Treatment of acute myeloid leukemia with hypomethylating agents and 2-o, 3-o desulfated heparinoids

Abstract

Methods are presented for treating cancers and hematopoietic stem cell disorders, comprising administering to a subject with a cancer or hematopoietic stem cell disorder who is receiving a treatment regimen, a heparin derivative capable of inhibiting, reducing, abrogating or otherwise interfering with the binding of CXCL12 to CXCR4, wherein the cancer or hematopoietic stem cell disorder is one in which interaction of CXCL12 with CXCR4 privileges the cancer or disordered HSCs against therapeutic intervention. In preferred embodiments, the heparin derivative is a substantially 2-O, 3-O-desulfated heparin derivative.

What is claimed is: 
     
         1 . A method of treating cancer, comprising:
 adjunctively administering to a patient receiving an antineoplastic treatment regimen a CXCL12-interacting heparinoid, in an amount and at a time effective to enhance effectiveness of the antineoplastic treatment regimen.   
     
     
         2 . The method of  claim 1 , wherein the cancer being treated is one in which interaction of CXCL12 with CXCR4 privileges the cancer against therapeutic intervention. 
     
     
         3 . The method of  claim 2 , wherein the cancer being treated is one in which neoplastic cells migrate to and/or reside in one or more privileged anatomic sites. 
     
     
         4 . The method of  claim 3 , wherein the privileged anatomic site is bone marrow. 
     
     
         5 . The method of  claim 3 , wherein the cancer is a hematologic cancer. 
     
     
         6 . The method of  claim 3 , wherein the cancer has substantial potential to metastasize to the bone marrow. 
     
     
         7 . The method of  claim 6 , wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lung cancer and melanoma. 
     
     
         8 . The method of  claim 7 , wherein the cancer is lung cancer. 
     
     
         9 . The method of  claim 8 , wherein the lung cancer is non-small cell lung cancer. 
     
     
         10 . The method of  claim 3 , wherein the cancer is selected from the group consisting of kidney cancer, thyroid cancer, or neuroblastoma. 
     
     
         11 . The method of  claim 3 , wherein the cancer is selected from the group consisting of metastatic prostate cancer, metastatic lung cancer, metastatic breast cancer, and metastatic neuroblastoma. 
     
     
         12 . The method of  claim 3 , wherein the cancer is characterized by post treatment minimal residual disease. 
     
     
         13 . The method of  claim 12 , wherein the cancer characterized by post treatment minimal residual disease is selected from the group consisting of breast cancer, glioblastoma, lung cancer, prostate cancer, acute myeloid leukemia and chronic myelogenous leukemia. 
     
     
         14 . The method of any one of  claims 1  to  13 , wherein the antineoplastic treatment is chemotherapy. 
     
     
         15 . The method of any one of  claims 1  to  13 , wherein the antineoplastic treatment is antibody therapy. 
     
     
         16 . The method of any one of  claims 1  to  13 , wherein the antineoplastic treatment is immunotherapy. 
     
     
         17 . The method of any one of  claims 1  to  13 , wherein the antineoplastic treatment comprises radiation therapy. 
     
     
         18 . The method of any one of  claims 1  to  13 , wherein the antineoplastic treatment is a myelosuppressive antineoplastic treatment. 
     
     
         19 . The method of any one of  claims 1  to  13 , wherein the antineoplastic treatment is a non-myelosuppressive antineoplastic treatment. 
     
     
         20 . The method of  claim 19 , wherein the non-myelosuppressive antineoplastic treatment regimen does not cause a grade 1, grade 2, grade 3, or grade 4 thrombocytopenia when administered without adjunct administration of a CXCL12-interacting heparinoid. 
     
     
         21 . The method of  claim 19 , wherein the non-myelosuppressive treatment is with a therapeutic agent selected from one or more of crizotinib, seliciclib, afatinib, aldesleukin, alemtuzumab; axitinib, belinostat, sorafenib, bosutinib, brentuximab vedotin, carfilzomib, ceritinib, dabrafenib, dasatinib, everolimus, ibritumomab tiuxetan, ibrutinib, idelalisib, ipilimumab, nilotinib, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, ponatinib, ramucirumab, regorafenib, romidepsin, sipuleucel, temsirolimus, tositumomab, trametinib, vandetanib, vemurafenib, vismodegib, vorinostat, or ziv-aflibercept. 
     
     
         22 . The method of any one of  claims 1  to  21 , wherein the CXCL12-interacting heparinoid is capable of inhibiting binding of CXCL12 to CXCR4. 
     
     
         23 . The method of  claim 22 , wherein the CXCL12-interacting heparinoid capable of inhibiting binding of CXCL12 to CXCR4 is characterized by an IC 50  of about 0.05 μg/ml or less, about 0.04 μg/ml or less, about 0.03 μg/ml or less, about 0.02 μg/ml or less, or about 0.01 μg/ml or less. 
     
     
         24 . The method of  claim 22 , wherein the CXCL12-interacting heparinoid capable of inhibiting binding of CXCL12 or CXCR4 is characterized by an IC 90  of about 0.7 μg/ml or less, about 0.6 μg/ml or less, about 0.5 μg/ml or less, or about 0.4 μg/ml or less. 
     
     
         25 . The method of  claim 22 , wherein the CXCL12-interacting heparinoid is capable of effecting at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60% inhibition of the binding of CXCL12 to CXCR4 at a concentration that, if achieved in plasma, would not effect substantial anticoagulation. 
     
     
         26 . The method of any one of  claims 1  to  25 , wherein the CXCL12-interacting heparinoid is characterized by HSC mobilizing activity. 
     
     
         27 . The method of any one of  claims 1  to  26 , wherein the CXCL12-interacting heparinoid is characterized by neoplastic cell mobilizing activity from a privileged anatomic site. 
     
     
         28 . The method of  claim 27 , wherein the privileged anatomic site is bone marrow. 
     
     
         29 . The method of any one of  claims 1  to  28 , wherein the CXCL12-interacting heparinoid is substantially desulfated at the 2-O position and/or 3-O position. 
     
     
         30 . The method of  claim 29 , wherein the 2-O and/or 3-O-desulfated heparin derivative is not substantially desulfated at the 6-O or N positions. 
     
     
         31 . The method of  claim 29  or  30 , wherein the CXCL12-interacting heparinoid is at least 85% desulfated at the 2-O position. 
     
     
         32 . The method of  claim 29  or  30 , wherein the CXCL12-interacting heparinoid is at least 85% desulfated at the 3-O position. 
     
     
         33 . The method of  claim 29 , wherein the CXCL12-interacting heparinoid is at least 85% desulfated at each of the 2-O and 3-O positions. 
     
     
         34 . The method of  claim 33 , wherein the CXCL12-interacting heparinoid is at least 95% desulfated at each of 2-O and 3-O positions. 
     
     
         35 . The method of any one of  claims 29  to  34 , wherein the CXCL12-interacting heparinoid has an average molecular weight of about 8 kDa to about 15 kDa. 
     
     
         36 . The method of  claim 35 , wherein the CXCL12-interacting heparinoid has an average molecular weight of about 11 kDa to about 13 kDa. 
     
     
         37 . The method of any one of  claims 29  to  36 , wherein the CXCL12-interacting heparinoid is obtained by alkaline hydrolysis of unfractionated heparin. 
     
     
         38 . The method of any one of  claims 29  to  36 , wherein the CXCL12-interacting heparinoid is associated with a multivalent cation. 
     
     
         39 . The method of  claim 38 , wherein the multivalent cation is Mg 2+  or Ca 2+ . 
     
     
         40 . The method of  claim 39 , wherein a multivalent cation is present during alkaline hydrolysis. 
     
     
         41 . The method of any one of  claims 22  to  25 , wherein the CXCL12-interacting heparinoid is a low molecular weight heparin capable of inhibiting binding of CXCL12 to CXCR4. 
     
     
         42 . The method of  claim 41 , wherein the low molecular weight heparin is characterized by HSC mobilizing activity. 
     
     
         43 . The method of  claim 41 , wherein the low molecular weight heparin is characterized by neoplastic cell mobilizing activity from a privileged anatomic site. 
     
     
         44 . The method of  claim 43 , wherein the privileged anatomic site is bone marrow. 
     
     
         45 . The method of any one of  claims 1  to  44 , wherein the amount administered is effective to mobilize neoplastic cells from a privileged anatomic site. 
     
     
         46 . The method of  claim 45 , wherein the privileged anatomic site is bone marrow. 
     
     
         47 . The method of  claim 45 , wherein the CXCL12-interacting heparinoid is administered in an amount effective to decrease the number of neoplastic cells in the bone marrow by at least 50%. 
     
     
         48 . The method of any one of  claims 1  to  47 , wherein the CXCL12-interacting heparinoid is administered intravenously. 
     
     
         49 . The method of  claim 48 , wherein the CXCL12-interacting heparinoid is administered as a continuous infusion. 
     
     
         50 . The method of  claim 49 , wherein the CXCL12-interacting heparinoid is administered by a continuous intravenous infusion. 
     
     
         51 . The method of any one of  claims 1  to  47 , wherein the CXCL12-interacting heparinoid is administered as one or more bolus injections. 
     
     
         52 . The method of any one of  claims 1  to  47  and  51 , wherein the CXCL12-interacting heparinoid is administered subcutaneously. 
     
     
         53 . The method of any one of  claims 1  to  47 , wherein the CXCL12-interacting heparinoid is administered in an intravenous bolus followed by a continuous infusion 
     
     
         54 . The method of any one of  claims 1  to  53 , wherein the CXCL12-interacting heparinoid is administered prior to the antineoplastic treatment. 
     
     
         55 . The method of any one of  claims 1  to  53 , wherein the CXCL12-interacting heparinoid is administered concurrently with the antineoplastic treatment. 
     
     
         56 . The method of any one of  claims 1  to  53 , wherein the CXCL12-interacting heparinoid is administered prior to and concurrently with the antineoplastic treatment. 
     
     
         57 . The method of any one of  claims 1  to  53 , wherein the CXCL12-interacting heparinoid is administered in one or more cycles of induction therapy, one or more cycles of maintenance therapy, and/or one or more cycles of consolidation therapy. 
     
     
         58 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered prior to the induction therapy. 
     
     
         59 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered concurrently with the induction therapy. 
     
     
         60 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered prior to and concurrently with the induction therapy. 
     
     
         61 . The method of any one of  claims 58  to  60 , wherein the CXCL12-interacting heparinoid is administered at each cycle of the induction therapy. 
     
     
         62 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered prior to the consolidation therapy. 
     
     
         63 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered concurrently with the consolidation therapy. 
     
     
         64 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered prior to and concurrently with the consolidation therapy. 
     
     
         65 . The method of  claim 62  to  64 , wherein the CXCL12-interacting heparinoid is administered at each cycle of the consolidation therapy. 
     
     
         66 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered prior to the maintenance therapy. 
     
     
         67 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered concurrently with the maintenance therapy. 
     
     
         68 . The method of  claim 57 , wherein the CXCL12-interacting heparinoid is administered prior to and concurrently with the maintenance therapy. 
     
     
         69 . The method of any one of  claims 66  to  68 , wherein the CXCL12-interacting heparinoid is administered at each cycle of the maintenance therapy. 
     
     
         70 . In a method for treating a cancer by administering to a subject in need thereof an antineoplastic treatment, the improvement comprising:
 administering to the subject a CXCL12-interacting heparinoid in an amount and at a time effective to enhance effectiveness of the antineoplastic treatment.   
     
     
         71 . The method of  claim 70 , wherein the antineoplastic therapeutic is non-myelosuppressive antineoplastic treatment. 
     
     
         72 . The method of  claim 2 , wherein the cancer being treated is one in which stromal cell expression of CXCL12 protein exerts a prosurvival influence on tumor cells. 
     
     
         73 . The method of  claim 72 , wherein the CXCL12-interacting heparinoid is administered in an amount effective to reduce CXCL12-CXCR4 interaction. 
     
     
         74 . The method of  claim 73 , wherein the CXCL12-interacting heparinoid is administered in an amount effective to reduce tumor-specific immunosuppression. 
     
     
         75 . The method of any one of  claims 72 - 74 , wherein the cancer is selected from adenocarcinomas. 
     
     
         76 . The method of  claim 75 , wherein the cancer is selected from primary and metastatic carcinomas. 
     
     
         77 . The method of  claim 76 , wherein the cancer is selected from prostate, colorectal, breast, ovarian, bladder, lung, and hepatocellular carcinoma. 
     
     
         78 . The method of any one of  claims 72 - 77 , wherein the CXCL12-interacting heparinoid is substantially desulfated at the 2-O position and/or 3-O position. 
     
     
         79 . The method of  claim 78 , wherein the 2-O and/or 3-O-desulfated heparin is not substantially desulfated at the 6-O or N positions. 
     
     
         80 . The method of  claim 78  or  79 , wherein the CXCL12-interacting heparinoid is at least 85% desulfated at the 2-O position. 
     
     
         81 . The method of  claim 78  or  79 , wherein the CXCL12-interacting heparinoid is at least 85% desulfated at the 3-O position. 
     
     
         82 . The method of  claim 78  or  79 , wherein the CXCL12-interacting heparinoid is at least 85% desulfated at each of the 2-O and 3-O positions. 
     
     
         83 . The method of  claim 82 , wherein the CXCL12-interacting heparinoid is at least 95% desulfated at each of 2-O and 3-O positions. 
     
     
         84 . The method of any one of  claims 78  to  83 , wherein the CXCL12-interacting heparinoid has an average molecular weight of about 8 kDa to about 15 kDa. 
     
     
         84 . The method of  claim 84 , wherein the CXCL12-interacting heparinoid has an average molecular weight of about 11 kDa to about 13 kDa. 
     
     
         85 . The method of any one of  claims 78  to  84 , wherein the CXCL12-interacting heparinoid is obtained by alkaline hydrolysis of unfractionated heparin. 
     
     
         86 . The method of any one of  claims 72  to  85 , wherein the antineoplastic treatment regimen comprises administration of at least one checkpoint inhibitor. 
     
     
         87 . The method of  claim 86 , wherein the checkpoint inhibitor is selected from the group consisting of an anti-CTLA-4 monoclonal antibody, anti-PD1 monoclonal antibody, and anti-PDL1 monoclonal antibody, and combinations thereof. 
     
     
         88 . The method of  claim 87 , wherein the antineoplastic treatment regimen further comprises administration of one or more chemotherapeutic agents. 
     
     
         89 . The method of  claim 87 , wherein the antineoplastic treatment regimen further comprises administration of at least one kinase inhibitor. 
     
     
         90 . The method of  claim 89 , wherein the kinase inhibitor is selected from the group consisting of crizotinib, afatinib, axitinib, bosutinib, ceritinib, dabrafenib, dasatinib, ibrutinib, nilotinib, ponatinib, regorafenib, trametinib, vandetanib, vemurafenib, and sorafenib. 
     
     
         91 . The method of  claim 18 , wherein the antineoplastic treatment regimen includes administration of one or more of an alkylating agent, antimetabolite, anthracycline, topoisomerase inhibitor or mitotic inhibitor. 
     
     
         92 . The method of  claim 18 , wherein the antineoplastic regimen comprises administration of one or more of venetoclax, decitabine, LY573636, aldesleukin, bortezomib, ixazomib, tipifarnib, panobinostat, pracinostat, clorfarabine, alvocidib, lenolidamide, dasatinib, volasertib, sorafenib, CP-351, vosaroxin, etoposide, mitoxantrone, guadecitabine, gemtuzumab ozogamicin, SGN-CD33A, BI 836858, AGS67E, arsenic trioxide, vorinostat, binimetinib, trametinib, BVD-523, E6201, vyxeos, AZD1775, 8-chloro-adenosine, cladribine, flutarabine, capecitidine, pomalidomide, erwinaze, treosulfan, alisertib, gedatolisib, ruxolitinib, LY2606368, OXi4503, gliteritinib, sunitinib, lestaurtinib, midostaurin, quizartinib, crenolanib, pacritinib, AKN-028, FLX925 or E6201. 
     
     
         93 . The method of  claim 18 , wherein the antineoplastic regimen comprises administration of one or more of a FMS-related tyrosine kinase-3 inhibitor, a tyrosine kinase inhibitor, a proteasome inhibitor, a histone deacetylase inhibitor, a CD-33 inhibitor, a MEK inhibitor, a purine analog, an asparaginase, an mTOR inhibitor or an Aurora Kinase inhibitor. 
     
     
         94 . The method of  claim 19 , wherein the antineoplastic treatment regimen includes administration of one or more of a kinase inhibitor, a VEGFR inhibitor, a VEGFR2 inhibitor, a PDGFR inhibitor, a Src family kinase inhibitor, a hedgehog inhibitor, a retinoid X receptor activator, a histone methyltransferase inhibitor, a BCL2 inhibitor, an AKT inhibitor, a CXCR4 inhibitor, an mTOR inhibitor, an Mdm2 antagonist, an Mdm2 inhibitor, a CD25 inhibitor, a CD47 inhibitor, an IL-3R inhibitor, a BCR-Abl inhibitor, a HSP90 inhibitor, an HGF inhibitor, a MET inhibitor and a bromodomain and extra-terminal domain (BET) inhibitor and a BRD4 inhibitor. 
     
     
         95 . The method of  claim 19 , wherein the antineoplastic treatment regimen includes administration of one or more of crizotinib, seliciclib, afatinib, aldesleukin, alemtuzumab; axitinib, belinostat, bosutinib, brentuximab vedotin, carfilzomib, ceritinib, dabrafenib, dasatinib, everolimus, ibritumomab tiuxetan, ibnutinib, sorafenib, idelalisib, ipilimumab, nilotinib, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, ponatinib, ramucirumab, regorafenib, romidepsin, sipuleucel, temsirolimus, tositumomab, trametinib, vandetanib, vemurafenib, vismodegib, vorinostat, ziv-aflibercept, cabozantinib, selinexnor, PF-4449913, erismodegib, GO-203-2C, thioridazine, nivolumab, bexarotene, EPZ-5676, ABT-199, GSK2141795, entospletinib, TAK-659, CPI-613, B1-8040, LY2510924, plerixafor, mozobil, OCV-501, pacritinib, eltrombopag, promacta, revolade, nintedanib, vargatef, rapamycin, MEN1112, ipilimumab, idasanutlin, RO6839921, AMG-232, ADCT-301, KHK2823, CWP232291, SL-401, CC-90002, GSK2879552, lirilumab, BGB324, OTX-015, TEN-010, I-BET 762, CPI-203, CPI-0610, AG-120, AG-221 or IDH305. 
     
     
         96 . The method of  claim 9 , wherein the antineoplastic treatment regimen comprises chemotherapy and radiation therapy. 
     
     
         97 . The method of  claim 9 , wherein the antineoplastic treatment regimen comprises a kinase inhibitor and radiation therapy. 
     
     
         98 . The method of  claim 9 , wherein the antineoplastic treatment regimen comprises an antibody therapy and radiation therapy. 
     
     
         99 . A method of treating a hematopoietic stem cell disorder, comprising:
 adjunctively administering to a subject with a hematopoietic stem cell disorder who is receiving a stem cell disorder treatment regimen, a CXCL12-interacting heparinoid, in an amount and at a time effective to enhance effectiveness of the treatment regimen.   
     
     
         100 . The method of  claim 99 , wherein the hematopoietic stem cell disorder is myelodysplastic syndrome (MDS). 
     
     
         101 . The method of  claim 100 , wherein the treatment regimen comprises administering a hypomethylating agent. 
     
     
         102 . The method of  claim 101 , wherein the hypomethylating agent is azacitidine. 
     
     
         103 . The method of any of the preceding claims, wherein the treatment leads to reduced metastasis in the patient compared to those patients not treated with the CXCL12-interacting heparinoid. 
     
     
         104 . The method of any of the preceding claims, wherein the treatment leads to increased survival in the patient compared to those patients not treated with the CXCL12-interacting heparinoid.