was much increased in CINs (20/21 = 95%) and cervical squamous cell cancer (56/70 = 80%) and localized to the dysplastic/neoplastic squamous cells and mononuclear cells, respectively. There was also a significant increase (each Po0.001) in PD L1 detection in mononuclear cells when comparing cervical squamous cell cancers to endometrial (22/115 = 19%) and ovarian adenocarcinomas (5/40 = 13%). Co-expression analyses showed that the primary inflammatory cell that contained PD L1 was the CD8+ lymphocyte that strongly concentrated around the dysplastic CIN cells and nests of invasive squamous cancer cells. These data show that PD L1 is a solid biomarker of productive HPV infection of the cervix and that it is significantly upregulated in both the carcinoma and surrounding inflammatory cells in cervical cancer when compared with other gynecologic malignancies. This suggests that anti-PD L1 therapy may have a role in the treatment of cervical cancer.

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Section: Cell Culturementioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Co-expression Analysismentioning

confidence: 99%

Section: In Situ Hybridizationmentioning

confidence: 99%

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Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

et al. 2015

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“…The viral capsid proteins, including the viral adhesin molecules s1 and s1s, trigger apoptotic pathways characterized by activation of initiator caspases-8 and -9 and release of cytochrome c and Smac/ DIABLO into the cytosol (29). Efforts to elucidate the exact signaling networks that culminate in tumor cell apoptosis are ongoing (30,31). The immunomodulatory impact of reovirus infection is gaining prominence as a mechanism of oncolysis (32).…”

Section: Mechanism Of Tumor Lysismentioning

confidence: 99%

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

Zhao

Chester

Rajasekaran

et al. 2016

Molecular Cancer Therapeutics

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The dominant cancer treatment modalities such as chemotherapy, radiotherapy, and even targeted kinase inhibitors and mAbs are limited by low efficacy, toxicity, and treatmentresistant tumor subclones. Oncolytic viral therapy offers a novel therapeutic strategy that has the potential to dramatically improve clinical outcomes. Reovirus, a double-stranded benign human RNA virus, is a leading candidate for therapeutic development and currently in phase III trials. Reovirus selectively targets transformed cells with activated Ras signaling pathways; Ras genes are some of the most frequently mutated oncogenes in human cancer and it is estimated that at least 30% of all human tumors exhibit aberrant Ras signaling. By targeting Rasactivated cells, reovirus can directly lyse cancer cells, disrupt tumor immunosuppressive mechanisms, reestablish multicellular immune surveillance, and generate robust antitumor responses. Reovirus therapy is currently being tested in combination with radiotherapy, chemotherapy, immunotherapy, and surgery. In this review, we discuss the current successes of these combinatorial therapeutic strategies and emphasize the importance of prioritizing combination oncolytic viral therapy as reovirus-based treatments progress in clinical development.

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Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS‐activated tumors

Villalona‐Calero

Lam

Otterson

et al. 2015

Cancer

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BACKGROUND The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents. METHODS This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)–mutated/amplified non–small cell lung cancer. RESULTS Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m2 for paclitaxel on day 1, and 3×1010 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m2 for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months. CONCLUSIONS Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration.

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Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples

Cited by 48 publications

References 25 publications

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

Enhanced expression of PD L1 in cervical intraepithelial neoplasia and cervical cancers

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS‐activated tumors

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