A Multi-Pronged Modulation of Signaling Pathways in Targeting Breast Cancer Stem Cells.

Abstract

Emerging evidence suggest that cancer stem cells (CSCs) are an essential target for effective cancer therapy because CSCs drive tumor growth, chemo-resistance, tumor relapse, and metastasis. The goal of this study was to test the hypothesis that deregulation of multiple pathways essential for CSCs selectively targets breast CSCs and thus prevents relapse. To test the hypothesis, two types of drugs under clinical development, 17AAG (Heat shock protein 90 inhibitor) and SAHA (histone deacetylase inhibitor), were selected for their ability to modulate multiple oncogenic signaling pathways. In achieving our goal, the first objective was to evaluate whether 17AAG and SAHA have ability to inhibit breast CSCs. The efficacy of these two drugs in inhibiting CSCs was evaluated by utilizing in vitro and mouse xenograft models. The results support for hypothesis that modulation of multiple proteins and genes that are essential for CSC activity effectively diminishes breast CSCs and abolishes their capability of initiating tumors. In addition, mechanisms through which 17AAG and SAHA take effect in suppressing CSCs were revealed. Since there is no suitable endpoint to evaluate anti-CSC agents in clinical trials, the second objective was to identify an appropriate method to assess the clinical efficacy of anti-CSC agents. The current method to assess clinical efficacy of cancer treatment is to measure shrinkage of bulk tumors. However, CSCs compose small fraction of the cancer cells, so even a complete elimination of CSCs only leads to little reduction in tumor size. For this reason, the use of anti-CSC agents as an adjuvant treatment has been proposed as the most suitable model to assess the efficacy of anti-CSC agents. To compare the extent of clinical benefit to which 17AAG is able to achieve in adjuvant or advanced settings, mouse xenograft models bearing early- or advanced-stage tumors were generated to mimic adjuvant or advanced settings. The results show that the use of an anti-CSC agent (17AAG) as adjuvant therapy substantially inhibited the tumor progression. In conclusion, this study reveals that Hsp90 and HDAC are two potential anti-CSC therapeutic targets and provides evidence that 17AAG, administrated in adjuvant treatment, effectively prevents tumor recurrence.