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

Authors:
  • ADAnna Dubrovska
    Anna Dubrovska
  • JEJimmy Elliott
    Jimmy Elliott
  • RSRichard J. Salamone
    Richard J. Salamone
  • SKSungeun Kim
    Sungeun Kim
  • LALindsey J. Aimone
    Lindsey J. Aimone
  • JWJohn R. Walker
    John R. Walker
  • JWJames Watson
    James Watson
  • MSMaira Sauveur-Michel
    Maira Sauveur-Michel
  • CGCarlos Garcia-Echeverria
    Carlos Garcia-Echeverria
  • CCCharles Y. Cho
    Charles Y. Cho
  • VRVenkateshwar A. Reddy
    Venkateshwar A. Reddy
  • PSPeter G. Schultz
    Peter G. Schultz
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Abstract
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 vitromaintenance 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. ©2010 AACR.