Let-7 microrna and mimetics thereof as therapeutics for cancer

Inactive Publication Date: 2010-12-09
IMMUNE DISEASE INST INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0036]Another aspect of the present invention relates to a pharmaceutical composition comprising a let-7 miRNA and a pharmaceutically acceptable carrier, wherein the let-7 miRNA binds to and inhibits an RNA transcript comprising a let-7 target sequence.
[0037]Another aspect of the present invention relates to a pharmaceutical composition comprising an agent which increases the expression of a let-7 miRNA and a pharmaceutically acceptable carrier, wherein the let-7 miRNA binds to and inhibits an RNA transcript comprising a let-7 target sequence.
[0038]Another aspect of the present invention relates to a pharmaceutical composition comprising an agent which decreases the expression of at least one of miR-129, miR-140, miR-184 or miR-198 and a pharmaceutically acceptable carrier.
[0039]In some embodiments, a pharmaceutical composition as disclosed herein comprises a let-7 miRNA or an agent which increases a let-7 miRNA, and the

Problems solved by technology

Although there is a growing consensus that cancer stem cells are important in generating tumors and for resistance to therapy a

Method used

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  • Let-7 microrna and mimetics thereof as therapeutics for cancer
  • Let-7 microrna and mimetics thereof as therapeutics for cancer
  • Let-7 microrna and mimetics thereof as therapeutics for cancer

Examples

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Example 1

[0307]Low-dose chemotherapy selects for tumor-initiating breast cancer cells. Resistance to chemotherapy distinguishes tumor-initiating cells from other cancer cells1,2,17. Accordingly, treatment with chemotherapy should enrich for tumor stem cells compared to more differentiated progeny. To examine this, the inventors compared the proportion of self-renewing cancer cells in primary breast cancer tissues surgically removed from patients with poorly differentiated invasive breast cancer who received four cycles of preoperative chemotherapy with tumors from matched untreated patients. Freshly isolated cells were cultured in suspension in medium supplemented with epidermal growth factor (EGF), B27 and insulin to generate mammospheres (or emboid bodies), a previously described method for culturing both mammary gland progenitor cells25 and breast tumor-initiating cells10. The self-renewal potential of breast tumor-initiating cells can be gauged by their capacity to give rise to ...

Example

Example 2

[0310]Breast tumor-initiating cells have reduced expression of let-7 miRNAs and let-7 homologues or let-7 mimetics. The inventors used miRNA microarrays to compare miRNA expression in mammosphere-derived SK-3rd with their in vitro differentiated progeny and the parental SKBR3 cells. As has been reported for ES cells22,27, most of the 52 miRNAs that were reproducibly expressed above background in any of the 3 cell lines had reduced expression in SK-3rd compared with either the differentiated SK-3rd cells or SKBR3 (FIG. 2a). Cluster analysis of multiple samples showed a clear distinction between mammospheric cells and the other two adherent lines (data not shown). Using ANOVA analysis on the normalized chip data, we identified a number of human miRNAs whose expression in mammospheric cells was significantly different from the differentiated and parent cells. Among them, the let-7 family emerged as the most consistently and significantly reduced miRNAs. let-7 was initially ide...

Example

Example 3

[0311]let-7 activity is low in breast cancer stem cells and increases during differentiation. To investigate let-7 function, the inventors transfected a luciferase reporter vector containing a let-7 target sequence in its 3′UTR into SK-3rd, differentiated SK-3rd and SKBR3. Luciferase activity was suppressed by 52% in differentiated SK-3rd cells (Pd). Infection of SK-3rd with a lentivirus expressing let-7a pre-miRNA enhanced miRNA expression and function comparably to that of the differentiated progeny cells (FIG. 2b-d). Co-transfection of differentiated SK-3rd cells, SKBR3 or let-7a lentivirus-infected SK-3rd with a let-7 antisense oligonucleotide (ASO) significantly reduced the suppression in luciferase activity mediated by endogenous or exogenous let-7 (Pd).

[0312]Since RAS is a major target of let-7 miRNAs31, the inventors next compared HRAS1 mRNA and protein expression in the 3 cell lines. H-RAS protein was highly expressed in SK-3rd stem cells, but was greatly reduced i...

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Abstract

The present invention relates to methods to treat or prevent cancers in a subject, in particular the present invention relates to a method of treating and/or preventing cancer comprising targeting cancer stem cells by administering miRNAs which have reduced expression or are lacking in the cancer stem cells. In some embodiments, the miRNAs that are reduced or lacking in cancer stem cells are let-7 miRNAs. In alternative embodiments, the present invention relates to a method of treating and/or preventing cancer comprising targeting cancer stem cells by administering miRNAs which have increased expression levels in the cancer stem cells. Another aspect of the present invention relates to methods to enrich for a cancer stem cell population. Another aspect of the present invention relates to methods to identify miRNAs which contribute to the self-renewal capacity of cancer stem cells.

Description

CROSS REFERENCED APPLICATIONS[0001]This Application claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Ser. No. 60 / 898,610 filed Jan. 31, 2007, the contents of which is incorporated herein in its entirety by reference.GOVERNMENT SUPPORT[0002]This invention was made with government support to ES under Contract No. 30525022 awarded by the National Science Foundation of China, Contract No. 2005CB724605 awarded by the 973 Program Project from Ministry of Science and Technology of China.BACKGROUND OF THE INVENTION[0003]Accumulating evidence suggests that many cancers are maintained in a hierarchical organization of rare, slowly dividing tumor-initiating cells, rapidly dividing amplifying cells (precursor cells) and differentiated tumor cells1,2. Tumor-initiating (also termed cancer stem) cells have been identified in hematologic3-5, brain6-8, breast9,10 prostate11 and colon cancers12. Stem cells, which are self-renewing and can differentiate into heterogeneous cell po...

Claims

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Application Information

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IPC IPC(8): A61K31/713A61K31/7088A61K38/16A61K39/395A61K38/22A61P35/00C12N15/113
CPCA61K31/7105A61K45/06A61K47/484A61K31/7088C12N2310/141C12N2310/111C12N15/113C12N2310/11A61K47/6807A61P35/00
Inventor LIEBERMAN, JUDYSONG, ERWEIYU, FENGYANHU, XIAOQU
Owner IMMUNE DISEASE INST INC
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