P0059 Induction of apoptosis in breast cancer cells through combined intracellular delivery of a tumour-suppressor gene and small interfering RNAs against growth factor receptor and anti-apoptotic genes

Abstract

Background The mechanisms underlying the development of breast cancer are complex and vary among individual tumours. These mechanisms include genetic and epigenetic alterations and resulting changes in the activity of signalling pathways. Current treatment strategies for metastatic breast cancer (MBC) depend upon patient and tumour classification; menopausal status, hormone receptor status, and HER2 status can all be considered, as can site of metastatic disease (bone or soft tissue). The choice of treatment in metastatic disease usually involves systemic endocrine therapy or cytotoxic chemotherapy, with an anti-HER2 agent when appropriate. Novel agents are needed because many of the current therapies have limitations. These include drug resistance, lack of target receptor expression in tumours (e.g., only 25% of breast cancer tumours have HER2 expression), lack of specificity, and relatively small improvements in survival. Advances in the understanding of the aetiology and biology of breast cancer have identified key targets among the multiple signalling pathways involved in the development, growth, and survival of breast cancer cells. As such, targeted therapies are among the most promising new agents for the treatment of breast cancer. Methods The main objective of the project is the restoration of p53 activity and the silencing of HER2, EGFR, and IGF1 genes through the delivery of normal p53 gene and specific validated siRNA, respectively, using carbonate apatite nanoparticles both in vitro and in vivo. Concurrently, the sensitivity of breast cancer cells to the traditional anti-cancer drugs, such as doxorubicin, cisplatin, and paclitaxel will be tested following individually and combined delivery p53 gene and the siRNAs against both growth factor receptor genes and anti-apoptotic genes. Findings The in vitro analysis of siRNAs together and in combination with p53 and anticancer drugs helped to identify potential targets for the treatment of breast cancer. Interpretation Preclinical studies in animal models of breast cancer should be done through tumour-targeted delivery of siRNA in combination with passively diffusible anti-cancer drugs and p53.