Ryoko Kikuchi

Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers.

OBJECTIVES Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. METHODS Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m(2) of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. RESULTS Overall response rate was 33%, and clinical benefit rate (CR+PD+SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. CONCLUSION The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.

Stathmin is involved in the cooperative effect of Zoledronic acid and gefitinib on bone homing breast cancer cells in vitro

Zoledronic acid (Zol) is the most potent inhibitor of bone resorption among the bisphosphonates and is commonly used for inhibiting bone metastasis. However, it remains unclear whether Zol provides a survival benefit. Recent findings indicate that epidermal growth factor (EGF) signaling is an important mediator of bone metastasis. Thus, we examined the combined effects of Zol and an EGF receptor-tyrosine kinase inhibitor, gefitinib, on the proliferation and invasion of a bone-seeking clone and the breast cancer cell line MDA-MB-231. Combined treatment with Zol and gefitinib synergistically inhibited both invasion and cell proliferation of the bone-seeking clone, but not those of the MDA-MB-231 cells. Two-dimensional difference gel electrophoresis and mass spectrometry demonstrated that stathmin was down-regulated during these cooperative effects. Stathmin is a signal transduction regulatory factor which plays an important role in cell division and malignant tumor development. Our data suggest that stathmin may be a promising target molecule for blocking bone metastasis of breast cancer.

Abstract LB-226: The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma

Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS. In this study, we evaluated the effects of addition of cabozantinib (C) to T and B. Methods: From 2009 to 2015, total 18 patients (pts) with heavily pretreated relapsed ULMS were enrolled. They were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Since 2013, we expected better efficacy, nine pts out of 18 pts were treated by adding C (140mg/body/week) which is a c-MET inhibitor (TB, n = 9, CTB, n = 9). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse events were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: As shown in Table, three (18%) of 17 pts had complete response (CR), two (12%) had partial response (PR) and eight (47%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD>3mo) were 29% and 76%, respectively. The median progression-free survival was 9.6 (3 - 58) months. When compared CTB with TB, CBR was better in CTB (87.5% vs 67%), but the median administration cycles and progression free interval were not improved. Two peritoneal perforation were observed in CTB. Conclusions: Not only TB but also CTB showed remarkable effect in heavily pretreated relapsed ULMS. These results warrant further prospective and randomized studies. Citation Format: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi. The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-226.

Abstract 3948: Proteome analysis of ovarian cancer cell lines under hypoxic conditon by two-dimensional difference gel electrophoresis (2D-DIGE)

The cancer cells which survived hypoxia are known to have aggressive properties and can easily metastasize to other regions, however, the molecular basis of hypoxia-induced changes of cancer cells is not clear. We used a proteomic approach to identify the hypoxia-responsive proteins in 3 ovarian cancer cell lines, KFr13, RMUG-S and ES-2. The cell lines were incubated under lower oxygen concentration (5%) and under normal oxygen concentration (20%) in 48 hours. Even in lower oxygen concentration, the cells survived and increased in number in these 48 hours. The total proteins from the cells were extracted and analysed by 2D-DIGE and MALDI-TOF-MS. We identified the protein, HRP1, whose molecular weight is 71KDa, that all 3 cell lines showed decreased expression under lower oxygen condition compared with normal condition. HRP1 secretion is a growth arrest signal for rat mammary adenocarcionma cells. HRP1 is one of the new candidates for hypoxia-related proteins in ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3948. doi:1538-7445.AM2012-3948

Abstract 318: Hierarchical clustering analysis of array CGH data identifies clinicopathologically distinct groups of lymph-node-negative invasive breast cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL If high-risk group of lymph node-negative (pN0) invasive breast cancer is accurately identified by a molecular diagnosis of biopsy or surgically resected tumor specimens, it would be beneficial for choosing the most appropriate adjuvant or neoadjuvant therapies. In this study, we examined genomic copy-number alterations of the 800 cancer-related genes in 51 pN0 primary invasive breast cancers (20 relapsed and 31 non-relapsed cases) surgically resected from 51 patients at the NCCH, Tokyo, between 1990 and 1994. DNA isolated from acetone-fixed paraffin-embedded tissues using microdissection were labeled directly with fluorescence dyes and subjected to array-based comparative genomic hybridizaton (array-CGH). Although copy number differences between relapsed and non-relapsed cases were unclear, unsupervised hierarchical clustering analysis was by using these 800 cancer-related genes resulted in identification of three cluster groups with significant differences in clinical outcome. Group 1 was mostly (9 of 13) composed ER(−)/HER2(−) cases, group 2 comprised 9 ER(+)/HER2(−), 8 ER(+)/HER2(+), and 6 ER(−)/HER2(+) cases, and group 3 was mostly (12 of 15) composed of ER(+)/HER2(−) cases. By the log-rank test for overall survival (OS), group 1 showed significantly worse outcome than group 2 (p = 0.0138), but no significant difference was observed in relapse-free survival (RFS) between these groups (p = 0.17). Among 20 patients who suffered relapsed later, both OS and RFS rates of group 1 were significantly higher than those of group 2 (p = 0.0083 and 0.0018). Representative genes that amplified in group 1 were CCND2(12p13.32), CDKN1B(12p13.1), whereas those kind genes in group 2 were ERBB2(17q12), NGFR(17q21.33). This work demonstrates that hierarchical clustering of array-CGH data by using 800 cancer related genes can classify pN0 invasive breast cancers into clinically relevant groups and might pave the way to develop a new tool to estimate the risk of relapse and death in patients with pN0 breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 318. doi:10.1158/1538-7445.AM2011-318