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Mirnas useful to reduce lung cancer tumorigenesis and chemotherapy resistance and related compositons and methods

A composition, tumor technology, applied in the fields of biochemical equipment and methods, DNA/RNA fragments, microorganisms, etc., can solve the problems of NSCLC cell proliferation, survival, invasion, etc.

Inactive Publication Date: 2015-01-21
OHIO STATE INNOVATION FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although NSCLC is a distinctly heterogeneous disease comprising distinct morphological and molecular subtypes, activation of epidermal growth factor receptor (EGFR) and MET (receptor tyrosine kinase (RTK) for hepatocyte growth factor) is a common and with the rat sarcoma (RAS)-mitogen-activated protein kinase 1 (ERK) and phosphoinositide-3-kinase (PI3K)-v-akt murine thymoma virus oncogene homolog 1 (AKT) axes Associated with stimuli that lead to NSCLC cell proliferation, survival and invasion
[0009] The tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib effectively target EGFR in individuals with NSCLC, but these therapeutics are ultimately limited by the emergence of mutations and other molecular mechanisms that confer drug resistance

Method used

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  • Mirnas useful to reduce lung cancer tumorigenesis and chemotherapy resistance and related compositons and methods
  • Mirnas useful to reduce lung cancer tumorigenesis and chemotherapy resistance and related compositons and methods
  • Mirnas useful to reduce lung cancer tumorigenesis and chemotherapy resistance and related compositons and methods

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0271] Discussion of Example 1

[0272] EGFR and MET receptor tyrosine kinases control the metastatic behavior and gefitinib resistance of NSCLC by regulating the expression of specific miRNAs.

[0273] MET is a regulator of miR-221 and miR-222 expression. To determine pathways involved in NSCLC tumorigenesis and drug resistance, we investigated miRNAs regulated by EGFR and MET tyrosine kinases. Specifically, miR-30b, miR-30c, miR-221 and miR-222 (which are regulated by both EGFR and MET) and miR-103 and miR-203 (which are only regulated by MET) were examined herein.

[0274] It has now been shown herein that gefitinib treatment contributes via downregulation of miR-30b, miR-30c, miR-221 and miR-222 and thus upregulation of APAF-1 and BIM in gefitinib-sensitive HCC827 and PC9 cells. Trigger programmed cell death. Likewise, gefitinib treatment did not reduce miR-30b, miR-30c, miR-221 and miR-222 expression in gefitinib-resistant Calu-1, A549 and HCC827GR cells as a result of...

Embodiment 2

[0284] TaqMan Array MicroRNA Card

[0285] TaqMan Arrays Human MicroRNA Cards (Applied Biosystem) Set v3.0 is a set of two cards containing a total of 384 TaqMan MicroRNA Assays / cards, which enables the accurate quantification of 754 human miRNAs. Three TaqMan MicroRNA assays (as endogenous controls to aid in data normalization) and one non-human TaqMan MicroRNA assay (as a negative control) were included on each array. Additional pre-amplification steps can be performed by using Megaplex PreAmp Primers, Human Pool Set v3.0 (for cases where sensitivity is paramount or where samples are limited).

[0286] in vivo experiment

[0287] A549 cells were stably infected with control miRNAs, miR-103 and miR-203 or with control inhibitors of miRNAs or lentiviral inhibitors (SBI) of miR-221 and miR-30c. We will 5×10 6 Live cells were injected subcutaneously into the right flank of 6-week-old male nude mice (Charles River Breeding Laboratories). Treatment started 7 days after tumor c...

Embodiment 3

[0297] Depletion of Dicer by miR-103 reduces cell migration and promotes gefitinib sensitivity.

[0298] Partial attenuation of Dicer by miR-103 promotes cell migration, whereas more complete knockdown of Dicer attenuates cell viability and reduces cell migration. There was a significant downregulation of Dicer after MET silencing or miR-103 enhanced expression ( Figure 22A ), which showed that almost complete silencing of Dicer by miR-103 in this system could promote the reduction of cancer cell motility and induce programmed cell death. To experimentally elucidate this phenomenon, we transfected A549 and Calu-1 cells with Dicer siRNA, which induced significant knockdown of Dicer to levels similar to those achieved by miR-103 expression ( Figure 22B ). Global attenuation of Dicer in A549 and Calu-1 cells compared to control cells had a significant effect on cell migration and gefitinib resistance ( Figure 22C ,22D). Furthermore, Dicer silencing reduced the expression o...

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Abstract

Disclosed are compositions, such as nucleic acids, vectors, cells, animal models and the like, useful to reduce tumor growth, cancer cell migration and various other cancer pathologies associated with EGFR (epidermal growth factor receptor) and MET (the receptor tyrosine kinase for hepatocyte growth factors) dyregulation, particularly in non-small cell lung carcinoma.

Description

[0001] Inventors: Carlo M. Croce, Michela Garofalo [0002] Cross References to Related Applications [0003] This application claims the benefit of US Provisional Application 61 / 569,237, filed December 10, 2011, the disclosure of which is incorporated herein by reference for all purposes. [0004] Statement Regarding Federally Funded Research [0005] This invention was made with Government support under Grant No. CA113001 awarded by the National Institutes of Health. The US Government has certain rights in this invention. Background of the invention [0006] No admission is made that the background art disclosed in this section legally constitutes prior art. [0007] MiRNAs repress gene expression by inhibiting mRNA translation or by promoting mRNA degradation, and are considered master regulators of various processes ranging from proliferation to apoptosis. Loss and gain of miRNA function contribute to cancer development through the upregulation and silencing of differe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/11C12N5/00C07H21/04
CPCC12N15/1135C12N15/1138A61K31/496C12N2320/31A61K31/5377C12N2310/113C12N2310/141C12N15/113A61K45/06A61P17/02A61P35/00A61P43/00
Inventor C·M·克劳斯M·加罗法洛
Owner OHIO STATE INNOVATION FOUND
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