Abstract 16: Thermal enhancement with optically activated gold nanoshells sensitizes breast cancer stem cells to radiation therapy

Abstract

Abstract Background Metastatic disease and recurrence are hypothesized to result, at least in part, from the residual cancer stem cells (CSCs), also referred to as tumor-initiating cells (TICs), which evade initial treatment. In several genetically engineered mouse (GEM) models that resemble human breast cancer, the tumor subpopulation CD29+/CD24+/lin− has been shown to be more tumorigenic as compared to other subpopulations by both in vitro and in vivo assays. We and others have demonstrated that the tumorigenic CD29+/CD24+/lin− subpopulation repairs radiation-induced DNA strand breaks more efficiently than the other subpopulations. Therefore, we hypothesized that hyperthermia, known to inhibit DNA repair, may radiosensitize CSCs to radiation therapy (RT) by delaying and inhibiting the repair of DNA strand breaks. Methods To test this hypothesis, we assayed for tumorigenic CD29+/CD24+/lin− cells in a p53null mouse mammary tumor model with and without radiation, and in combination with hyperthermia (42°C) administered using optically-activated gold nanoshells. We then determined the percentage of functional CSCs by FACS analysis and limiting dilution transplantation assays. Results These studies confirmed that CD29+/CD24+/lin− cells were more radiation resistant and that their relative proportion was increased after RT, as compared to the other cell populations. In contrast, post-irradiation treatment with 20 minutes of local hyperthermia, using intravenously administered optically activated gold nanoshells, a larger reduction in tumor size was observed, without a concomitant increase in the percentage of CD29+/CD24+/lin− tumorigenic cells. Using functional limiting dilution transplantation assays to assay for CSCs, we demonstrated that 48 hours after treatment cells derived from tumors treated with RT and hyperthermia exhibited a decreased frequency of TICs compared to untreated controls, while in contrast tumors treated with RT alone exhibited an increase in TIC frequency. Thus, there was a 20-fold difference in TIC frequency between the RT only, and RT and hyperthermia treated tumors. Importantly some of the tumors that grew out after radiation and hyperthermia treatment were less aggressive histologically as compared to those treated with radiation alone, which actually displayed a more aggressive histology than mock treated tumors. These results obtained with the GEM model were validated using two different primary triple-negative breast cancer xenografts. Conclusion These results suggest that localized hyperthermia administered using optically-active gold nanoshells serves as a simple strategy to selectively sensitize radioresistant CSCs to enhance their response to radiation therapy. Supported by grants NCI R01 CA112305 and CA16303. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 16.