Methods of detecting a polypeptide having anaplastic lymphoma kinase activity in kidney cancer

Abstract

The invention provides methods to identify, diagnose, and treat kidney cancer through the detection of expression and/or activity of anaplastic lymphoma kinase (ALK). The detection of the presence of a polypeptide with ALK kinase activity (e.g., by detecting expression and/or activity of the polypeptide), identify those kidney cancers that are likely to respond to an ALK-inhibiting therapeutic.

What is claimed is: 
     
         1 . A method for detecting the presence or activity of a polypeptide with ALK kinase activity in a biological sample from a mammalian kidney cancer or suspected mammalian kidney cancer, said method comprising the steps of: (a) obtaining a biological sample from a mammalian kidney cancer or suspected mammalian kidney cancer and (b) contacting the biological sample with a detection molecule selected from the group consisting of a reagent that detects ALK kinase activity, a reagent that detects a polypeptide with ALK kinase activity, and a reagent that detects to a polynucleotide encoding the polypeptide with ALK kinase activity, wherein reaction of the detection molecule with the biological sample indicates said polypeptide with ALK kinase activity is present or active in said mammalian kidney cancer or suspected mammalian kidney cancer. 
     
     
         2 . The method of  claim 1 , wherein the mammalian kidney cancer or suspected mammalian kidney cancer in which the presence or activity of said polypeptide with ALK kinase activity is detected is identified as a mammalian kidney cancer or suspected mammalian kidney cancer belonging to a subset of kidney cancers driven by ALK kinase activity. 
     
     
         3 . The method of  claim 1 , wherein the mammalian kidney cancer or suspected mammalian kidney cancer in which the presence or activity of said polypeptide with ALK kinase activity is detected is identified as a mammalian kidney cancer or suspected mammalian kidney cancer likely to respond to an ALK-inhibiting therapeutic. 
     
     
         4 . A method for identifying a mammalian kidney cancer or suspected mammalian kidney cancer that belongs to a subset of kidney cancers driven by ALK kinase activity, said method comprising the steps of (a) contacting a biological sample obtained from a mammalian kidney cancer or suspected mammalian kidney cancer with at least one detection molecule selected from the group consisting of a reagent that detects ALK kinase activity, a reagent that detects a polypeptide with ALK kinase activity, and a reagent that detects to a polynucleotide encoding the polypeptide with ALK kinase activity, and (b) detecting reaction of the detection molecule with said biological sample, wherein the reaction of the detection molecule with said biological sample indicates that said mammalian kidney cancer or suspected mammalian kidney cancer is driven by ALK kinase activity. 
     
     
         5 . The method of  claim 4 , wherein said mammalian kidney cancer or suspected mammalian kidney cancer driven by ALK kinase activity is likely to respond to a composition comprising at least one ALK-inhibiting therapeutic. 
     
     
         6 . A method for identifying a mammalian kidney cancer or suspected mammalian kidney cancer that belongs to a subset of kidney cancers driven by ALK kinase activity, said method comprising the steps of (a) contacting a biological sample obtained from a mammalian kidney cancer or suspected mammalian kidney cancer with at least one detection molecule selected from the group consisting of a reagent that detects ALK kinase activity, a reagent that detects a polypeptide with ALK kinase activity, and a reagent that detects to a polynucleotide encoding the polypeptide with ALK kinase activity, and (b) detecting reaction of the detection molecule with said biological sample, wherein the reaction of the detection molecule with said biological sample indicates that said mammalian kidney cancer or suspected mammalian kidney cancer is driven by ALK kinase activity and wherein said mammalian kidney cancer or suspected mammalian kidney cancer driven by ALK kinase activity is likely to respond to a composition comprising at least one ALK-inhibiting therapeutic. 
     
     
         7 . The method of  claim 1 ,  4 , or  6 , wherein the polypeptide with ALK kinase activity is aberrantly expressed full-length ALK protein. 
     
     
         8 . The method of  claim 1 ,  4 , or  6 , wherein the polypeptide with ALK kinase activity is an ALK fusion polypeptide comprising at least a portion of a first fusion member and at least a portion of a second fusion member, wherein the second fusion member is an ALK protein. 
     
     
         9 . The method of  claim 5 , wherein the first fusion member is selected from the group consisting of a NPM polypeptide, a ALO17 polypeptide, a TFG polypeptide, a MSN polypeptide, a TPM3 polypeptide, a TPM4 polypeptide, an ATIC polypeptide, a MYH9 polypeptide, a CLTC polypeptide, a SEC31L1 polypeptide, an RANBP2 polypeptide, a CARS polypeptide, an EML4 polypeptide, a KIF5B polypeptide, and a VCL polypeptide. 
     
     
         10 . The method of  claim 1 ,  4 , or  6 , wherein the reagent that detects ALK kinase activity is a substrate of ALK kinase or a reagent that specifically binds to phosphorylated ALK protein. 
     
     
         11 . The method of  claim 10 , wherein the method is implemented in an in vitro kinase assay format. 
     
     
         12 . The method of  claim 1 ,  4 , or  6 , wherein the reagent that detects a polypeptide with ALK kinase activity is a reagent that specifically binds to the polypeptide with ALK kinase activity. 
     
     
         13 . The method of  claim 12 , wherein the reagent that specifically binds to the polypeptide with ALK kinase activity is an antibody that specifically binds to the polypeptide with ALK kinase activity. 
     
     
         14 . The method of  claim 13 , wherein the antibody specifically binds to a full length ALK protein. 
     
     
         15 . The method of  claim 13 , wherein the polypeptide with ALK kinase activity is an ALK fusion polypeptide comprising at least a portion of a first fusion member and at least a portion of a second fusion member, wherein the second fusion member is an ALK protein and the antibody specifically binds the ALK fusion polypeptide. 
     
     
         16 . The method of  claim 15 , wherein the antibody specifically binds to a portion of the ALK protein present in the ALK fusion polypeptide, a portion of the first fusion member present in the ALK fusion polypeptide, or a junction between the first fusion member and the portion of the ALK protein present in the ALK fusion. 
     
     
         17 . The method of  claim 12 , wherein said method is implemented in a format selected from the group consisting of a flow cytometry assay, an immunohistochemistry (IHC) assay, an immunofluorescence (IF) assay, an Enzyme-linked immunosorbent assay (ELISA) assay, a Western blotting analysis assay, and a mass spectrometry assay. 
     
     
         18 . The method of  claim 1 ,  4 , or  6 , wherein the reagent that detects a polynucleotide encoding the polypeptide with ALK kinase activity is a nucleic acid probe or primer that hybridizes to said polynucleotide. 
     
     
         19 . The method of  claim 18 , wherein the nucleic acid probe or primer is selected from the group consisting of a polymerase chain reaction (PCR) probe, an in situ hybridization (ISH) probe, and a Southern blotting probe. 
     
     
         20 . The method of  claim 18 , wherein said method is implemented in a format selected from the group consisting of a polymerase chain reaction (PCR) assay, an in situ hybridization (ISH) assay, and a Southern blotting assay. 
     
     
         21 . The method of  claim 1 ,  4 , or  6 , Therein the detection molecule is detectably labeled. 
     
     
         22 . The method of  claim 1 ,  4 , or  6 , wherein said mammalian kidney cancer or suspected mammalian kidney cancer is a granular cell cancer or a squamous cell cancer. 
     
     
         23 . The method of  claim 1 ,  4 , or  6 , wherein said biological sample comprises at least one circulating tumor cell from said mammalian kidney cancer or suspected mammalian kidney cancer. 
     
     
         24 . The method of  claim 1 ,  4 , or  6 , wherein said biological sample comprises cells obtained from a tumor biopsy, a tumor fine needle aspirate, or a pleural effusion. 
     
     
         25 . The method of  claim 1 ,  4 , or  6 , wherein said mammalian kidney cancer or suspected mammalian kidney cancer is from a human. 
     
     
         26 . A method for determining whether a compound inhibits the progression of a mammalian kidney cancer or suspected mammalian kidney cancer driven by a polypeptide with ALK kinase activity, said method comprising the step of determining whether said compound inhibits the expression and/or activity of said polypeptide in said cancer mammalian kidney cancer or suspected mammalian kidney cancer. 
     
     
         27 . The method of  claim 26 , wherein inhibition of the expression and/or activity of the polypeptide is determined using at least one detection molecule selected from the group consisting of a reagent that detects ALK kinase activity, a reagent that detects a polypeptide with ALK kinase activity, and a reagent that detects to a polynucleotide encoding the polypeptide with ALK kinase activity. 
     
     
         28 . A method for inhibiting the progression of a mammalian kidney cancer or suspected mammalian kidney cancer driven by a polypeptide with ALK kinase activity, said method comprising the step of inhibiting the expression and/or activity of said polypeptide in said mammalian kidney cancer or suspected mammalian kidney cancer. 
     
     
         29 . The method of  claim 26  or  28 , wherein the mammalian kidney cancer or suspected mammalian kidney cancer is from a human. 
     
     
         30 . The method of  claim 28 , wherein expression and/or activity of said polypeptide is inhibited with a composition comprising a ALK-inhibiting therapeutic. 
     
     
         31 . A method for treating a mammalian patient with mammalian kidney cancer or suspected mammalian kidney cancer driven by a polypeptide with ALK kinase activity, said method comprising the step of administering a composition comprising a therapeutically effective amount of an ALK-inhibiting therapeutic to the mammalian patient. 
     
     
         32 . The method of  claim 26 ,  28 , or  31 , wherein said polypeptide is a full length ALK polypeptide aberrantly expressed in said mammalian kidney cancer. 
     
     
         33 . The method of  claim 26 ,  28 , or  31 , wherein said polypeptide is an ALK fusion polypeptide. 
     
     
         34 . The method of  claim 33 , wherein said ALK fusion polypeptide is selected from the group consisting of an NPM-ALK fusion polypeptide, an ALO17-ALK fusion polypeptide, an MSN-ALK fusion polypeptide, a TPM3-ALK fusion polypeptide, TPM4-ALK fusion polypeptide, an ATIC-ALK fusion polypeptide, a MYH9-ALK fusion polypeptide, a CLTC-ALK fusion polypeptide, a SEC31L1-ALK fusion polypeptide, an RANBP2-ALK fusion polypeptide, a CARS-ALK fusion polypeptide, an EMLA-ALK fusion polypeptide, a KIF5B-ALK fusion polypeptide, a TFG-ALK fusion polypeptide, and a VCL-ALK fusion polypeptide. 
     
     
         35 . A method for treating a mammalian patient having a mammalian kidney cancer or suspected mammalian kidney cancer comprising the steps of:
 (a) detecting the presence or activity of said polypeptide with ALK kinase activity a biological sample of the mammalian kidney cancer or suspected mammalian kidney cancer of the patient; and   (b) administering a therapeutically effective amount of a composition comprising an ALK-inhibiting therapeutic to the mammalian patient.   
     
     
         36 . The method of  claim 31  or  35 , wherein the mammalian patient is a human. 
     
     
         37 . The method of  claim 3 ,  5 ,  6 ,  30 ,  31  or  35 , wherein the ALK-inhibiting therapeutic is selected from the group consisting of PE-02341066, NVT TAE-684, and AP26113. 
     
     
         38 . The method of  claim 3 ,  5 ,  6 ,  30 ,  31  or  35 , wherein the ALX-inhibiting therapeutic is selected from the group consisting of CEP-14083, CEP-14513, CEP11988, WHI-P131 and WHI-P154.