Targeting micro RNAS MIR-409-5P, MIR-379 AND MIR-154* to treat prostate cancer bone metastasis and drug resistant lung cancer

A prostate cancer, mir-379 technology, applied in the field of microRNA and cancer, can solve problems such as insufficient understanding of bone metastasis

Inactive Publication Date: 2014-10-01
CEDARS SINAI MEDICAL CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The pathogenesis of bone metastases is still poorly understood

Method used

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  • Targeting micro RNAS MIR-409-5P, MIR-379 AND MIR-154* to treat prostate cancer bone metastasis and drug resistant lung cancer
  • Targeting micro RNAS MIR-409-5P, MIR-379 AND MIR-154* to treat prostate cancer bone metastasis and drug resistant lung cancer
  • Targeting micro RNAS MIR-409-5P, MIR-379 AND MIR-154* to treat prostate cancer bone metastasis and drug resistant lung cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] MicroRNA expression profiling in a bone metastatic model of prostate cancer reveals elevated expression of miR-409-5p

[0164]Two cell-based models of PCa bone metastases derived from PCa patients, the human ARCaP model (ARCaP E and ARCaP M ) (E-epithelial, M-stromal) and LNCaP models (LNCaP and C4-2) for MiRNA profiling ( figure 1 A) (15,16). ARCP E and LNCaP are less invasive and do not metastasize to bone, while C4-2 and ARCaP M It is highly aggressive and metastasizes to the bone. In these cell lines, miR-409-5p, miR-379, and miR-154* were expressed in highly bone-metastatic ARCaP M cells are up-regulated ( figure 1 D). miR-409-5p is produced from an immature transcript and is transcribed from the 5' end of the pre-miRNA. When injected intracardiacly into mice, ARCaP M The cells have 100% bone metastatic capacity (17). The ARCaP model is a model of epithelial to mesenchymal transition (17). Consistent with previously described EMT-associated miRNAs, com...

Embodiment 2

[0166] Overexpression of miR-409 in normal prostate leads to tumor growth

[0167] To test whether miR-409 is oncogenic, the inventors injected human embryonic kidney 293T cells transfected with a miR-409 expressing lentiviral vector carrying green fluorescent protein (GFP) or a control vector carrying a GFP plasmid (System biosciences). 293T cells were orthotopically injected into nude mice, and tumor progression was monitored using a tumor-specific infrared dye (IR783) (19). The rationale behind this procedure is that lentivirus will be secreted from the resulting cells (293T) and will infect the prostate epithelium and stroma. Strikingly, tumors developed in the miR-409 expressing prostate in three out of four mice within 3 to 5 months ( image 3 A). Control mice did not develop tumors. Tumors are green fluorescent and show tumor-specific dye uptake ( image 3 A). Tumor sections were formalin-fixed and paraffin-embedded and H&E stained. Tumor sections were graded by a...

Embodiment 3

[0169] Inhibition of miR-409-5p in mesenchymal metastatic prostate cancer cells (ARCaPM) leads to cell death, upregulation of miR-409-5p target genes (tumor suppressors), and reversal of epithelial-to-mesenchymal transition (EMT to MET)

[0170] Inhibition of miR-409-5p using lentiviral-based anti-miR-409-5p resulted in significant cell death in metastatic prostate cancer cells ( Figure 4 A). In ARCaP stably transfected with miR-409-5p inhibitor constructs compared to control M In cells, the expression of miR-409-5p was decreased. Evaluation of miR-409-5p targeting mRNAs including TUSC4, PHC3, and STAG2, compared to ARCaP M Control (ARCaP M -C) cells, in miR-409-5p knockdown cells (ARCaP M -409-5pi) in metastatic prostate cancer cells, these mRNAs were increased. TUSC4 is a tumor suppressor protein that is missing in solid tumors. PHC3 is part of the polycomb group protein involved in transcriptional repression and regulation of cell fate (20). siRNA-mediated downregul...

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Abstract

The present invention describes methods of treating cancer, cancer metastasis, and drug resistant cancers using miRNA inhibitors; for example, inhibitors of miR-409-5p. Also described are methods of using the miRNA as biomarkers; for example, to predict responsiveness to a cancer drug, to detect a disease state of cancer.

Description

[0001] Statement Regarding Federally Funded Research [0002] The United States Government has a paid-up patent right to this invention and has the right under limited circumstances to require the patent owner to license others to practice the invention on reasonable terms as specified in the terms of Grant No. CA122602 awarded by the National Institutes of Health. technical field [0003] The present invention relates to microRNAs and cancer; particularly prostate cancer bone metastases and drug resistant lung cancer. Background technique [0004] All publications herein are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claim...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7088C12Q1/68A61P35/00
CPCA61K31/713C12Q1/6886G01N33/5011C12Q2600/178A61K31/7105C12Q2600/106C12N15/113C12Q2600/158A61P11/00A61P13/08A61P15/00A61P19/00A61P35/00A61P35/04
Inventor L·W·K·钟S·乔尔森M·古鲁拉扬A·杰恩
Owner CEDARS SINAI MEDICAL CENT
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