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Sudo T.,Section of Translational Research | Sudo T.,Hyogo Cancer Center | Oka N.,Section of Translational Research | Mikami Y.,Kyoto University
International Journal of Gynecological Cancer | Year: 2013

Objective: Cervical cancer is the second most common cancer in females worldwide, and the majority of squamous cell carcinomas and adenocarcinomas are associated with highrisk human papillomavirus (HPV) infection. However, the relationship between clear cell carcinoma of the cervix (CCCC) and HPV is unclear. In this study, we sought to determine if HPV infection is associated with CCCC and to elucidate the signaling pathways involved. Methods: We collected samples from 13 CCCC patients and collated the relevant clinicopathologic data.We then evaluated the presence of HPV types 16, 18, 31, 33, 35, 52, and 58 by broad-spectrum amplification by polymerase chain reaction and HPV types 39, 45, 51, 56, 59, and 68 by nested polymerase chain reaction assay that combines degenerate E6/E7 consensus primers and type-specific primers from extracted genomic DNA. Immunohistochemistry was used to analyze the expression of EGFR (epidermal growth factor receptor), HER2, PTEN (phosphatase and tensin homolog), phospho-AKT, phospho-mTOR (mammalian target of rapamycin), p16INK4a, and p53. EGFR and HER2 gene amplification was determined by fluorescence in situ hybridization. Results: Patients with stage IB CCCC had a better 3-year overall survival rate compared with those with advanced-stage cancer (100% vs 44%; P = 0.014). High-risk HPVs were not detected in any of the cases examined. EGFR immunostaining was observed in 9 (75%) of 12 patients, HER2 in 3 (25%) of 12, PTEN in 6 (50%) of 12, and phospho-AKT in 7 (58%) of 12, and phospho-mTOR in 6 (50%) of 12. EGFR amplification could not be detected, but HER2 amplification was identified in 1 of (12.5%) 8 cases. Conclusions: Patients with stage I CCCC demonstrated good overall survival and rare recurrence. Clear cell carcinoma of the cervix is unrelated to high-risk HPVinfection; hence, current vaccines will not prevent the incidence of CCCC. However, increased EGFR or HER2 expression or activation of AKT or mTOR was observed in all cases, indicating that inhibitors of tyrosine kinases or the AKT-mTOR pathway may be suitable treatment regimens for CCCC. © 2013 by IGCS and ESGO.

Andoh T.,Kobe Gakuin University | Fujimoto T.,Hyogo Cancer Center | Sudo T.,Section of Translational Research | Suzuki M.,Kyoto University | And 9 more authors.
Applied Radiation and Isotopes | Year: 2014

Clear cell sarcoma (CCS) is a rare malignant tumor with a poor prognosis. In our previous study, the tumor disappeared under boron neutron capture therapy (BNCT) on subcutaneously-transplanted CCS-bearing animals. In the present study, the tumor disappeared under this therapy on model mice intramuscularly implanted with three different human CCS cells. BNCT led to the suppression of tumor-growth in each of the different model mice, suggesting its potentiality as an alternative to, or integrative option for, the treatment of CCS. © 2013 Elsevier Ltd.

Sudo T.,Section of Translational Research
International Journal of Clinical Oncology | Year: 2012

Ovarian cancer accounts for approximately 4% of cancer deaths in women worldwide, with around 225,000 estimated new cases diagnosed each year and 140,000 related deaths. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stages of the disease; consequently, 50% of cases present with advanced metastatic cancer, and 5-year survival rates are limited to 10-30%. Furthermore, disease recurrence occurs in a high proportion of cases, and the survival rate is only 30% even in patients who are sensitive to platinum-based chemotherapy. This review describes the increased characterization of the molecular mechanisms involved in the development and progression of ovarian cancer, and how this has resulted in improved therapeutic strategies with molecular-targeted agents. These include targeting BRCA mutations to affect DNA repair, inhibition of the mTOR and MAPK pathways, and anti-angiogenesis therapies. Ultimately, personalized therapy using novel biomarkers in parallel with improved early detection techniques could significantly enhance the prognosis of ovarian cancer patients. © Japan Society of Clinical Oncology 2012.

Tanioka M.,Hyogo Cancer Center | Tanioka M.,Kobe University | Sakai K.,Kinki University | Sudo T.,Section of Translational Research | And 8 more authors.
Breast Cancer Research and Treatment | Year: 2014

Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P ≤ 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients. © 2014, Springer Science+Business Media New York.

Shigetomi H.,Nara Medical University | Sudo T.,Section of Translational Research | Shimada K.,Nara Medical University | Uekuri C.,Nara Medical University | And 6 more authors.
International Journal of Gynecological Cancer | Year: 2014

Objective: Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1β (HNF-1β) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1β in regulation of the cell cycle in CCA. Methods: To clarify the effects of HNF-1β on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF- 1A had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1β (+) cells were arrested in G2 phase because of DNA damage. Results: HNF-1β (j) cells died because of a checkpoint mechanism. G2 arrest of HNF-1β (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1β (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damageY induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. Conclusions: The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA. Copyright © 2014 by IGCS and ESGO.

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