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Methods and compositions relating to carcinoma stem cells

A cancer stem cell and cell technology, applied in the field of microRNA, can solve the problems of killing and limited cell proliferation potential

Inactive Publication Date: 2011-02-23
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since most cells in cancer have limited proliferative potential, tumor shrinkage primarily reflects the ability to kill these cells
Treatment specifically targeting cancer stem cells may produce longer-lasting responses and cure metastatic tumors

Method used

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  • Methods and compositions relating to carcinoma stem cells
  • Methods and compositions relating to carcinoma stem cells
  • Methods and compositions relating to carcinoma stem cells

Examples

Experimental program
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Effect test

Embodiment 1

[0150] Identifying gene signatures of breast cancer stem cells

[0151] We had previously identified BCSCs as CD44 based on CD44 and CD24 expression + CD24 - / 低 pedigree. The expression of cell surface markers in normal mammary epithelial cells isolated from three breast reduction samples was defined as ESA + pedigree - (CD64 - , CD31 - , CD140b - , CD45 - ). We looked for BCSCs isolated from 6 patients (3 with primary malignant pleural effusions and 3 with mammary tumors grown as solid tumor xenografts in immunodeficient mice) with 3 reductions by microarray analysis. Differentially expressed genes between normal human breast epithelial cells produced by reduction mammoplasties. A panel of 186 genes was selected based on a two-fold difference in expression levels, with t-test P values ​​< 0.005 for all samples. The false discovery rate (FDR) was controlled using the Beniamini-Hochberg procedure. According to the above criteria, the FDR of the genes in the list is le...

Embodiment 2

[0158] Development of markers useful as prognostic and predictive tools from formalin-fixed paraffin-embedded (FFPE) tumor specimens. The differentially expressed sequences in BCSCs identified herein were used to generate markers (in situ hybridization probes) to determine the number and location of tumor stem cells in formalin-fixed paraffin-embedded (FFPE) tissues. All breast cancer biopsy and slide specimens were analyzed by histological examination using thin sections of formalin-fixed paraffin-embedded material. Thus, a large collection of tumor specimens is maintained in the archives of the Department of Surgical Pathology across the country for the histological study of CSCs and the role they play in clinical outcome and response to adjuvant therapy.

[0159] The clinical significance of these findings was determined using tissue microarrays (TMA) containing tumor specimens with known clinical outcomes in formalin-fixed paraffin-embedded (FFPE). Prognostic or predictiv...

Embodiment 3

[0166] Targeting pathways that confer CSC resistance to standard cytotoxic chemotherapy. Targeting pathways that confer CSC resistance to therapy using exogenous miRNAs or synthetic shRNAs. Three different published methods have been used to deliver shRNA: liposome delivery (see Sorensen et al. (2003) J Mol Biol 327, 761-6), conjugation of shRNA to atellocolagen (see Takeshita et al. (2005) ProcNatl Acad Sci USA 102, 12177-82) and conjugation of shRNA to monoclonal antibody / protamine complexes (see Song et al. (2005) Nat Biotechnol 23, 709-17). The third approach uses antibodies that specifically target cancer cells. In the latter case, antibodies specifically binding to CSCs or targeting all cancer cells were tested. Identification of antibodies targeting CSC or all cancer cells in specific xenograft tumors by flow cytometry.

[0167] Xenograft tumors derived from tumors from 6 different patients were examined to determine whether systemic delivery of shRNA enhanced chemoth...

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Abstract

MicroRNA markers of breast cancer stem cells (BCSC) are provided herein. The markers are polynucleotides that are differentially expressed in BCSC as compared to normal counterpart cells. Uses of the markers include use as targets for therapeutic intervention; as targets for drug development, and for diagnostic or prognostic methods relating to breast cancer and BCSC cell populations. BCSCs have the phenotype of having lower expression of certain miRNAs compared to normal breast epithelial cells, or to cancer cells that are not cancer stem cells.

Description

[0001] government rights [0002] This invention was made with government support under contract CA104987 awarded by the NIH National Cancer Institute. The government has certain rights in this invention. Background of the invention [0003] Breast cancer is the most common malignancy among American women. Although currently available treatments shrink metastases, these effects are temporary and the vast majority of patients with stage 4 breast cancer die from metastases. Traditional treatments, including radiation, chemotherapy, and hormone therapy, are useful, but have been limited by the emergence of cancer cells that are resistant to treatment. New methods are needed to detect and treat breast cancer. [0004] As with many other types of solid tumors, the major cause of mortality is the spread of cancer from the primary site to distant organs and tissues. This is caused by the invasion of cancer cells from the original tumor into the surrounding breast tissue as well a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q2600/178C12Q2600/16C12Q1/6886C12Q2600/118C12Q2600/136A61P35/00
Inventor M·克拉克Y·西莫诺
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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