Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma
Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma
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DOI：
10.1158/1078-0432.ccr-10-1601
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发表时间：
2010-12-01
影响因子：
11.5
通讯作者：
Schultz, Peter G.
中科院分区：
文献类型：
--
作者：
Dubrovska, Anna;Elliott, Jimmy;Schultz, Peter G.
目的：癌症干细胞假说预测，标准的前列腺癌单一疗法可以消除大量肿瘤细胞，但不能消除肿瘤起始细胞群，最终导致复发。许多研究试图确定实体瘤和癌症干细胞之间的潜在差异。实验设计：我们以前的数据表明，PTEN/PI3K/AKT通路对于CD133(+)/CD44(+)前列腺癌前体细胞的体外维持至关重要，因此，靶向PI3K信号转导可能有助于前列腺癌的治疗。结果：在这里，我们发现双重PI3K/mTOR抑制剂NVP-BEZ235抑制PI3K活性导致体内CD133(+)/CD44(+)前列腺癌前体细胞数量减少。此外，PI3K/mTOR调节剂NVP-BEZ235(消除前列腺癌前体细胞)和化疗药物泰索帝(针对实体瘤)在前列腺癌移植瘤模型中的联合治疗明显比单一疗法更有效。结论：这种联合治疗最终导致具有PTEN E91D突变的癌症前体细胞的扩张，提示对PTEN突变的分析可以预测双重治疗的治疗反应。临床癌症资源；16(23)；5692-702。(C)2010年AACR。
Purpose: The cancer stem cell hypothesis predicts that standard prostate cancer monotherapy eliminates bulk tumor cells but not a tumor-initiating cell population, eventually leading to relapse. Many studies have sought to determine the underlying differences between bulk tumor and cancer stem cells.Experimental Design: Our previous data suggest that the PTEN/PI3K/AKT pathway is critical for the in vitro maintenance of CD133(+)/CD44(+) prostate cancer progenitors and, consequently, that targeting PI3K signaling may be beneficial in treatment of prostate cancer.Results: Here, we show that inhibition of PI3K activity by the dual PI3K/mTOR inhibitor NVP-BEZ235 leads to a decrease in the population of CD133(+)/CD44(+) prostate cancer progenitor cells in vivo. Moreover, the combination of the PI3K/mTOR modulator NVP-BEZ235, which eliminates prostate cancer progenitor populations, and the chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors in a prostate cancer xenograft model than monotherapy.Conclusion: This combination treatment ultimately leads to the expansion of cancer progenitors with a PTEN E91D mutation, suggesting that the analysis of PTEN mutations could predict therapeutic response to the dual therapy. Clin Cancer Res; 16(23); 5692-702. (C)2010 AACR.