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Translocation and mutant ros kinase in human non-small cell lung carcinoma

A kinase domain, recombinant host cell technology, used in the detection, diagnosis and treatment of cancer

Active Publication Date: 2009-09-09
CELL SIGNALING TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The development of this drug represents a significant advance over traditional treatments for CML and ALL, chemotherapy and radiation, which are plagued by well-known side effects and because they cannot Specifically targets the underlying cause of malignancy, often resulting in limited efficacy

Method used

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  • Translocation and mutant ros kinase in human non-small cell lung carcinoma
  • Translocation and mutant ros kinase in human non-small cell lung carcinoma
  • Translocation and mutant ros kinase in human non-small cell lung carcinoma

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preparation example Construction

[0241] The preparation of various targeting antibodies against receptor kinases and their use to inhibit the activity of the targeted receptors has been described. See, for example, U.S. Patent Publication No. 20040202655, "Antibodies to IGF-IReceptor for the Treatment of Cancers", October 14, 2004, Morton et al; ", April 15, 2004, Raisch et al., U.S. Patent Publication No. 20040033543, "Treatment of Renal Carcinoma Using Antibodies Against the EGFr", February 19, 2004, Schwab et al. Standard methods for making and using receptor tyrosine kinase activity inhibiting antibodies are well known in the art. See, eg, European Patent No. EP1423428, "Antibodies that Block Receptor Tyrosine Kinase Activation, Methods of Screening for and Uses Thereof" June 2, 2004, Borges et al.

[0242] Can also use phage display method to prepare ROS-specific antibody inhibitors, phage library construction and recombinant antibody selection scheme in the well-known reference CURRENT PROTOCOLS INIMMU...

Embodiment 1

[0289] Identification of ROS kinase activity in NSCLC cell lines by total phosphopeptide profiling

[0290] The total phosphorylation profile of kinase activation in several human NSCLC cell lines including HCC78 was detected using a recently described and efficient mass spectrometric characterization technique for the isolation and modification of peptides from complex mixtures ("IAP" technique, see Rush et al., supra). . IAP technique using phosphotyrosine-specific antibody (CELLSIGNALING TECHNOLOGY, INC., Beverly, MA, 2003 / 04 Cat. #9411) to isolate and subsequently determine phosphotyrosine-containing peptides from extracts of NSCLC cell lines .

[0291] In particular, the use of the IAP approach facilitates the identification of activated tyrosine kinases in NSCLC cell lines to identify novel drivers in this disease.

[0292] cell culture

[0293] HCC78 cells obtained from DSMZ (German National Resource Center for Biological Material) were grown in RPMI-1640 medium (i...

Embodiment 2

[0309] Analysis of ROS Kinase Expression in NSCLC Cell Lines by Western Blot

[0310] The observation that HCC78 NSCLC cell lines but not other NSCLC cell lines express activated ROS kinases was confirmed by Western blot analysis of cell extracts using antibodies specific for ROS and other receptor tyrosine kinases (RTKs) and downstream kinases.

[0311] Add Protease Arrest with TM (G. Biosciences) 1X Cell Lysis Buffer (CellSignaling Technology) lysed HCC78 cells and separated by electrophoresis. All antibodies and reagents used in western blotting were from Cell Signaling Technology, Inc. (Beverly, MA). Western blotting was performed as described in "Western Immunoblotting Protocol" (Cell Signaling Technology, Inc., 2005-2006 catalog). Anti-ROS antibody was obtained from Santa Cruz Biotechnology, Inc.

[0312] Figure 5 Indicates the Western blot results. Among various NSCLC cell lines, only HCC78 expressed ROS protein. The ROS protein in HCC78 has a much smaller molecu...

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Abstract

In accordance with the invention, a novel gene translocation, (4p15, 6q22), in human non-small cell lung carcinoma (NSCLC) that results in a fusion proteins combining part of Sodium-dependent Phosphate Transporter lsoform NaPi-3b protein (SLC34A2) with Proto- oncogene Tyrosine Protein Kinase ROS Precursor (ROS) kinase has now been identified. The SLC34A2-ROS fusion protein is anticipated to drive the proliferation and survival of a subgroup of NSCLC tumors. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ROS kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The disclosed identification of the new fusion protein enables new methods for determining the presence of these mutant ROS kinase polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides, which are also provided by the invention.

Description

[0001] related application [0002] This application claims priority and benefits to USSN 60 / 760,634, filed January 20, 2006 (currently pending), the disclosure of which is incorporated herein by reference. field of invention [0003] The present application basically relates to proteins and genes involved in cancer, the present application also relates to the detection, diagnosis and treatment of cancer. Background of the invention [0004] Many cancers are characterized by disruptions in cellular signaling pathways that lead to abnormal control of cellular processes or lead to uncontrolled cell growth and proliferation. These disruptions are often due to altered activity of specific signaling proteins such as kinases. One of these cancers is non-small cell lung cancer (NSCLC). NSCLC is the leading cause of cancer death in the United States and accounts for approximately 87% of all lung cancers. There are about 151,000 new NSCLC patients in the United States each year, a...

Claims

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Application Information

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IPC IPC(8): C12N15/00C07H21/02C07K5/00
CPCC12Q2600/156C12Q1/68C12Q1/6886C07K14/82G01N33/574G01N33/50A61K39/00A61K31/7088C12N15/1135C12N9/12C07K2319/00A61P35/00
Inventor 郭爱兰A·波塞马托
Owner CELL SIGNALING TECHNOLOGY
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