ROS Kinase in Lung Cancer

a technology of ros kinase and lung cancer, which is applied in the direction of instruments, drug compositions, peptides, etc., can solve the problems of lung cancer and inability to respond completely

Inactive Publication Date: 2012-08-16
CELL SIGNALING TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034]In further aspects, the invention provides a method for determining whether a compound inhibits the progression of a mammalian lung cancer or suspected mammalian lung cancer characterized by the expression of a polypeptide with ROS activity, said method comprising the step of determining whether said compound inhibits the expression of said polypeptide in said cancer. In another aspect, the invention provides a method for inhibiting the progression of a mammalian cancer or suspected mammalian cancer characterized by the expression of a polypeptide with ROS activity, said method comprising the step of inhibiting the expression and / or activity of said polypeptide in said mammalian lung cancer or suspected mammalian lung cancer. In some embodiments, the cancer is from a human.

Problems solved by technology

The development of such drugs represents a significant advance over the conventional therapies for CML and ALL, chemotherapy and radiation, which are plagued by well known side-effects and are often of limited effect since they fail to specifically target the underlying causes of the cancer.
Unfortunately, lung cancer is often not diagnosed at an early stage, and it often does not respond completely to surgery even when combined with chemotherapy or radiotherapy.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification of ROS Kinase Activity in an NSCLC Cell Line by Global Phosphopeptide Profiling

[0236]The global phosphorylation profile of kinase activation in several human NSCLC cell lines, including HCC78, were examined using the IAP technique for the isolation and mass spectrometric characterization of modified peptides from complex mixtures (see U.S. Pat. Nos. 7,300,753 and 7,198,896). The IAP technique was performed using a phosphotyrosine-specific antibody (commercially available from CELL SIGNALING TECHNOLOGY, INC., Danver, Mass., Cat. #9411) to isolate, and subsequently characterize, phosphotyrosine-containing peptides from extracts of the NSCLC cell lines.

[0237]Specifically, the IAP approach was employed to facilitate the identification of activated tyrosine kinases in the NSCLC cell lines, in order to identify novel drivers of this disease.

Cell Culture.

[0238]HCC78 cells were obtained from DSMZ (the German National Resource Centre for Biological Material), grown in RPMI-164...

example 2

Detection of Mutant ROS Kinase Expression in a Human Cancer Sample Using Global Phosphopeptide Profiling

[0250]In order to further confirm the incidence of the ROS fusion mutation in human NSCLC, several human NSCLC tumors were examined, using the IAP technique of global phosphopeptide profiling described above (see Example 1), to identify ROS phosphopeptides in these tumors. Tumor samples (dissected tumors snap frozen and kept in liquid nitrogen) were obtained from a clinical collaborator in China (Second Xiangya Hospital, Central South University Changsha, Hunan, P.R. China).

[0251]Briefly, between about 300 milligrams-500 milligrams of tumor tissue were homogenized. For example, the tissue was homogenized and lysed in urea lysis buffer (20 mM HEPES pH 8.0, 9M urea, 1 mM sodium vanadate, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate) at 1.25×108 cells / ml and sonicated. Sonicated lysates were cleared by centrifugation at 20,000×g, and proteins were reduced and alkylated as ...

example 3

Western Blot Analysis of ROS Kinase Expression in an NSCLC Cell Line

[0253]The observation that the HCC78 NSCLC cell line—but not the other NSCLC cell lines—expresses activated ROS kinase was confirmed by Western blot analysis of cell extracts using antibodies specific for ROS and other receptor tyrosine kinases (RTKs) and downstream kinases.

[0254]HCC78 cells were lysed in 1× cell lysis buffer (Cell Signaling Technology) supplemented with Protease Arrest™ (G Biosciences) and separated by electrophoresis. All antibodies and reagents for immunoblotting were from Cell Signaling Technology, Inc. (Danvers, Mass.). Western blotting was carried out as described in “Western Immunoblotting Protocol” (Cell Signaling Technology, Inc., 2005-2006 catalogue). Anti-ROS antibody was obtain from Santa Cruz Biotechnology, Inc.

[0255]FIG. 1 shows the western blot results. Only HCC78 express ROS protein among many different NSCLC cell lines. ROS protein in HCC78 has much smaller molecular weight than wil...

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Abstract

The invention provides the identification of the presence of polypeptides with ROS kinase activity in mammalian lung cancer. In some embodiments, the polypeptide with ROS kinase activity is the result of a fusion between a ROS-encoding polynucleotide and a polynucleotide encoding a second (non-ROS) polypeptide. Three different fusion partners of ROS are described, namely proteins encoded by the FIG gene, the SLC34A2 gene, and the CD74 gene. The invention enables new methods for determining the presence of a polypeptide with ROS kinase activity in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer (e.g., an lung cancer).

Description

RELATED APPLICATIONS[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 12 / 581,126 filed Oct. 17, 2009 (pending) which itself is a continuation-in-part of U.S. patent application Ser. No. 12 / 218,834, filed Jul. 18, 2008 (pending), which itself claims priority to and the benefit of PCT Patent Application No. PCT / US2007 / 001360 filed Jan. 19, 2007 (expired) and U.S. Provisional Patent Application Ser. No. 60 / 760,634, filed Jan. 20, 2006 (expired). This application also is a continuation-in-part of PCT Patent Application No. PCT / US2010 / 024109 filed Feb. 12, 2010 (pending) which itself claims priority to and benefit of U.S. Provisional Patent Application Ser. No. 61 / 207,484 filed Feb. 12, 2009 (expired). This application also is a continuation-in-part of U.S. patent application Ser. No. 12 / 738,210 filed Apr. 15, 2010 (pending) which is a US national stage filing of PCT Patent Application No. PCT / US08 / 11968 filed Oct. 20, 2008 which itself claim priority t...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4545A61K31/506G01N33/574G01N33/53C12Q1/68A61P35/00G01N33/573
CPCC12Q1/6886C12Q2600/106G01N2333/912G01N33/57423C12Q2600/156A61P11/00A61P35/00A61P43/00G01N33/574C07K19/00C12Q1/68
Inventor RIMKUNAS, VICTORIA MCGUINNESSHAACK, HERBERTGU, TING-LEIGUO, AILANPOSSEMATO, ANTHONY PAULCROSBY, KATHERINE ELEANORTUCKER, MEGHAN ANNREEVES, CYNTHIA
Owner CELL SIGNALING TECHNOLOGY
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