TY - JOUR
T1 - siRNA therapeutics for breast cancer
T2 - recent efforts in targeting metastasis, drug resistance, and immune evasion
AU - Ngamcherdtrakul, Worapol
AU - Yantasee, Wassana
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/12
Y1 - 2019/12
N2 - Small interfering RNA (siRNA) has an established and precise mode of action to achieve protein knockdown. With the ability to target any protein, it is very attractive as a potential therapeutic for a plethora of diseases driven by the (over)expression of certain proteins. Utilizing siRNA to understand and treat cancer, a disease largely driven by genetic aberration, is thus actively investigated. However, the main hurdle for the clinical translation of siRNA therapeutics is to achieve effective delivery of siRNA molecules to tumors and the site of action, the cytosol, within cancer cells. Several nanoparticle delivery platforms for siRNA have been developed. In this Review, we describe recent efforts in developing siRNA therapeutics for the treatment of cancer, with particular emphasis on breast cancer. Instead of conventionally targeting proliferation and apoptosis aspects of tumorigenesis, we focus on recent attempts in targeting cancer's metastasis, drug resistance, and immune evasion, which are considered more challenging and less manageable in clinics with current therapeutic molecules. siRNA can target all proteins, including traditionally undruggable proteins, and is thus poised to address these clinical challenges. Evidence also suggests that siRNA can be superior to antibodies or small molecule inhibitors when inhibiting the same druggable pathway. In addition to cancer cells, the role of the tumor microenvironment has been increasingly appreciated. Components in the tumor microenvironment, particularly immune cells, and thus siRNA-based immunotherapy, are under extensive investigation. Lastly, multiple siRNAs with or without additional drugs can be codelivered on the same nanoparticle to the same target site of action, maximizing their potential synergy while limiting off-target toxicity.
AB - Small interfering RNA (siRNA) has an established and precise mode of action to achieve protein knockdown. With the ability to target any protein, it is very attractive as a potential therapeutic for a plethora of diseases driven by the (over)expression of certain proteins. Utilizing siRNA to understand and treat cancer, a disease largely driven by genetic aberration, is thus actively investigated. However, the main hurdle for the clinical translation of siRNA therapeutics is to achieve effective delivery of siRNA molecules to tumors and the site of action, the cytosol, within cancer cells. Several nanoparticle delivery platforms for siRNA have been developed. In this Review, we describe recent efforts in developing siRNA therapeutics for the treatment of cancer, with particular emphasis on breast cancer. Instead of conventionally targeting proliferation and apoptosis aspects of tumorigenesis, we focus on recent attempts in targeting cancer's metastasis, drug resistance, and immune evasion, which are considered more challenging and less manageable in clinics with current therapeutic molecules. siRNA can target all proteins, including traditionally undruggable proteins, and is thus poised to address these clinical challenges. Evidence also suggests that siRNA can be superior to antibodies or small molecule inhibitors when inhibiting the same druggable pathway. In addition to cancer cells, the role of the tumor microenvironment has been increasingly appreciated. Components in the tumor microenvironment, particularly immune cells, and thus siRNA-based immunotherapy, are under extensive investigation. Lastly, multiple siRNAs with or without additional drugs can be codelivered on the same nanoparticle to the same target site of action, maximizing their potential synergy while limiting off-target toxicity.
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U2 - 10.1016/j.trsl.2019.08.005
DO - 10.1016/j.trsl.2019.08.005
M3 - Review article
C2 - 31487500
AN - SCOPUS:85071970498
SN - 1931-5244
VL - 214
SP - 105
EP - 120
JO - Translational Research
JF - Translational Research
ER -