2010 Fiscal Year Final Research Report
Anti-tumor activity of p110 isoform selective inhibitors targeting Ras-PI3K pathway.
| Project/Area Number |
21791544
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
ODA Katsutoshi The University of Tokyo, 医学部附属病院, 助教 (30359608)
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| Project Period (FY) |
2009 – 2010
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| Keywords | Ras / PI3K / SNPタイピングアレイ法 / 染色体不安定性 / 染色体コピー数異常 / 予後不良因子 / AKT1 / 子宮体癌 |
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| Research Abstract |
We elucidated various factors involved in the Ras-PI3K pathway activation through genome-wide comprehensive survey in endometrial carcinomas. In addition, we evaluated anti-tumor activity of an mTOR inhibitor in endometrial cancer cell lines.
1. We published the first report showing oncogenic mutation of AKT1 (E17K) mutation in endometrial cancer samples. We detected AKT1 (E17K) mutations in two out of the 89 endometrial carcinomas (2.2%). These two AKT1 mutant tumors do not possess any other mutations in PIK3CA, PTEN and K-Ras in the Ras-PI3K pathway.
2. We performed a comprehensive genomic survey in 31 endometrial carcinomas for chromosomal imbalances, microsatellite instability (MSI) status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 29%, one to four changes (CIN-intermediate) in 55%, and no changes (CIN-negative) in 16%. Positive MSI was less common in CIN-extensive tumors, compared with CIN-intermediate/negative tumors. Multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. We demonstrated that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability.
3. We added RAD001 (everolimus, an mTOR inhibitor) to 13 endometrial cancer cell lines. We confirmed by MTT assay that RAD001 suppressed cell proliferation in these cells, especially in ten out of the eleven cell lines with mutations of PIK3CA, PTEN and/or K-Ras in the Ras-PI3K pathway.
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Research Products
(38 results)
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[Journal Article] Multifunctional transcription factor TFII-I is an activator of BRCA1 function.2010
Author(s)
Tanikawa M, Wada-Hiraike O, Nakagawa S, Shirane A, Hiraike H, Koyama S, Miyamoto Y, Sone K, Tsuruga T, Nagasaka K, Matsumoto Y, Ikeda Y, Shoji K, Oda K, Fukuhara H, Nakagawa K, Kato S, Yano T, Taketani Y.
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Journal Title
Br J Cancer 104
Pages: 1349-1355
Peer Reviewed
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[Journal Article] Oral immunization with a Lactobacillus casei vaccine expressing human papillomavirus (HPV) type 16 E7 is an effective strategy to induce mucosal cytotoxic lymphocytes against HPV16 E7.2010
Author(s)
Adachi K, Kawana K, Yokoyama T, Fujii T, Tomio A, Miura S, Tomio K, Kojima S, Oda K, Sewaki T, Yasugi T, Kozuma S, Taketani Y
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Journal Title
Vaccine 28
Pages: 2810-2817
Peer Reviewed
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[Journal Article] Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway.2010
Author(s)
Murayama Hosokawa S, Oda K, Nakagawa S, Ishikawa S, Yamamoto S, Shoji K, Ikeda Y, Uehara Y, Fukayama M, McCormick F, Yano T, Taketani Y, Aburatani H
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Journal Title
Oncogene 29
Pages: 1897-1908
Peer Reviewed
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[Journal Article] Repression of estrogen receptor beta function by putative tumor suppressor DBC1.2010
Author(s)
Koyama S, Wada Hiraike O, Nakagawa S, Tanikawa M, Hiraike H, Miyamoto Y, Sone K, Oda K, Fukuhara H, Nakagawa K, Kato S, Yano T, Taketani Y
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Journal Title
Biochem Biophys Res Commun 392
Pages: 357-362
Peer Reviewed
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[Journal Article] Identification of DBC1 as a transcriptional repressor for BRCA1.2010
Author(s)
Hiraike H, Wada Hiraike O, Nakagawa S, Koyama S, Miyamoto Y, Sone K, Tanikawa M, Tsuruga T, Nagasaka K, Matsumoto Y, Oda K, Shoji K, Fukuhara H, Saji S, Nakagawa K, Kato S, Yano T, Taketani Y
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Journal Title
Br J Cancer 102
Pages: 1061-1067
Peer Reviewed
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[Journal Article] Reply, Somatic mutations are present in all members of the AKT family in endometrial carcinoma.2009
Author(s)
Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike Wada O, Nei T, Kawana K, Kuramoto H, Aburatani H, Yano T, Taketani Y
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Journal Title
Br J Cancer. 101
Pages: 1220-1221
Peer Reviewed
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[Journal Article] The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas.2009
Author(s)
Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike Wada O, Nei T, Kawana K, Kuramoto H, Aburatani H, Yano T, Taketani Y
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Journal Title
Br J Cancer. 101
Pages: 145-148
Peer Reviewed
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