Oncolytic Adenovirus for the Targeting of Paclitaxel-Resistant Breast Cancer Stem Cells

Area of Science:

• Oncolytic virotherapy
• Cancer stem cell biology
• Molecular oncology

Background:

• Adjuvant therapies reduce breast cancer recurrence, but resistance emerges due to breast cancer stem cells (BCSCs).
• Oncolytic adenoviruses (OAds) show potential for cancer cell targeting, but their efficacy against BCSCs is not well understood.

Purpose of the Study:

• To evaluate a modified oncolytic adenovirus (OAd-hNIS) for targeting breast cancer stem cells (BCSCs).
• To assess the potential of OAd-hNIS in overcoming therapy resistance and reducing breast cancer recurrence and metastasis.

Main Methods:

• Utilized a Cox-2 promoter-controlled, Ad5/3 fiber-modified OAd encoding human sodium iodide symporter (hNIS).
• Employed BCSC-enriched estrogen receptor-positive (ER+), paclitaxel-resistant (TaxR) cells and tumorsphere assays.
• Assessed OAd-hNIS binding, oncolysis, hNIS expression, and efficacy in inhibiting tumorsphere formation and reversing paclitaxel resistance.

Main Results:

• OAd-hNIS demonstrated enhanced binding and superior oncolysis in breast cancer cells, including ER+ cells, with no activity in normal cells.
• Adenovirus death protein deletion improved NIS expression.
• OAd-hNIS effectively targeted TaxR BCSCs, showing superior killing and hNIS expression compared to parental cells.
• The vector inhibited tumorsphere formation, reversed paclitaxel resistance, and destroyed established tumorspheres.

Conclusions:

• OAd-hNIS shows significant potential as a therapeutic agent against therapy-resistant ER+ breast cancer stem cells.
• This approach may offer a new strategy for studying and targeting breast cancer recurrence and metastasis.
• OAd-hNIS efficacy in targeting BCSCs warrants further investigation for clinical applications.