2009 Fiscal Year Final Research Report
Heat shock protein 90 inhibitors overcome chemoradiotherapy resistance conferred by erbB2 and NFκB overexpression in muscle-invasive bladder cancer
| Project/Area Number |
19791103
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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 |
Urology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
YOSHIDA Sochiro Tokyo Medical and Dental University, 医学部・附属病院, 医員 (80383280)
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| Project Period (FY) |
2007 – 2009
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| Keywords | 浸潤性膀胱癌 / 化学放射線療法 / anti-apoptotic protein |
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| Research Abstract |
Improvement of response of bladder cancer to chemoradiotherapy is expected not only to provide the patients a chance of bladder preservation but to improve their survival outcomes. We identified key molecules responsible for chemoradiotherapy resistance in clinical cohort. In the patients with muscle bladder cancer underwent radiotherapy plus concomitant cisplatin at low-dose (low-dose chemoradiotherapy, LCRT) as an induction therapy prior to curative surgery, overexpression of erbB2 and nuclear NFκB p65 in transurethral biopsy specimens obtained prior to LCRT significantly and independently associates with LCRT resistance. Destabilizing erbB2 and inhibiting nuclear translocation of NFκB by using Heat shock protein 90 (Hsp90) inhibitor; 17-DMAG, sensitizes bladder cancer cell lines (T24, UM-UC-3 and 5637) to in vitro LCRT by enhancing apoptosis. This sensitizing effect was not observed in primarily cultured normal human urothelial (NHU) cells. Pretreatment with Hsp90 inhibitor; 17-AAG, successfully overcame in vivo LCRT resistance of human bladder cancer xenograft of UM-UC-3 bladder cancer cells overexpressing erbB2 and NFκB. Hsp90 inhibitors, simultaneously abrogating erbB2 and NFκB pathways, tumor-selectively sensitize bladder cancer cells to LCRT and overcome LCRT resistance in preclinical models.These results encourage clinical trials of Hsp90 inhibitors adjunct to chemoradiotherapy to improve oncological outcomes and QOL in patients with muscle bladder cancer.
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Research Products
(13 results)
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[Remarks] 受賞:
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[Remarks] (1) Yoshida S, et al. Diffusion-weighted magnetic resonance imaging in diagnosis of upper urinary tract cancer. Prize for the Third Best Abstract (Oncology). Awarded by European Association of Urology, 2010 at 25^<th> Anniversary EAU Congress, Barcelona, Spain, 16-20 April 2010.
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[Remarks] (2) Yoshida S, et al. Best poster presentation award in Poster Session 2: Diffusion-weighted magnetic resonance imaging in diagnosis of upper urinary tract cancer. Awarded by European Association of Urology, 2010.
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[Remarks] (3) Koga F, Kawakami S, Yoshida S, et al. Best poster presentation award in Poster Session 61: Treatment of advanced stage bladder cancer. Awarded by European Association of Urology, 2008.
