Methods for treatment of lymphomas with mutations in cell cycle genes

Abstract

The present disclosure identifies a novel subtype of follicular lymphoma (FL) characterized by dysregulation of the cyclin/CDK/RB proliferative pathway. This subtype of FL is associated with increased malignancy and mortality, relative to FL which is not associated with cell cycle dysregulation. Accordingly, this disclosure presents novel methods to subtype FL and stratify patient risk by detection of biomarkers associated with RB inactivation. This disclosure further presents novel therapies for the treatment of FL subtyped by inactivation of RB.

What is claimed is: 
     
         1 . A method of subtyping follicular lymphoma (FL) in a patient, comprising detecting a biomarker associated with inactivation of the retinoblastoma (RB) protein in a sample from said patient. 
     
     
         2 . The method of  claim 1 , wherein said biomarker is phosphorylated RB. 
     
     
         3 . The method of  claim 2 , wherein phosphorylated RB is detected by Western Blot, ELISA, protein microarray, or immunohistochemistry. 
     
     
         4 . The method of  claim 2 , wherein phosphorylated RB is detected using an antibody that recognizes phospho-RB-Ser608, phospho-RB-Ser612, phospho-RB-Ser780, phospho-RB-Ser795, phospho-RB-Ser807 or phospho-RB-Ser811. 
     
     
         5 . The method of  claim 1 , wherein said biomarker is a genetic alteration of the Rb locus. 
     
     
         6 . The method of  claim 5 , wherein said genetic alteration of the Rb locus is detected by one or more of: karyotype analysis, DNA microarray, amplification of RB mDNA, DNA sequencing, copy number analysis, and fluorescence in situ hybridization. 
     
     
         7 . The method of  claim 1 , wherein said biomarker is an increased level or activity of cyclin dependent kinase 4 (CDK4), determined by detecting an increased level or activity of the CDK4 protein, or by detecting a genetic alteration of the CDK4 locus. 
     
     
         8 . The method of  claim 1 , wherein said biomarker is an increased level or activity of Cyclin D3, determined by detecting an increased level or activity of the Cyclin D3 protein, or by detecting a genetic alteration in the Cyclin D3 gene. 
     
     
         9 . The method of  claim 1 , wherein said biomarker is a decreased level or activity of p16, determined by detecting a decreased level or activity of the p16 protein, or by detecting a genetic alteration in the CDNK2a/b gene locus. 
     
     
         10 . The method of  claim 1 , wherein the sample is a sample of tumor tissue, blood, or cerebro-spinal fluid. 
     
     
         11 . A pharmaceutical composition for treating follicular lymphoma, comprising a B-cell lymphoma-2 (BCL2) inhibitor and a cyclin-dependent kinase (CDK) inhibitor. 
     
     
         12 . The composition of  claim 11 , wherein the CDK inhibitor is an inhibitor of CDK4/6. 
     
     
         13 . The composition of  claim 11 , wherein the CDK inhibitor is selected from the group consisting of PD-0332991, Flavopiridol, AT7519M, P276-00, AG-024322, LEE011, LY2835219, P1446A-05, and BAY 1000394. 
     
     
         14 . The composition of  claim 11 , wherein the BCL2 inhibitor is selected from the group consisting of ABT-737, Obatoclax mesylate, Navitoclax, and TW-37. 
     
     
         15 . A method of treating follicular lymphoma (FL) in a patient identified as having retinoblastoma (RB)-inactivated FL, comprising administering a combination of a B-cell lymphoma-2 (BCL2) inhibitor and a cyclin-dependent kinase (CDK)4/6 inhibitor in an amount effective to treat RB-inactivated FL in said patient. 
     
     
         16 . The method of  claim 15 , wherein the patient has been identified as having retinoblastoma (RB)-inactivated FL by detecting a biomarker associated with inactivation of the retinoblastoma (RB) protein in a sample from said patient. 
     
     
         17 . The method of  claim 16 , wherein said biomarker is selected from one or more of the group consisting of phosphorylated RB protein, increased level or activity of cyclin-dependent kinase (CDK)4, increased level or activity of Cyclin D3, and decreased level or activity of p16. 
     
     
         18 . The method of  claim 16 , wherein said biomarker is a genetic alteration in one or more of the Rb locus, the CDK4 locus, the Cyclin D3 locus, or the CDKN2A/B locus. 
     
     
         19 . The method of  claim 15 , wherein the CDK4/6 inhibitor is selected from the group consisting of PD-0332991, Flavopiridol, AT7519M, P276-00, AG-024322, LEE011, LY2835219, P1446A-05, and BAY 1000394. 
     
     
         20 . The method of  claim 15 , wherein the BCL2 inhibitor is selected from ABT-737, Obatoclax mesylate, Navitoclax, or TW-37.