| Project/Area Number |
26290060
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Chiba Cancer Center (Research Institute) |
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Principal Investigator |
Nagase Hiroki 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究所長 (90322073)
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| Co-Investigator(Kenkyū-buntansha) |
渡部 隆義 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究員 (60526060)
越川 信子 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究員 (90260249)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | がん / ドライバー遺伝子 / 遺伝子変異 / DNA副溝結合化合物 / ピロールイミダゾールポリアミド / アルキル化剤 / 抗癌治療薬 / がんドライバー遺伝子変異 / 変異遺伝子標的治療 / DNA配列認識化合物 / マイナーグルーブバインダー / KRAS / 免疫チェックポイント阻害 / 遺伝子 / 抗生物質 / 薬学 / ゲノム / 抗がん剤 / 分子標的治療 |
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| Outline of Final Research Achievements |
Critical driver oncogenic proteins, such as RAS and MYC, are difficult therapeutic targets due to the smooth 3D surface. A new approach that directly target driver genes is needed.
Pyrrole-Imidazole polyamide (PIP) specifically recognizes DNA minor groove in a sequence dependent manner. We synthesized a series of PIP-drug conjugates targeting cancer driver genes. PIP conjugates targeting the cancer genome often showed reasonable anti-cancer effect and target gene modification as expected. It is also confirmed the anti-cancer efficacy in mouse models of human cancer with little or no adverse event. Intriguingly, pharmacokinetic studies suggested PIP conjugates showed the enhanced permeability and retention (EPR) like effect, which may take additional advantage of restricted local effects of PI-polyamide conjugates only in tumor and tumor environments for cancer therapeutics.
Thus, PI-polyamide conjugates targeting the mutated cancer genome is a promising strategy for cancer therapeutics.
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