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TUMOR CELL MALIGNANT TRANSFORMATION SUPPRESSOR AND ANTI-TUMOR AGENT

Foreign code F170008935
File No. (AF42P001)
Posted date Jan 19, 2017
Country WIPO
International application number 2016JP062757
International publication number WO 2016178374
Date of international filing Apr 22, 2016
Date of international publication Nov 10, 2016
Priority data
  • P2015-093980 (May 1, 2015) JP
Title TUMOR CELL MALIGNANT TRANSFORMATION SUPPRESSOR AND ANTI-TUMOR AGENT
Abstract The present invention provides an anti-tumor agent and a suppressor for suppressing malignant transformation of tumor cells through means such as acquisition of metastasis capability and acquisition of apoptosis resistance. The present invention pertains to: a tumor cell malignant transformation suppressor that suppresses or inhibits acquisition of metastasis capability or acquisition of apoptosis resistance by tumor cells and of which the active ingredient is a substance that suppresses or inhibits the function of the Zic5 gene; a method for suppressing malignant transformation of tumor cells in an animal other than human, wherein acquisition of metastasis capability or acquisition of apoptosis resistance by tumor cells is suppressed or inhibited by suppressing or inhibiting the function of the Zic5 gene; an anti-tumor agent that is used for treating prostate cancer and of which the active ingredient is a substance that suppresses or inhibits the function of the Zic5 gene; and a tumor cell malignancy marker which is the expression level of the Zic5 gene.
Outline of related art and contending technology BACKGROUND ART
Malignant melanoma is, in the melanocytes melanogenic cells with malignant tumor that is cancerous. Healing but with early detection, which causes remoteness in cases as low as 5 - year survival rate is about 10%, effective therapy has not been established (for example, see non-patent document 1 and 2.). In addition, greater than or equal to about 60-70% of the cases BRAFV600E gene also has been confirmed. BRAF downstream MEK (MAPK path MAPKKK) (MAPK path MAPKK) phosphorylate activated, further downstream by activated MEK ERK (MAPK path MAPK) is phosphorylated by activating, growth, survival, invasion, metastasis related to many proteins are activated (for example, see non-patent document 3.). BRAFV600E and strong constitutively BRAF mutation is activated, one cause of melanoma 1 and, at present, with respect to the selective inhibitors of mutant BRAF (PLX4032, vemurafenib) was used in clinical trials, have been confirmed by response rate is high. However, gene expression or splicing variant of BRAF, secreted from the stromal cells such as the expression of hepatocyte growth factor (HGF), by various mechanisms, BRAF inhibitor drug resistance to occur, the effect thereof is limited has been reported (for example, see non-patent document 4-6.).
Epithelial cancers that gains the ability to cause the transition as one of 1, epithelial mesenchymal transformation (Epithelial Mesenchymal Transition; EMT) has been known. Is EMT, epithelial-mesenchymal cell transformation of the cells to obtain phenomenon, resulting in EMT, epithelial cell adhesion molecule expression between E- cadherins is known as the amount of power. In addition, the EMT, Snail, Slug, Twist is controlled by a transcription factor such as the film has been made clear, these factors to control expression of cadherin E- or the like, are known to cause EMT (for example, see non-patent document 7.).
In melanoma, metastasis cases and many EMT is changing expression of the associated gene, one of the causes of transition enhancement EMT program is suggested (for example, see non-patent document 8.). Also, melanoma with mutations in BRAF, Zeb1 by of the constitutively activated BRAF, induced expression of transcription factors such as Twist 1, suppression of expression of the cadherin E- by a factor of these occurs, caused exacerbation of the melanoma cell-like phenomenon has been observed that the EMT (for example, see non-patent document 9.). E - The expression level of cadherin in many melanoma has a reduced, decreased expression of cadherin E- are significantly elevated in cases that the recurrence rate is reported (for example, see non-patent document 10.). These findings suggest that, reduced expression of cadherin E- exacerbation of melanoma and has been suggested to be associated with.
On the other hand, as well as cancer EMT, a critical phenomenon at the time of occurrence of the initial embryos and, the original intestinal intussusception and are involved in the differentiation of neuroepithelial cells. Neuroepithelial cells, part of the dorsal neural tube cause EMT, departing from the epithelial tissue and gains the ability to move, the peripheral nervous system, glial cells, satellite cells, melanocytes, fibroblasts ivory, craniofacial and differentiate into cartilage and the like. In neuroepithelial cells EMT, Snail, Slug, Twist E- by transcription factors such as is induced on the reduced expression of cadherin (for example, see non-patent document 7 and 11.).
Scope of claims (In Japanese)[請求項1]
Zic5遺伝子の機能を抑制又は阻害する物質を有効成分とし、腫瘍細胞の転移性能獲得又はアポトーシス抵抗性獲得を抑制又は阻害する、腫瘍細胞の悪性化抑制剤。
[請求項2]
前記Zic5遺伝子の機能を抑制又は阻害する物質が、Zic5遺伝子を標的とするsiRNAである、請求項1に記載の腫瘍細胞の悪性化抑制剤。
[請求項3]
前記Zic5遺伝子の機能を抑制又は阻害する物質が、Zic5タンパク質とE-カドヘリンをコードする遺伝子のプロモーター配列との相互作用を阻害する物質、Zic5タンパク質の核内局在を阻害する物質、又はZic5タンパク質を分解する物質である、請求項1に記載の腫瘍細胞の悪性化抑制剤。
[請求項4]
前記腫瘍細胞が、メラノーマ細胞又は前立腺がん細胞である、請求項1~3のいずれか一項に記載の腫瘍細胞の悪性化抑制剤。
[請求項5]
前記腫瘍細胞が、BRAF阻害剤耐性を有する、請求項1~4のいずれか一項に記載の腫瘍細胞の悪性化抑制剤。
[請求項6]
ヒト以外の動物の腫瘍細胞の悪性化を抑制する方法であって、
Zic5遺伝子の機能を抑制又は阻害することにより、腫瘍細胞の転移性能獲得又はアポトーシス抵抗性獲得を抑制又は阻害する、腫瘍細胞の悪性化抑制方法。
[請求項7]
Zic5遺伝子の機能の抑制又は阻害を、RNA干渉により、Zic5遺伝子の発現を阻害することにより行う、請求項6に記載の腫瘍細胞の悪性化抑制方法。
[請求項8]
Zic5遺伝子の機能を抑制又は阻害する物質を有効成分とし、メラノーマの治療に用いられる、抗腫瘍剤。
[請求項9]
BRAF阻害剤耐性を有するメラノーマ、又はBRAF阻害剤への治療適性のないメラノーマの治療に用いられる、請求項8に記載の抗腫瘍剤。
[請求項10]
Zic5遺伝子の機能を抑制又は阻害する物質を有効成分とし、前立腺がんの治療に用いられる、抗腫瘍剤。
[請求項11]
前記Zic5遺伝子の機能を抑制又は阻害する物質が、Zic5遺伝子を標的とするsiRNAである、請求項8~10のいずれか一項に記載の抗腫瘍剤。
[請求項12]
Zic5遺伝子の発現量からなる、腫瘍細胞の悪性度マーカー。
[請求項13]
被検腫瘍細胞のZic5遺伝子の発現量をマーカーとし、
被検腫瘍細胞のZic5遺伝子の発現量が多いほど、悪性度が高いと評価する、腫瘍細胞の悪性度の評価方法。
[請求項14]
前記被検腫瘍細胞が原発性腫瘍細胞であり、前記被検腫瘍細胞のZic5遺伝子の発現量が、所定の閾値以上である場合に、前記被検腫瘍細胞が転移性能又はアポトーシス抵抗性を獲得したリスクが高いと評価する、請求項13に記載の腫瘍細胞の悪性度の評価方法。
[請求項15]
Zic5遺伝子の発現量からなり、メラノーマ又は前立腺がんを検出する、腫瘍マーカー。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
  • Inventor
  • FUKAMI Kiyoko
  • SATOW Reiko
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
Reference ( R and D project ) CREST Creation of Innovative Technology for Medical Applications Based on the Global Analyses and Regulation of Disease-Related Metabolites AREA
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