Data from Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Our previous data suggest that the PTEN/PI3K/AKT pathway is critical for the <i>in vitro</i>maintenance of CD133<sup>+</sup>/CD44<sup>+</sup> prostate cancer progenitors and, consequently, that targeting PI3K signaling may be beneficial in treatment of prostate cancer.</p><p><b>Results:</b> 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<sup>+</sup>/CD44<sup>+</sup> prostate cancer progenitor cells <i>in vivo</i>. 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.</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 16(23); 5692–702. ©2010 AACR.</i></p></div>