Methods and compositions for the treatment of cancer
A technology of composition and cancer marker, which is used in the field of cancer treatment and composition, and can solve problems such as inefficiency and failure
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Embodiment 1
[0196] Example 1: Gene knockdown by EpCAM aptamer-siRNA chimera suppresses basal-like triple-negative breast cancer and its tumor-initiating cells
[0197] Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to treat cancer using RNA interference. EpCAM is a tumor-associated antigen highly expressed on common epithelial carcinomas and their tumor-initiating cells (T-ICs, also known as cancer stem cells). Here we demonstrate that an aptamer-siRNA chimera (AsiC, an EpCAM aptamer linked to the sense strand of siRNA and annealed to the antisense strand of siRNA) is selectively taken up and knocked down in EpCAM+ cancer cells in human cancer biopsies and in vitro. Reduced gene expression. PLK1EpCAM-AsiC inhibits colony and mammosphere formation in nude mice (in vitro T-IC assay), as well as by EpCAM+luminal and basal-A triple-negative breast cancer (TNBC) cell lines, but not EpCAM-mesenchymal basal cells -B Tumor in...
Embodiment 2
[0315] This paper describes the development of targeted siRNA delivery (aptamer-siRNA chimera (AsiC)) using chimeric RNAs composed of structured RNAs (termed aptamers) selected for high-affinity binding to covalently linked to siRNA to cell surface proteins. These AsiCs are taken up by cells expressing the receptor, which are recognized by aptamers and processed intracellularly to release active siRNA. This is a flexible platform that can be modified to target different cells by targeting specific cell surface receptors and can be engineered to knock down any gene or combination of genes.
[0316] This aptamer was selected for high affinity binding to human EpCAM (CD326 or ESA) expressed on all epithelial cells, but more highly expressed in breast cancers including poorly differentiated cells such as basal-like TNBC. All common cancers (lung, pancreas, prostate, breast and colon) have high EpCAM expression and can be efficiently targeted.
[0317] Here we demonstrate that ep...
Embodiment 3
[0320] A ubiquitous mechanism for regulating gene expression is called RNA interference. It uses small RNAs loaded with short complementary sequences to block the conversion of genetic information into proteins. Harnessing this endogenous process offers exciting possibilities to treat disease by knocking down the expression of disease-causing genes. The main hurdle is delivering small RNAs into cells where the RNA interference machinery resides. Over the past year, preliminary clinical studies have shown very promising results without significant toxicity in a small number of diseases caused by abnormal gene expression in the liver. However, delivery to the liver (an organ that traps particles in the blood) is easier to achieve than delivering the drug to metastatic tumor cells. Described herein is a strategy for targeting RNA into epithelial cancer cells, which is particularly useful for targeting the most aggressive form of breast cancer, triple-negative breast cancer (TNB...
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