Novel therapy targeting androgen receptor splice variants by inhibiting heat shock factor 1 (HSF1) for the treatment of castration-resistant prostate cancer
| Project/Area Number |
18K16686
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 56030:Urology-related
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| Research Institution | Dokkyo Medical University (2019)
Tokyo Medical and Dental University (2018) |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 前立腺癌 / ホルモン療法 / 化学療法 / 熱ショック因子 / 熱ショックタンパク質 / 去勢抵抗性 / 熱ショック蛋白質 / アンドロゲン受容体 / 去勢抵抗性前立腺癌 |
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| Outline of Final Research Achievements |
Inhibition of the molecular chaperone heat shock protein (HSP) 90 could provide a multifaceted approach to target castration resistant prostate cancer (CRPC) by degrading full-length AR (AR-FL) as well as various oncoproteins. Yet HSP90 inhibition has been shown to be ineffective in degrading AR variants (AR-Vs), suggesting that the stability and function of AR-Vs depend on other molecular chaperones. We tested whether inhibition of heat shock factor 1 (HSF1), the master transcription factor regulating all HSPs, could show antitumor activity by degrading AR-Vs.
Functional knockdown of HSF1 resulted in degradation of both AR-FL and AR-Vs. Among the small molecule library, HSF1 inhibitor triptolide was found to effectively inhibit both AR-FL and AR-Vs at nM concentrations. Triptolide, alone or combined with HSP90 inhibitor STA-9090 showed synergistic antitumor activity on xenograft model of AR-Vs expressing prostate cancer cells.
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| Academic Significance and Societal Importance of the Research Achievements |
高齢化に伴い前立腺癌の患者数は増加の一途を辿っている。去勢抵抗性前立腺癌は根治不能であり、病勢維持に有効な薬剤も限られているため、去勢抵抗性前立腺癌に対する新規治療法の開発は多くの患者に貢献する。本研究は去勢抵抗性前立腺癌に対する新規治療の可能性を示すのみならず、熱ショック因子(HSF1)という抗癌治療における新規標的分子を提唱した点で意義が大きい。
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Report
(3 results)
Research Products
(2 results)
