Cereblon isoforms and their use as biomarkers for therapeutic treatment

Abstract

Provided herein are cereblon isoforms and methods of their use as biomarkers for treating a disease, disorder, or condition with a treatment compound, e.g., thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin-3 (4H)-yl)-piperidine-2,6-dione, or (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.

1 .- 31 . (canceled) 
     
     
         32 . A method of identifying a subject having multiple myeloma who is likely to be responsive to a treatment with a treatment compound, comprising:
 a) determining the level of a biomarker in a biological sample from the subject, wherein the biomarker is an isoform of cereblon (CRBN), the isoform of CRBN having a deletion in exon 10 of CRBN; and   b) comparing the level of the biomarker in the biological sample from the subject to a reference level of the biomarker;   wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.   
     
     
         33 .- 49 . (canceled) 
     
     
         50 . The method of  claim 32 , wherein the level of the biomarker is measured by determining the mRNA level of the biomarker. 
     
     
         51 . The method of  claim 32 , wherein the level of the biomarker is measured by determining the cDNA level of the biomarker. 
     
     
         52 . The method of  claim 32 , wherein the level of the biomarker is measured by determining the protein level of the biomarker. 
     
     
         53 . The method of  claim 32 , wherein the treatment compound is an immunomodulatory compound. 
     
     
         54 . The method of  claim 53 , wherein the treatment compound is thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 
     
     
         55 . The method of  claim 53 , wherein the treatment compound is thalidomide. 
     
     
         56 . The method of  claim 53 , wherein the treatment compound is lenalidomide. 
     
     
         57 . The method of  claim 53 , wherein the treatment compound is pomalidomide. 
     
     
         58 . The method of  claim 53 , wherein the treatment compound is 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione. 
     
     
         59 . The method of  claim 53 , wherein the treatment compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 
     
     
         60 .- 102 . (canceled) 
     
     
         103 . The method of  claim 32 , further comprises administering the treatment compound to the subject determined to be likely responsive to the treatment. 
     
     
         104 . A method of selectively treating a subject having multiple myeloma, comprising:
 a) determining the level of a biomarker in a biological sample from the subject, wherein the biomarker is an isoform of cereblon (CRBN), the isoform of CRBN having a deletion in exon 10 of CRBN;   b) comparing the level of the biomarker in the biological sample from the subject to a reference level of the biomarker;   c) administering a treatment compound to the subject, wherein the level of the biomarker in the biological sample from the subject is altered as compared to the reference level of the biomarker.   
     
     
         105 . The method of  claim 104 , wherein the treatment compound is thalidomide, lenalidomide, pomalidomide, 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. 
     
     
         106 . The method of  claim 105 , wherein the treatment compound is pomalidomide. 
     
     
         107 . The method of  claim 32 , wherein the isoform of CRBN has deletion of amino acids 339 to 382 in the amino acid sequence of CRBN. 
     
     
         108 . The method of  claim 103 , wherein the isoform of CRBN has deletion of amino acids 339 to 382 in the amino acid sequence of CRBN.