Precise targeting of POLR2A as a therapeutic strategy for human triple negative breast cancer

Abstract

TP53 is the most frequently mutated or deleted gene in triple negative breast cancer (TNBC). Both the loss of TP53 and the lack of targeted therapy are significantly correlated with poor clinical outcomes, making TNBC the only type of breast cancer that has no approved targeted therapies. Through in silico analysis, we identified POLR2A in the TP53 -neighboring region as a collateral vulnerability target in TNBC tumours, suggesting that its inhibition via small interfering RNA (siRNA) may be an amenable approach for TNBC targeted treatment. To enhance bioavailability and improve endo/lysosomal escape of siRNA, we designed pH-activated nanoparticles for augmented cytosolic delivery of POLR2A siRNA (siPol2). Suppression of POLR2A expression with the siPol2-laden nanoparticles (siPol2@NPs) leads to enhanced growth reduction of tumours characterised by hemizygous POLR2A loss. These results demonstrate the potential of the pH-responsive nanoparticle and the precise POLR2A targeted therapy in TNBC harbouring the common TP53 genomic alteration.

Efficient Gene Therapy of Pancreatic Cancer via a Peptide Nucleic Acid (PNA)‐Loaded Layered Double Hydroxides (LDH) Nanoplatform

“…iii) Then, driven by proton sponge effect of LDH, [ 15 ] PNA is released from lysosome and eventually diffuse into the nucleus. [ 16 ] iv) Finally, based on its unique specificity and stability, PNA recognizes and hybridizes the KRAS G12D sequence in double‐stranded DNA to form PNA–DNA hybrids with high stability. The formation of PNA–DNA hybrids at the mutant site inhibits the transcription of the mutant KRAS gene, consequently resulting in the downregulations of oncogenic KRAS and the downstream effectors.…”

“…In addition, the size of short PNA chain (13 bp, about 4.5 nm) is smaller than that of the nuclear pore (50–70 nm), which meets the size requirements of entering the nucleus through the nuclear pore. [ 16 ] Compared with the free PNA without carrier, the nuclear uptakes of PNA from LDH/PNA were considerably higher than free PNA, as demonstrated by the lightened nuclei by the green fluorescence from FITC (Figure S8a, Supporting Information). Fluorescence spectrum further show that the green fluorescence of FITC from LDH/PNA overlaps well with that of nucleus tracker blue, as evidenced by the clear cyan emissions (Figure S8b, Supporting Information).…”

Manipulation of the dually thermoresponsive behavior of peptide‐based vesicles through modification of collagen‐like peptide domains

“…At 80 C, the data inFigure 4dsuggest a lack of vesicles likely due to complete unfolding of the triple helix and subsequent vesicle dissociation. The apparent differences in morphology between the solubilized conjugates inFigure 4aandFigure 4dlikely results from the intact CLP triple helices that are present at 4 C relative to the completely unfolded, monomeric ELP-CLP conjugates that are present at 80 C. Further TEM analysis of F6-GPO7 vesicles incubated at 25 C was conducted using a multi-step PTA staining procedure (Supporting Information Section 1.5), which resulted in a more facile observation of the bilayer of the vesicles (similar to vesicular bilayer morphologies observed via TEM by others[81][82][83] ) (Figure S24); measured bilayer thicknesses were indicated to be 11.5 ± 2 nm, in reasonable agreement with the predicted thickness of an F6-…”

Bioengineered siRNA-Based Nanoplatforms Targeting Molecular Signaling Pathways for the Treatment of Triple Negative Breast Cancer: Preclinical and Clinical Advancements

“…Kren et al prepared novel Tenfibgen-coated nanocapsules (TBG nanocapsules) containing anti-CDK11 siRNA or anti-CK2 siRNA targeting Tenascein-C receptors that are found abundantly within the breast cancer stroma. Intravenous administration of these gene therapeutics suppresses mRNA and protein expression causing significant reduction in tumor cell proliferation and growth [ 70 ].…”

“…TNBC cell lines embracing hemizygous loss of POLR2A are more sensitive than those harboring the wild type for siRNA nanotherapeutics, as a result, knockdown of POLR2A expression cause selective TNBC cell death with no cytotoxicity. Inhibition of tumor growth by targeting POLR2A was not influenced with the status of TP 53 loss [ 70 ].…”