Methods and pharmaceutical compositions for treating lymphoid malignancy

Abstract

The present invention provides, inter alia, methods for treating, preventing, or ameliorating the effects of a lymphoid malignancy, such as those associated with a mutated phosphatase and tensin homolog (PTEN) gene, or T-cell acute lymphoblastic leukemia (T-ALL). These methods include administering to a subject an effective amount of a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. The present invention also provides pharmaceutical compositions for treating the effects of a lymphoid malignancy. This invention further provides a method for identifying a subject who may benefit from co-treatment with a PI3Kδ inhibitor and a PI3Kγ inhibitor. This method includes determining from a sample of the subject whether the subject has a mutated PTEN gene. Additionally, this invention provides methods for identifying a compound that has both PI3Kδ and PI3Kγ inhibitory activity.

What is claimed is: 
     
         1 . A method for treating, preventing, or ameliorating the effects of a lymphoid malignancy comprising administering to a subject in need thereof an effective amount of a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. 
     
     
         2 . The method according to  claim 1 , wherein the lymphoid malignancy is T-cell acute lymphoblastic leukemia (T-ALL) or T-cell acute lymphoblastic lymphoma. 
     
     
         3 . The method according to  claim 2 , wherein the lymphoid malignancy is T-ALL. 
     
     
         4 . The method according to  claim 1 , wherein the PI3Kδ inhibitor is selected from the group consisting of a biologic, a chemical, and combinations thereof. 
     
     
         5 . The method according to  claim 4 , wherein the PI3Kδ inhibitor is selected from the group consisting of AMG-319; PI3-delta inhibitors, Cellzome; PI3-delta/gamma inhibitors, Cellzome; CHR-4432; XL-499; CAL-120; CAL-129; CAL-130; CAL-253; CAL-263; GS-1101 (CAL-101); benzimidazole series, Genentech; PI3 kinase delta inhibitors, Genentech; PI3 kinase inhibitor, Roche-4; PI3 kinase inhibitors, Roche; PI3 kinase inhibitors, Roche-5; pictilisib; PI3 kinase delta inhibitors, Incozen; PI3 kinase delta inhibitors-2, Incozen; PI3-delta inhibitors, Intellikine; PI3-delta/gamma inhibitors, Intellikine; PI3K delta/gamma inhibitors, Intellikine-1; KAR-4139; KAR-4141; PI3 kinase delta inhibitor, Merck KGaA; OXY-111A; PI3-alpha/delta inhibitors, Pathway Therapeutics; PI3-delta inhibitors, Pathway Therapeutics-1; PI3-delta inhibitors, Pathway Therapeutics-2; PI3-delta/gamma inhibitors, Pathway Therapeutics; SF-1126; X-339; IC87114; TG100-115; and combinations thereof. 
     
     
         6 . The method according to  claim 5 , wherein the PI3Kδ inhibitor is CAL-130. 
     
     
         7 . The method according to  claim 4 , wherein the PI3Kδ inhibitor is a nucleic acid comprising an shRNA. 
     
     
         8 . The method according to  claim 1 , wherein the PI3Kγ inhibitor is selected from the group consisting of a biologic, a chemical, and combinations thereof. 
     
     
         9 . The method according to  claim 8 , wherein the PI3Kγ inhibitor is selected from the group consisting of PI3-delta/gamma inhibitors, Cellzome; PI3-gamma inhibitor, Cellzome; PI3-gamma inhibitor Evotec; PI3 kinase inhibitors, Roche; pictilisib; IPI-145; PI3-delta/gamma inhibitors, Intellikine; PI3K delta/gamma inhibitors, Intellikine-1; KIN-1; PI3-delta/gamma inhibitors, Pathway Therapeutics; PI3-gamma inhibitors, Pathway Therapeutics; SC-103980; SF-1126; AS-041164; AS-604850; TG100-115; AS-605240; CAL-130; and combinations thereof. 
     
     
         10 . The method according to  claim 9 , wherein the PI3Kγ inhibitor is CAL-130. 
     
     
         11 . The method according to  claim 8 , wherein the PI3Kγ inhibitor is a nucleic acid comprising an shRNA. 
     
     
         12 . The method according to  claim 1 , further comprising co-administering to the subject at least one chemotherapeutic agent. 
     
     
         13 . The method according to  claim 12 , wherein the chemotherapeutic agent is selected from the group consisting of actinomycin, amsacrine, anthracycline, busulfan, cisplatin, cytoxan, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, mitoxantrone, taxotere, teniposide, triethylenethiophosphoramide, hydrocortisone, cortisone, methylprednisolone, prednisolone, dexamethasone, prednisone, betamethasone, triamcinolone, beclometasone, fludrocortisones, deoxycorticosterone, aldosterone, oxaliplatin, zoledronic acid, ibandronate, verapamil, podophyllotoxin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, transplatinum, 5-fluorouracil, vincristin, vinblastin, methotrexate, L-asparaginase, rapamycin, dibenzazepine (DBZ), uramustine, carmustine, lomustine, streptozocin, temozolomide, oxaliplatin, idarubicin, topotecan, premetrexed, 6-mercaptopurine, darcarbazine, fludarabine, 5-fluorouracil, arabinosycytosine, 5-fluorouracil, arabinosylcytosine, capecitabine, gemcitabine, decitabine, vinca alkaloids, paclitaxel (Taxol®), docetaxel (Taxotere®), ixabepilone (Ixempra®), and combinations thereof. 
     
     
         14 . The method according to  claim 12 , wherein the chemotherapeutic agent is a glucocorticoid selected from the group consisting of hydrocortisone, cortisone, methylprednisolone, prednisolone, dexamethasone, prednisone, betamethasone, triamcinolone, beclometasone, fludrocortisones, deoxycorticosterone, aldosterone, and combinations thereof. 
     
     
         15 . The method according to  claim 12 , wherein the chemotherapeutic agent is dexamethasone. 
     
     
         16 . A method for treating, preventing, or ameliorating the effects of a lymphoid malignancy associated with a mutated phosphatase and tensin homolog (PTEN) gene in a subject comprising administering to the subject an effective amount of a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. 
     
     
         17 . The method according to  claim 16 , wherein the PI3Kδ inhibitor and the PI3Ky inhibitor are CAL-130. 
     
     
         18 . A pharmaceutical composition for treating the effects of a lymphoid malignancy comprising a pharmaceutically acceptable carrier and an effective amount of a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , which is in a unit dosage form. 
     
     
         20 . The pharmaceutical composition according to  claim 18 , further comprising an effective amount of dexamethasone. 
     
     
         21 . A method for treating a subject suffering from T-cell acute lymphoblastic leukemia (T-ALL) comprising administering to the subject an effective amount of a pharmaceutical composition comprising a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. 
     
     
         22 . The method according to  claim 21  further comprising administering an effective amount of a glucocorticoid selected from the group consisting of hydrocortisone, cortisone, methylprednisolone, prednisolone, dexamethasone, prednisone, betamethasone, triamcinolone, beclometasone, fludrocortisones, deoxycorticosterone, aldosterone, and combinations thereof. 
     
     
         23 . The method according to  claim 22 , wherein the glucocorticoid is dexamethasone. 
     
     
         24 . A method for lowering tumor burden in a subject suffering from T-cell acute lymphoblastic leukemia (T-ALL) comprising administering to the subject an effective amount of a pharmaceutical composition comprising a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor. 
     
     
         25 . The method according to  claim 24  further comprising administering an effective amount of a glucocorticoid selected from the group consisting of hydrocortisone, cortisone, methylprednisolone, prednisolone, dexamethasone, prednisone, betamethasone, triamcinolone, beclometasone, fludrocortisones, deoxycorticosterone, aldosterone, and combinations thereof. 
     
     
         26 . The method according to  claim 25 , wherein the glucocorticoid is dexamethasone. 
     
     
         27 . A method for identifying a subject who may benefit from co-treatment with a phosphoinositide 3-kinase-delta (PI3Kδ) inhibitor and a phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitor comprising determining from a sample of the subject whether the subject has a mutated PTEN gene, wherein the presence of the mutated PTEN gene is indicative of a subject who may benefit from co-treatment with a PI3Kδ inhibitor and a PI3Kγ inhibitor. 
     
     
         28 . A method for identifying a compound that has both phosphoinositide 3-kinase-delta (PI3Kδ) and phosphoinositide 3-kinase-gamma (PI3Kγ) inhibitory activity comprising:
 (a) contacting a cell with the compound; and 
 (b) determining whether the compound modulates an antigen receptor-induced activity in the cell; 
 
       wherein a compound that modulates the antigen receptor-induced activity has both PI3Kδ and PI3Kγ inhibitory activity.