Abstract 3907: Targeting cancer stem cells with microRNA therapeutics and particle radiation in challenging cancer models

Abstract

Abstract Remarkable progress has been made in the understanding and treatment of human cancer, resulting in greatly improved survival for many patients. However, such achievements remain incomplete or out of reach for some hard-to-treat cancers, such as pancreatic cancer or triple-negative breast cancer. Chondrosarcoma is resistant to conventional radiation therapy and to chemotherapy. Innovative approaches focusing on those challenging cancer models are therefore highly expected. There is now wide acknowledgment that tumors are generally heterogeneous and that cancer treatment failure, relapse or metastasis may be related a small population of stem-like cells that are capable of self-renewing and of causing the different lineage of cancer cells comprising a tumor. These cancer stem cells (CSCs) are more radio-resistant than their non-CSC counterparts and have a distinct molecular signature. CSCs and differentiated cancer cells seem to coexist in a dynamic equilibrium influenced by the micro-environment and by specific micro-RNA expression patterns. The development of new therapeutic strategies (such as micro-RNA modulating strategies) that selectively target CSCs is currently receiving increasing attention. Particle radiation therapy (such as carbon-ion therapy) is effective at treating various radioresistant tumors and has already achieved promising results. Approaches combining high-LET radiation therapy and targeted-therapy have been suggested for tumors with bad prognosis.We have described a new molecular pathway in basal-like breast cells, resulting in the generation of breast CSCs. Maintenance of the CSC phenotype required the downregulation of miR-29 expression and the upregulation of Klf4 expression. Restoring miR-29 with mimic administration might therefore improve breast cancer therapy efficiency by targeting CSCs. For those reasons, we have evaluated the ability of several microRNA-modulating treatments to reverse CSC phenotype in three experimental in vitro models (pancreatic cancer, chondrosarcoma, triple-negative breast cancer), in combination with exposure spread-out Bragg peak (SOBP) carbon-ion beam (at the HIMAC medical accelerator). In triple-negative breast cells, miR-29 mimic administration increased radiation-induced cell death and decreased the proportion of CSCs. We identified several other microRNA mimic treatments capable of improving carbon-ion therapy efficiency by targeting radioresistant CSCs in those experimental models. Citation Format: Guillaume Vares, Yannick Saintigny, Sei Sai, Hirotaka Sugawara, Tetsuo Nakajima. Targeting cancer stem cells with microRNA therapeutics and particle radiation in challenging cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2017-3907