Methods for treating pten deficient epithelial cancers using a combination of anti-pi3kbeta and anti-immune checkpoint agents

Abstract

The present invention relates to methods for treating PTEN deficient epithelial cancers using a combination of anti-PI3Kbeta and anti-immune checkpoint agents.

1 . A method of treating a subject afflicted with a cancer that is deficient in phosphatase and tensin homolog (PTEN) comprising administering to the subject a therapeutically effective amount of at least one agent that inhibits or blocks both phosphoinositide 3-kinase isoform beta (PI3Kbeta) and an immune checkpoint, wherein the cancer is an epithelial cancer. 
     
     
         2 . The method of  claim 1 , wherein the at least one agent is a single agent that inhibits or blocks both PI3Kbeta and the immune checkpoint. 
     
     
         3 . The method of  claim 1 , wherein the at least one agent comprises a first agent that selectively inhibits or blocks PI3Kbeta and a second agent that selectively inhibits or blocks the immune checkpoint, optionally wherein the first agent and the second agent comprise a small molecule that inhibits or blocks PI3Kbeta and/or the immune checkpoint. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the at least one agent comprises an RNA interfering agent which inhibits expression of PI3Kbeta and/or the immune checkpoint, optionally wherein the RNA interfering agent is a small interfering RNA (siRNA), small hairpin RNA (shRNA), or a microRNA (miRNA). 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the at least one agent comprises
 a) an antisense oligonucleotide complementary to PI3Kbeta and/or the immune checkpoint,   b) a peptide or peptidomimetic that inhibits or blocks PI3Kbeta and/or the immune checkpoint; and/or   c) an aptamer that inhibits or blocks PI3Kbeta and/or the immune checkpoint.   
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the at least one agent is an antibody and/or an intrabody, or an antigen binding fragment thereof, which specifically binds to PI3Kbeta protein and/or the immune checkpoint protein, optionally wherein the antibody and/or intrabody, or antigen binding fragment thereof, is murine, chimeric, humanized, composite, or human. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 10 , wherein the antibody and/or intrabody, or antigen binding fragment thereof, is detectably labeled, comprises an effector domain, comprises an Fc domain, and/or is selected from the group consisting of Fv, Fav, F(ab′)2), Fab′, dsFv, scFv, sc(Fv)2, and diabodies fragments. 
     
     
         13 . The method of  claim 10 , wherein the antibody and/or intrabody, or antigen binding fragment thereof, is conjugated to a cytotoxic agent, optionally wherein the cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, a biologic agent, a toxin, and a radioactive isotope. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, VISTA, B7-H2, B7-H3, PD-L1, B7-H4, B7-H6, 2B4, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, BTLA, SIRPalpha, CD47, CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, IDO, CD39, arginase, CD73, and A2aR, optionally wherein a) the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, TIM-3, and LAG-3 and/or b) wherein the immune checkpoint is PD-1. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the at least one agent comprises a selective PI3Kbeta inhibitor, optionally wherein the selective PI3Kbeta inhibitor has at least 2-fold more selectivity for the PI3Kbeta isoform as compared to a non-PI3Kbeta isoform selected from the group consisting of PI3Kalpha, PI3Kdelta, and PI3Kgamma. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the at least one agent comprises 5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine (BKM120) and/or (-)-2-[[(1R)-1-[7-Methyl-2-(3-morpholinyl)-4-ox-4H-pyrido[1,2-a]-pyrimidin-9-yl]ethyl]amino]benzoic acid (KIN193). 
     
     
         21 . The method of  claim 1 , wherein the at least one agent
 a) reduces the number of proliferating cells in the cancer and/or reduces the volume or size of a tumor of the cancer,   b) increases the number of viable CD8+ T cells within a tumor of the cancer, and/or c) is administered in a pharmaceutically acceptable formulation.   
     
     
         22 - 23 . (canceled) 
     
     
         24 . The method of  claim 1 , further comprising administering to the subject a therapeutic agent or regimen for treating the cancer, optionally wherein the therapeutic agent is hormone therapy. 
     
     
         25 . The method of  claim 1 , wherein the PTEN deficiency comprises a mutation to a genomic nucleic acid sequence encoding PTEN, optionally wherein the mutation is selected from the group consisting of a missense mutation, a nonsense mutation, a frameshift mutation, an insertion mutation, a deletion mutation, and a rearrangement mutation. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the PTEN deficiency is determined to be very low or null, as assessed by immunohistochemistry, or is a mutation to a genomic nucleic acid sequence encoding PTEN protein and the mutation is a missense mutation, a nonsense mutation, a frameshift mutation, an insertion mutation, a deletion mutation, or a rearrangement mutation of a PTEN codon C71, R130, R233, D268, T319 or X70, or phosphatase or C2 domains, optionally wherein the PTEN deficiency is a) a null mutation and/or 2) a germline or somatic null mutation. 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the cancer has a p53 deficiency. 
     
     
         31 . The method of  claim 30 , wherein the p53 deficiency is a mutation to a genomic nucleic acid sequence encoding p53 protein and the mutation is a missense mutation, a nonsense mutation, a frameshift mutation, an insertion mutation, a deletion mutation, or a rearrangement mutation of a p53 codon L45, Y126, P151, S166, R175, C176, H179, G187, H193, L194, R196, R213, Y220, C242, G245, R248, R249, R273, R280, D281, R282, E286, E294, or transactivation, DNA-binding or oligomerization domains, optionally wherein the p53 deficiency is a) a null mutation and/or 2) a germline or somatic null mutation. 
     
     
         32 . The method of  claim 31 , wherein the p53 deficiency is a germline or somatic p53 null mutation. 
     
     
         33 . The method of  claim 32 , wherein the epithelial cancer is a breast cancer, an ovarian cancer, or a prostate cancer, optionally wherein a) the breast cancer is triple negative breast cancer (TNBC) and/or metastatic TNBC, or b) wherein the ovarian cancer is serous ovarian cancer. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the subject is
 a) an animal model of the epithelial cancer, optionally wherein the animal model is an orthotopic xenograft animal model of a human-derived epithelial cancer and/or a mouse model;   b) a mammal, optionally wherein the mammal is a mouse or a human.   
     
     
         38 - 42 . (canceled)