Anti-cancer and anti-inflammatory therapeutics and methods thereof

A cancer and protein technology, applied in gene therapy, anti-tumor drugs, pharmaceutical formulations, etc., can solve the problems of inability to provide direct connection of DKK3, destruction of secretion, etc.

Inactive Publication Date: 2018-09-28
UNIV OF MASSACHUSETTS
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Surprisingly, targeted knockout of the mouse Dkk3 gene disrupts the putative secretory DKK3 isoform, rendering it unable to provide a direct link between DKK3 and the Wnt / β-catenin signaling pathway

Method used

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  • Anti-cancer and anti-inflammatory therapeutics and methods thereof
  • Anti-cancer and anti-inflammatory therapeutics and methods thereof
  • Anti-cancer and anti-inflammatory therapeutics and methods thereof

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Experimental program
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Embodiment

[0167] Dkk3 tml Cni Mutant mice were generated by interfering with exon 2 of the Dkk3 gene, which contains a biologically important CpG island and encodes the N-terminal 71 amino acid signal peptide sequence and N-terminal glycosylation of secreted DDK3 site ( Image 6 a). (Kobayashi et al. 2002 Gene 282, 151-158; Lodygin et al. 2005 Cancer Res65, 4218-4227; Sato et al. 2007 Carcinogenesis 28, 2459-2466.) There are two DKK3 isoforms in the meninges of the wild-type control group , glycosylated DDK3 accounts for about 75% of the total DDK3, and DKK3b accounts for about 25% ( Image 6 b, Figure 14 b).

[0168] Dkk3 tml Cni The expected loss of glycosylated DKK3 by targeting mutations in exon 2 was shown in the meninges of mutant mice. However, DKK3b not only exists but also upregulates about twice the amount ( Image 6 ), thus confirming that the smaller 30 kDa isoform is not a hydrolyzed fragment of the larger DKK3, and raising the possibility that epigenetic modificati...

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Abstract

The invention relates to the discovery of a vital new component of the Wnt pathway that regulates trafficking of beta-catenin to the cell nucleus and novel therapeutic approaches to cancer treatment.Disclosed herein is a previously unknown, essential component of the Wnt / beta-catenin signaling pathway that governs the quantity of beta-catenin delivered to the cell nucleus. This intracellular inhibitor of beta-catenin signaling (IBS) is transcribed from a second transcriptional start site adjacent to exon 3 of the Dkk3 gene and is required for early mouse development. IBS captures beta-catenindestined for the nucleus in a complex with beta-TrCP that is bound to the actin cytoskeleton and unavailable for nuclear translocation.

Description

[0001] Statements Involving Federally Funded Research or Development [0002] This invention was made with government-supported grants DK038772 and DK060051 awarded by the National Institutes of Health. The government has certain rights in the invention. [0003] CROSS-REFERENCE TO RELATED APPLICATIONS [0004] This application claims US Provisional Application Serial No. 62 / 243,612, filed on October 19, 2015, US Provisional Application Serial No. 62 / 281,702, filed on January 21, 2016, and US Provisional Application Serial No. 62 / 281,702, filed on August 29, 2016 The benefit of priority to No. 62 / 380,525, the entire contents of which are incorporated herein by reference in their entirety. technical field [0005] The present invention generally relates to anti-tumor and anti-inflammatory treatments and methods. More specifically, the present invention relates to novel therapeutics based on DKK3b regulation of β-TrCP E3 ubiquitination activity and a newly discovered componen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00C12N15/86A61K33/243
CPCC12N15/86A01K67/0275A01K2217/072A01K2227/105A01K2267/0331C07K14/4703A61P35/00A61K31/337A61K31/351A61K33/243A61K2300/00A61K48/005A61K38/00
Inventor 杰克·L·伦纳德卡尔·J·西敏黛博拉·M·伦纳德
Owner UNIV OF MASSACHUSETTS
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