Methods for determining drug efficacy for the treatment of diffuse large b-cell lymphoma, multiple myeloma, and myeloid cancers

Abstract

Provided herein, in some embodiments, are methods of using certain cereblon-associated proteins, such as Aiolos, Ikaros, interferon (IFN), and IFN pathway proteins, casein kinase 1, alpha 1 (CSNK1A1), and ZFP9, as biomarkers for use in predicting and monitoring clinical sensitivity and therapeutic response to certain compounds in patients having various diseases and disorders, such as cancers (e.g., diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), myelodysplasia syndromes (MDS) and acute myeloid leukemia (AML)) and IFN-associated disorders. Also provided herein, in certain embodiments, are methods of determining the efficacy of an immunomodulatory compound.

1 - 89 . (canceled) 
     
     
         90 . A method of monitoring interferon (IFN) therapy treatment response to a compound treatment in a patient having a cancer, or treating a cancer in a patient, comprising
 (a) obtaining a first sample from the patient,   (b) measuring the expression level of a biomarker in the first sample,   (c) administering the compound to the patient,   (d) obtaining a second sample from the patient,   (e) measuring the expression level of the biomarker in the second sample,   (f) comparing the expression levels of the biomarker in the first sample and the second sample, and   (g) administering to the patient a therapeutically effective amount of the compound when there is a likelihood of an effective IFN therapy treatment response;   wherein the biomarker is:
 (I) an interferon (IFN) pathway protein selected from the group consisting of DDX58, IFI27, IFIH1, IFIT1, IFIT3, IFITM3, IFN, ISG15, OAS3, STAT, STAT-PO4, TBK1, TBK1-PO4, and XAF1; or 
 (II) an IFN pathway protein selected from the group consisting of DDX58, DDX60, DDX60L, GBP1, IFI16, IFI27, IFI27L2, IFI35, IFI44, IFI44L, IFI6, IFIH1, IFIT1, IFIT2, IFIT3, IFIT5, IFITM2, IFNA16, IFNA5, IFNG, IFNGR1, IRF1, IRF2, IRF7, IRF8, ISG15, ISG20, MX1, MX2, OAS1, OAS2, OAS3, OASL, TLR1, TLR3, TLR4, TLR7, and TLR8; and 
   wherein an increased expression level of the biomarker in the second sample as compared to in the first sample indicates an likelihood of an effective IFN therapy treatment response; and   wherein the compound is lenalidomide, pomalidomide, thalidomide, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A), or 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound B), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a hydrate, a co-crystal, a clathrate, or a polymorph thereof.   
     
     
         91 - 96 . (canceled) 
     
     
         97 . The method of  claim 90 , wherein the first sample is obtained from a tumor biopsy, node biopsy, or a biopsy from bone marrow, spleen, liver, brain or breast. 
     
     
         98 . The method of  claim 90 , wherein the second sample is obtained from a tumor biopsy, node biopsy, or a biopsy from bone marrow, spleen, liver, brain or breast. 
     
     
         99 . The method of  claim 90 , wherein the second sample is from the same source as the first sample. 
     
     
         100 - 106 . (canceled) 
     
     
         107 . The method of  claim 90 , wherein the cancer is diffuse large B-cell lymphoma (DLBCL). 
     
     
         108 . The method of  claim 90 , wherein the cancer is multiple myeloma (MN). 
     
     
         109 . The method of  claim 90 , wherein the cancer is myelodysplastic syndrome (MDS). 
     
     
         110 . (canceled) 
     
     
         111 . The method of  claim 90 , wherein the cancer is acute myeloid leukemia (AML). 
     
     
         112 - 120 . (canceled) 
     
     
         121 . A method of monitoring IFN therapy treatment response to compound treatment in a patient having an IFN-associated disorder, or treating an IFN-associated disorder in a patient, comprising
 (a) obtaining a first sample from the patient,   (b) measuring the expression level of a biomarker in the first sample,   (c) administering the compound to the patient,   (d) obtaining a second sample from the patient,   (e) measuring the expression level of the biomarker in the second sample,   (f) comparing the expression levels of the biomarker in the first sample and the second sample, and   (g) administering to the patient a therapeutically effective amount of the compound when there is a likelihood of an effective IFN therapy treatment response;   
       wherein the biomarker is:
 (I) an interferon (IFN) pathway protein selected from the group consisting of DDX58, IFI27, IFIH1, IFIT1, IFIT3, IFITM3, IFN, ISG15, OAS3, STAT, STAT-PO4, TBK1, TBK1-PO4, and XAF1; or 
 (II) an IFN pathway protein selected from the group consisting of DDX58, DDX60, DDX60L, GBP1, IFI16, IFI27, IFI27L2, IF135, IFI44, IFI44L, IFI6, IFIH1, IFIT1, IFIT2, IFIT3, IFIT5, IFITM2, IFNA16, IFNA5, IFNG, IFNGR1, IRF1, IRF2, IRF7, IRF8, ISG15, ISG20, MX1, MX2, OAS1, OAS2, OAS3, OASL, TLR1, TLR3, TLR4, TLR7, and TLR8; and 
 
       wherein an increased expression level of the biomarker in the second sample as compared to in the first sample indicates an likelihood of an effective IFN therapy treatment response; and 
       wherein the compound is lenalidomide, pomalidomide, thalidomide, 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (Compound A), or 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound B), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a hydrate, a co-crystal, a clathrate, or a polymorph thereof. 
     
     
         122 - 133 . (canceled) 
     
     
         134 . The method of  claim 121 , wherein the IFN-associated disorder is conyloma accuminata. 
     
     
         135 . The method of  claim 121 , wherein the IFN-associated disorder is chronic hepatitis B. 
     
     
         136 . The method of  claim 121 , wherein the IFN-associated disorder is chronic hepatitis C. 
     
     
         137 . The method of  claim 121 , wherein the IFN-associated disorder is relapsing-remitting multiple sclerosis. 
     
     
         138 . The method of  claim 121 , wherein the IFN-associated disorder is chronic granulomatous disease. 
     
     
         139 - 146 . (canceled) 
     
     
         147 . The method of  claim 90 , wherein the IFN pathway protein is selected from the group consisting of DDX58, IFI27, IFIH1, IFIT1, IFIT3, IFITM3, IFN, ISG15, OAS3, STAT, STAT-PO4, TBK1, TBK1-PO 4 , and XAF1. 
     
     
         148 . The method of  claim 90 , wherein the IFN pathway protein is selected from the group consisting of DDX58, DDX60, DDX60L, GBP1, IFI16, IFI27, IFI27L2, IFI35, IFI44, IFI44L, IFI6, IFIH1, IFIT1, IFIT2, IFIT3, IFIT5, IFITM2, IFNA16, IFNA5, IFNG, IFNGR1, IRF1, IRF2, IRF7, IRF8, ISG15, ISG20, MX1, MX2, OAS1, OAS2, OAS3, OASL, TLR1, TLR3, TLR4, TLR7, and TLR8. 
     
     
         149 - 157 . (canceled) 
     
     
         158 . The method of  claim 90 , wherein the compound is lenalidomide, or stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 
     
     
         159 . (canceled) 
     
     
         160 . The method of  claim 90 , wherein the compound is pomalidomide, or stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 
     
     
         161 . (canceled) 
     
     
         162 . The method of  claim 90 , wherein the compound is thalidomide, or stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 
     
     
         163 . (canceled) 
     
     
         164 . The method of  claim 90 , wherein the compound is Compound A, or stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 
     
     
         165 . (canceled) 
     
     
         166 . The method of  claim 90 , wherein the compound is Compound B, or stereoisomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 
     
     
         167 . (canceled)