Medicament for treatment of liver cancer

a liver cancer and medicine technology, applied in the field of medicine for liver cancer, can solve the problems of high treatment cost, and achieve the effect of increasing the effect of sorafenib on liver cancer cells

Inactive Publication Date: 2020-01-02
GESELLSCHAFT FUR BIOTECHNOLOGISCHE FORSCHUNG MBH GBF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0026]It was found in in vitro assays using cultivated liver cancer cells of both murine and human origin, respectively, that the efficacy of Sorafenib against liver cancer cells was increased in the pres...

Problems solved by technology

However, at the time of diagnosis the majority of patients present with advanced tumor growth and are therefore not eligi...

Method used

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  • Medicament for treatment of liver cancer
  • Medicament for treatment of liver cancer
  • Medicament for treatment of liver cancer

Examples

Experimental program
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Effect test

example 1

Treatment of Liver Cancer In Vivo

[0045]As a representative of a human patient having liver cancer, a genetically manipulated mouse model (p19Arf− / −) was generated, in which liver cancers were induced by a constitutive expression of the oncogenic NrasG12V mutant.

[0046]The nucleic acid construct for generating liver carcinomas is schematically shown in FIG. 1, containing an expression cassette, wherein the coding sequence for NrasG12V is arranged between a 5′ promoter sequence and a 3′ polyadenylation site, which expression cassette is flanked by two inverted repeat elements (IR). For intrahepatic delivery of the expression cassette, this nucleic acid construct was administered in combination with a nucleic acid construct containing an expression cassette for the transposase sleeping beauty 13 (SB13) under the control of the constitutive phosphoglycerate kinase promoter (PGK). The mouse model receiving both nucleic acid constructs shown in FIG. 1 was p19Arf− / −, providing the genetic b...

example 2

Treatment of Liver Cancer

[0057]Again, mouse models were used for representing human liver cancer patients in treatment using Sorafenib in combination with an agent inhibiting the activity of Mapk14. As an example for a pharmaceutical agent for the inactivation of the activity of Mapk14, an shRNA (shMapk14.1095) specific for the murine mRNA encoding Mapk14 was used. The shRNA was provided by controlled expression using an expression cassette which is under the control of a tetracycline response element (TRE) of the otherwise constitutive viral promoter (PminCMV). The expression cassette contains the coding sequence for a shRNA molecule and the coding sequence of a GFP marker gene. The nucleic acid construct containing the expression cassette for the shRNA molecule and the coding sequence of a GFP marker gene under the control of the Tet-inducible promoter also contains a constitutive expression cassette for rtTA (rtetRVP16), which in the presence of Doxycycline (DOX) binds to the TRE...

example 3

Inactivation of Mapk14 by a Specific Kinase Inhibitor Increases the Efficacy of Sorafenib Against Liver Cancer Cell Lines

[0061]As an example for a medicament containing Sorafenib in combination with an inhibitor specific for Mapk14 kinase, BIRB-796, SB 202190 and SX 001 were tested in an in vitro assay. These in vitro experiments show the increased efficacy of Sorafenib when administered in combination with an inhibitor of Mapk14 kinase protein on the example of cultivated murine and human liver cancer cell lines.

[0062]In the assay, murine liver cancer cells (Nras arf− / −) were cultivated. Cultivated cells were treated with 10 μM Sorafenib, 2 μM BIRB, 12 μM BIRB and with a combination of 10 μM Sorafenib+2 μM BIRB, or a combination of 10 μM Sorafenib+12 μM BIRB. For each of these assays, a parallel assay was made, replacing Sorafenib or Mapk14 inhibitors by formulation agents without pharmaceutical active agent (carrier).

[0063]FIG. 8 shows the results of the viable cell count after tw...

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Abstract

The invention provides a pharmaceutical composition comprising Sorafenib in combination with an inhibitor of a specific kinase inhibitor as a medicament for the treatment or prevention of liver cancer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Divisional application of U.S. patent application Ser. No. 14 / 131,059, filed Apr. 10, 2014, which is a 371 national phase of PCT / EP2012 / 063445, filed Jul. 9, 2012, which claims the benefit of the filing date of U.S. Provisional Application No. 61 / 508,368, filed Jul. 15, 2011, which claims priority to European Application No. 11173379.6, filed Jul. 8, 2011, European Application No. 12162905.9, filed Apr. 2, 2012 and European Application No. 12161141.2, filed Mar. 23, 2013, the disclosures of which are incorporated, in their entirety, by this reference.[0002]The present invention relates to a medicament and to a pharmaceutical composition, respectively, which is suitable for the treatment or prevention of liver cancer, especially hepatocellular carcinoma (HCC) in human patients.SEQUENCE LISTING[0003]This application is being filed electronically via EFS-Web and includes an electronically submitted Sequence Listing in ....

Claims

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Application Information

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IPC IPC(8): A61K31/4412A61K31/713A61K31/4439A61K31/444A61K31/513A61K31/519A61K31/5377A61K31/5513A61K38/08
CPCA61K31/713A61K31/5513A61K31/519A61K38/08A61K31/513A61K31/444A61K31/5377A61K31/4439A61K31/4412A61K45/06A61K31/44A61P35/00A61K2300/00
Inventor ZENDER, LARSRUDALSKA, RAMONADAUCH, DANIEL
Owner GESELLSCHAFT FUR BIOTECHNOLOGISCHE FORSCHUNG MBH GBF
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