Glypican‐3 could be an effective target for immunotherapy combined with chemotherapy against ovarian clear cell carcinoma

Suzuki, Shiro; Yoshikawa, Toshiaki; Hirosawa, Tomoya; Shibata, Kiyosumi; Kikkawa, Fumitaka; Akatsuka, Yoshiki; Nakatsura, Tetsuya

doi:10.1111/j.1349-7006.2011.02003.x

Cited by 22 publications

(19 citation statements)

References 35 publications

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“…1A). In addition to these cell lines, the expression of miR-199b-5p was also reduced in other chemoresistant ovarian cancer cell lines: SKOV3, OVCA433 and ES-2 [16-18] (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer

et al. 2013

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Epithelial ovarian cancer is a highly lethal and aggressive gynecological malignancy. The high mortality rate is due in part to the fact that many advanced cancer patients become refractory to current chemotherapeutic agents, leading to tumor recurrence and death. However, the underlying mechanisms leading to chemoresistance remain obscure. Here, we report that the loss of miR-199b-5p due to progressive epigenetic silencing leads to the activation of the JAG1-mediated Notch1 signaling cascade, thereby leading to the development of acquired chemoresistance in ovarian cancer. Using miRCURY LNA™ microRNA array and Q-PCR analyses of two pairs of cisplatin-sensitive and –resistant ovarian cancer cell lines, we identified miR-199b-5p as significantly down-regulated in cisplatin-resistant ovarian cancer cells and confirmed that miR-199b-5p is clinically associated with advanced and poor survival ovarian cancers. Interestingly, the loss of miR-199b-5p could be restored by 5-Aza-dC-mediated demethylation, and methylated specific PCR (MS-PCR), bisulfite-sequencing and pyrosequencing revealed that the promoter region of miR-199b-5p was hypermethylated. Computational and mechanistic analyses identified JAG1 as a primary target of miR-199b-5p. Notably, the reduced expression of miR-199b-5p was found to be inversely correlated with the increased expression of JAG1 using an ovarian cancer tissue array. Enforced expression of miR-199b-5p sensitized ovarian cancer cells to cisplatin-induced cytotoxicity both in vitro and in vivo. Conversely, re-expression of miR-199b-5p and siRNA-mediated JAG1 knockdown or treatment with Notch specific inhibitor γ-secretase (GSI) attenuated JAG1-Notch1 signaling activity, thereby enhancing cisplatin-mediated cell cytotoxicity. Taken together, our study suggests that the epigenetic silencing of miR-199b-5p during tumor progression is significantly associated with acquired chemoresistance in ovarian cancer through the activation of JAG1-Notch1 signaling.

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“…1A). In addition to these cell lines, the expression of miR-199b-5p was also reduced in other chemoresistant ovarian cancer cell lines: SKOV3, OVCA433 and ES-2 [16-18] (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer

et al. 2013

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“…Previous studies have shown that GPC3 is also overexpressed in other malignant tumors, including melanomas, Wilms' tumor, hepatoblastoma, ovarian clear cell carcinoma, and lung squamous cell carcinoma (12,(25)(26)(27)(28). GPC3 might also be an effective target for immunotherapy against these tumors (29,30).…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

Sawada

Yoshikawa

Nobuoka

et al. 2012

Clinical Cancer Research

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Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC.Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-g ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS).Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers a-fetoprotein and/or des-g-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N ¼ 15) than in those with low frequencies (N ¼ 18; P ¼ 0.033).Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.

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“…We confirmed that a GPC3 144–152 peptide-specific CTL clone can recognize HLA-A2-positive and GPC3-positive ovarian CCC cell lines using an IFNγ ELISPOT assay, and that is can kill ovarian CCC cell lines 9 . We are currently conducting a phase II study with a GPC3-derived peptide vaccine in ovarian CCC patients (UMIN-CTR: 000003696).…”

mentioning

confidence: 52%

“…In addition, as the antitumor effect of the peptide vaccine alone is not dramatic in advanced cancer patients, we aim to develop combinational approaches 9 or strong antigen-specific immunotherapies, including adoptive cell transfer approaches following lymphodepletion 10 . Finally, clinical trials of the adoptive cell transfer of GPC3-specific CTLs in patients with HCC in Japan are planned.…”

mentioning

confidence: 99%

A glypican-3-derived peptide vaccine against hepatocellular carcinoma

et al. 2012

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Glypican‐3 could be an effective target for immunotherapy combined with chemotherapy against ovarian clear cell carcinoma

Cited by 22 publications

References 35 publications

Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer

Epigenetic silencing of microRNA-199b-5p is associated with acquired chemoresistance via activation of JAG1-Notch1 signaling in ovarian cancer

Phase I Trial of a Glypican-3–Derived Peptide Vaccine for Advanced Hepatocellular Carcinoma: Immunologic Evidence and Potential for Improving Overall Survival

A glypican-3-derived peptide vaccine against hepatocellular carcinoma

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