Targeting the EGFR-SGLT1 Interaction for Cancer Therapy

A cancer cell, composition technology, applied in the field of EGFR-SGLT1 interaction for targeted cancer therapy

Active Publication Date: 2016-02-24
UNIV HOUSTON SYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, mice with severely impaired EGFR tyrosine kinase activity are fully viable and show only some epithelial defects (Luetteke NC, et al., The mouse waved-2 phenotype results from a point mutation in the EG Freceptor tyrosine kinase, Genes & Development, 8(4):399-413 (1994))

Method used

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  • Targeting the EGFR-SGLT1 Interaction for Cancer Therapy
  • Targeting the EGFR-SGLT1 Interaction for Cancer Therapy
  • Targeting the EGFR-SGLT1 Interaction for Cancer Therapy

Examples

Experimental program
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Effect test

Embodiment approach

[0026] The key microdomain of EGFR, which is necessary for the full interaction and mutual stabilization of EGFR and SGLT1;

[0027] ■Activation / inactivation of EGFR on EGFR-SGLT1 interaction;

[0028] ■Measurement of EGFR and SGLT1 expression in prostate cancer tissues and cell lines;

[0029] Inhibitory effect of SGLT1 on the sensitivity of prostate cancer cells to EGFR tyrosine inhibitors;

[0030] ■ Amino acid sequence of the synthesized peptide ESD-01;

[0031] The effect of ESD-01 on the stability of EGFR and SGLT1 proteins in cancer cells; and

[0032] ■Effect of ESD-01 on the viability of non-cancer cells (HEK293) and several types of cancer cells cultured in vitro.

[0033] ■ ESD-01 peptide composed of L-amino acid or D-amino acid is also effective in killing cancer cells in vitro.

[0034] In one embodiment, the autophosphorylated region of EGFR (978-1210 amino acids) is required for adequate interaction of EGFR with SGLT1. This interaction is independent of the t...

Embodiment

[0058] cells and reagents. HEK293 cell line, prostate cancer cell line PC3, LNCaP, Du145, MDA-MB-231 and HCT116 cells were originally obtained from the American Type Culture Collection (ATCC) and cultured at 37 °C in 5% CO 2 , the cell lines were maintained in DMEM supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin. Mouse anti-Flag-tag antibody (F1804), proteasome inhibitor MG231 and phlorizin dihydrate were obtained from Sigma-Aldrich (St. Louis, MO). AEE788, gefitinib and erlotinib were obtained from Selleckchem (Houston, TX). Antibody against pEGFR (Y1173) (Catalog #2434L) was obtained from Cell Signaling (Danvers, MA). Monoclonal antibody against C225 was obtained from Dr. Lee Elis (M.D. Anderson Cancer Center). Rabbit anti-actin (cat# sc-7210), rabbit anti-HA-tag antibody (sc-805), anti-rabbit and mouse secondary antibodies labeled with horseradish peroxidase, and protein A / G conjugate Agarose pellets (catalogue number sc-2003) were obtained from ...

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Abstract

A compound can destabilize a binding interaction between an epidermal growth factor receptor (EGFR) and a sodium / glucose co-transporter 1 (SGLT 1). In one embodiment, the compound is a peptide derived from the interacting domain of EGFR. In another embodiment, the peptide is administered to a patient to treat cancer.

Description

[0001] Cross references to related applications: [0002] This application claims priority to US Provisional Application No. 61 / 821,028, filed May 8, 2013, which is hereby incorporated by reference in its entirety. [0003] Government funding: [0004] American Cancer Society (RSG-09-206-01) [0005] Department of Defense Prostate Cancer Research Program (W91ZSQ8334N607) Background of the invention [0006] Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase highly activated / overexpressed in most cancers of epithelial origin (Hynes NE et al., ERBBreceptors and cancer: the complexity of targeted inhibitors, Nature Reviews Cancer, 5(5):341-354 (2005) ). Inhibition of EGFR's tyrosine kinase activity has become a major strategy for EGFR-based cancer therapy. However, targeting EGFR by small-molecule inhibitors of receptor tyrosine kinases has not yielded satisfactory therapeutic efficacy. 各种人恶性肿瘤的总体应答率为10-20%(WeissJ.,FirstlineerlotinibforNSCLCpatientsnotse...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/04A61K31/70A61K38/00C07K14/00
CPCA61K31/7034A61K38/179A61K45/06A61K31/7042A61K31/70A61K31/5377A61K31/517A61K31/422A61K38/10A61P1/00A61P13/08A61P15/00A61P35/00A61P43/00A61K2300/00C07K7/08A61K31/519
Inventor 张伟华
Owner UNIV HOUSTON SYST
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