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Compositions and methods for treating cancer using rhoa dominant negative forms

A RHOA, cancer technology, applied in biochemical equipment and methods, peptide preparation methods, chemical instruments and methods, etc., can solve problems such as lack of molecular targeted therapy

Inactive Publication Date: 2020-06-12
DANA FARBER CANCER INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Therefore, gastric cancer and other epithelial / mesenchymal transition (EMT) cancers characterized by reduced and / or absent CDH1 expression are prone to early invasion and metastasis and lack effective molecularly targeted therapies

Method used

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  • Compositions and methods for treating cancer using rhoa dominant negative forms
  • Compositions and methods for treating cancer using rhoa dominant negative forms
  • Compositions and methods for treating cancer using rhoa dominant negative forms

Examples

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example

[0296] The invention is further illustrated by the following examples, which should not be construed as limiting.

example 1

[0297] Example 1: Materials and methods of Example 2

[0298] a . mouse colony

[0299] Mist1-CreERT2, Cdh1flox / flox, Tomation / GFP mice carrying conditional alleles in which the loxP site is located next to exons 2-3 of Cdh1 were generously provided by Timothy C. Wang, Columbia University. Cre recombinase was activated by oral administration of tamoxifen (Sigma, T5648) TAM (1-5 mg / 0.2 ml corn oil, as indicated). The ethics committee of Dana-Farber Cancer Institute approved all animal studies and procedures.

[0300] b . Isolation and Culture of Mouse Gastric Organoids

[0301] A protocol previously described by Miyoshi et al. (2013) Nat. Prot. 8:2471-2482 was performed as follows: Mice were euthanized using chemicals, stomachs were opened longitudinally, and the contents of paper towels were roughly removed thing. Wash the tissue with ice-cold PBS in a 90 mm Petri dish, then shake vigorously with about 20 ml of ice-cold PBS in a 50 ml centrifuge tube. After washing,...

example 2

[0308] Example 2: RHOA dominant negative mutants kill CDH1-null cancer cells

[0309]Diffuse gastric cancer (DGC), a highly lethal variant of gastric cancer, is prone to early invasion and metastasis, and lacks effective molecularly targeted therapies. Initiation of DGC is often followed by loss of the tumor suppressor CDH1 encoding the cell adhesion protein E-cadherin. Reduction and / or loss of E-cadherin (CDH1) is a key hallmark of invasive lobular breast cancer, and loss-of-function mutations targeting CDH1 are present in 50%-60% of invasive lobular breast cancers and are thought to is an early event commonly observed in matched lobular carcinoma in situ (McCart Reed et al (2015) Breast Cancer Res. 17:12). Here we demonstrate that ectopic expression of small GTPase RHOA dominant-negative forms (e.g., T19N, G17V, G17E, etc.) lead to marked inhibition of proliferation and induction of cell death in CDH1-null cells (but not cells with intact CDH1). These results are diffused ...

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Abstract

The present invention provides compositions and methods for treating cancers with reduced or absent CDH1 using a RHOA dominant negative polypeptide or biologically active fragment thereof, and / or a nucleic acid encoding a RHOA dominant negative polypeptide or biologically active fragment thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 583,166, filed November 8, 2017; the entire contents of said application are hereby incorporated by reference in their entirety. Background technique [0003] Gastric cancer is the third leading cause of cancer mortality in the world (Sutter et al. (2006) "World J. Gastroenterol." 12:380-387; Zhou et al. (2014) "Cancer ( Cancer Cell) 16:9-11; Cancer Genome Atlas Research Network (Cancer Genome Atlas Research Network) (2014) Nature 513:202-209). Despite the remarkable heterogeneity of gastric cancer, the two most prominent subtypes are gastrointestinal carcinoma (IGC) and diffuse gastric carcinoma (DGC). The name DGC is attributed to its lack of cellular cohesion, invasion of the entire stroma, and poor cellular differentiation (often with signet-ring cell morphology) that are characteristic. Families with inherited forms of DGC carry mutations i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/513A61K45/06A61P35/00C07K1/00G01N33/53G01N33/574
CPCA61K45/06C07K1/00G01N33/574A61P35/00G01N2333/914A61K38/46C07K2319/31C12N9/14C12Y306/05002A61K39/0011A61K39/001164A61K48/00
Inventor A·巴斯H·张
Owner DANA FARBER CANCER INST INC
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