Combination therapies including inhibitors of the extracellular domain of E-cadherin

A technology of extracellular domain and cadherin, which is applied in the field of combination therapy containing inhibitors of the extracellular domain of E-cadherin, which can solve the problem of low drug response rate

Inactive Publication Date: 2015-04-15
THE RES FOUND OF STATE UNIV OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These therapeutic strategies are limited in that only some tumors express the specific receptor / antigen at a defined stage of maturation, not all tumors with a certain histology and stage overexpress the target receptor / antigen (only 20% to 50% of breast Cancer overexpresses EGF receptor)
Consequently, response rates to these types of drugs remain low (Mendelson and Baselga, Oncogene 19 : 6550-6565, 2000; Ortega et al., Cancer Control 17 (1): 7-15, 2010)

Method used

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  • Combination therapies including inhibitors of the extracellular domain of E-cadherin
  • Combination therapies including inhibitors of the extracellular domain of E-cadherin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1: In vivo and in vitro efficacy of monoclonal antibodies targeting sEcad

[0103] We tested the in vivo efficacy of monoclonal antibodies targeting sEcad using MMTV-PyMT transgenic mice in which mammary gland-directed transgenic expression of the polyomavirus intermediate T antigen (PyMT) resulted in rapid degeneration of palpable tumors. occurs, the tumor develops into an aggressive adenocarcinoma that metastasizes to the lung (Guy et al., Mool. Cell Biol. 12 :954-961, 1992). Beginning at 47 days of age, mice were treated weekly with saline, IgG, or DECMA-1 (1 mg / kg in 200 μL of saline; Sigma) until sacrifice at 90 days of age. Treatment with anti-sEcad mAb caused a significant delay in tumor onset and reduced tumor burden (**p<0.01, ***p<0.001). Treated tumors exhibited reduced proliferation and increased apoptosis, the latter associated with increased p53 expression. Likewise, in HER2-positive (HER2+) Herceptin-resistant breast cancer xenografts, anti-sEc...

Embodiment 2

[0111] Example 2: Monoclonal antibodies against sEcad inhibit carcinogenesis by down-regulating multiple receptor tyrosine kinases and downstream MAPK-PI3K / Akt / mTOR and IAP pathways

[0112]Since the HER receptor family is an integral part of cancer growth and progression, we next assessed whether our anti-sEcad therapy inhibits tumorigenesis by modulating this pro-tumorigenic pathway. Our study revealed statistically significant expression levels of HER1, HER2, and IGF-1R in treated MMTV-PyMT (mainly HER1 and HER2) and cutaneous SCC xenograft tumors (mainly HER1, IGF-1R). significantly lower. As clinical trials combining HER-targeting agents with inhibitors of the PI3K / mTOR pathway are showing promise in patients (Hennessy et al., Nat. Rev. 4 :988-1004, 2005), we therefore next examined MAPK-PI3K / Akt / mTOR and IAP (i.e. survivin, livin, XIAP, c-IAP -1, C-IAP2, etc.) expression levels. Treated MMTV-PyMT tumors exhibited significant reductions in MEK1 / 2, ERK1 / 2, PI3K, Akt, mT...

Embodiment 3

[0124] Example 3: sEcad increases in human and mouse cancer and cell culture systems

[0125] Since sEcad has been previously reported to be upregulated in the serum of cancer patients (Katayama et al., Br J Cancer. 69 :580-585, 1994), we therefore first set out to determine whether endogenous sEcad levels were elevated in human or mouse cancer samples, body fluids or cell culture systems. To this end, we first assessed the expression levels of sEcad in HER2+ human breast tumor samples and human triple-negative breast cancer (TNBC) tumor samples and found significantly higher levels of sEcad compared with normal human breast tissue samples. In human cell culture studies, it was found that sEcad levels were significantly increased in conditioned medium of MCF-7 breast cancer cells compared to normal MCF-10A breast epithelial cells. In contrast, appreciable levels of sEcad were not found in HER2+SKBR3 and TNBCMDA-MB-231 cells, which could be attributed to the lack of E-cadherin...

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Abstract

The present invention is based on our work with E-cadherin, including soluble portions of this integral membrane glycoprotein. The compositions of the present invention include therapeutically effective amounts of a first agent that targets epitopes within one or more of the EC2-EC5 subdomains of the ectodomain of E-cadherin (induing these domains in the shed sEcad fragment) and a second agent that inhibits one or more of: endothelial tube formation; angiogenesis; the human epidermal growth factor receptor family (i.e. HER1-4); an insulin-like growth factor 1 receptor (IGF-1R); any other receptor tyrosine kinase receptor family member; the P13K-MAPK pathway; and the P13K / Akt / mTOR pathway. The compositions can be used in the treatment of epithelial cancers, and may effectively inhibit cellular proliferation, migration, and / or invasiveness. Thus, the present compositions can be used to inhibit tumor growth and metastasis. The present compositions can be used in the treatment of "triple negative" breast cancer patients (in whom breast cancer cells test negative for estrogen receptors, progesterone receptors, and HER2), as well as HER2 -positive and other HER2 -negative tumors. In addition to therapeutic and prophylactic treatment methods, the invention features methods in which cancer is staged depending on the relative amounts of full-length (FL) E-cadherin and soluble E-cadherin (sEcad) and / or with another predictive biomarker for cancer. The greater the amount of sEcad relative to the amount of FL E-cadherin, the more advanced the cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the filing date of U.S. Provisional Application No. 61 / 611,390, filed March 15, 2012, and U.S. Provisional Application No. 61 / 736,475, filed December 12, 2012. The contents of these prior applications are hereby incorporated by reference in their entirety. [0003] Statement Regarding Federally Funded Research [0004] This invention was made with Government support under grant numbers CA133910 and ES015832 from the National Institutes of Health. The US Government has certain rights in this invention. field of invention [0005] The compositions and methods of the present invention relate to sEcad, the soluble portion of the extracellular domain of the cell-cell adhesion protein E-cadherin, as well as MAPK-PI3K / Akt / mTOR, src and inhibitors of apoptosis (IAP: XIAP, survival Targeting of both cellular receptors or intracellular effectors in the signaling pathway of survivin, livin,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61K38/16A61K48/00A61P35/00
CPCA61K39/395A61K38/177C07K16/28A61K2039/505A61K39/3955C07K2317/73A61K45/06C07K16/30A61P35/00A61P35/04A61K2300/00
Inventor 萨比恩·布洛克松斯特法诺斯·吉尔卡尼德斯
Owner THE RES FOUND OF STATE UNIV OF NEW YORK
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