Methods for treating fibrotic cancers

Abstract

In part, the disclosure relates to methods of treating fibrotic cancers by administering one or more Serum Amyloid Protein (SAP) agonists. In certain aspects, the method further comprises the conjoint administration of an anti-cancer therapeutic, e.g., a chemotherapeutic agent. In certain aspects, the disclosure relates to methods of treating myelofibrosis by administering an SAP agonist and optionally one or more anti-cancer therapeutic agents.

1 . A method for treating myelofibrosis or improving the efficacy of an anti-cancer therapeutic in a patient with myelofibrosis, comprising administering to said patient a therapeutically effective amount of a serum amyloid P (SAP) agonist, and wherein said SAP polypeptide is to be administered multiple times in an initial loading dose during a first week of administration followed by one time every one to four weeks. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the SAP agonist is a glycosylated human SAP polypeptide comprising an N-linked oligosaccharide chain, and wherein at least one branch of the oligosaccharide chain terminates with a α2,3-linked sialic acid moiety. 
     
     
         5 . The method of  claim 4 , wherein all branches of the oligosaccharide chain terminate with α2,3-linked sialic acid moieties. 
     
     
         6 . The method of  claim 4 , wherein the oligosaccharide chain is substantially free of α2,6-linked sialic acid moieties. 
     
     
         7 . The method of  claim 1 , wherein the SAP polypeptide comprises an amino acid sequence at least 85% identical to SEQ ID NO: 1. 
     
     
         8 . The method of  claim 7 , wherein the SAP polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1. 
     
     
         9 . The method of  claim 1 , wherein the SAP polypeptide is a fusion protein comprising an SAP-domain and one or more heterologous domains, wherein the one or more heterologous domains enhance one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, formation of protein complexes, and/or purification. 
     
     
         10 . The method of  claim 8 , wherein the SAP polypeptide comprises the amino acid sequence of SEQ ID NO: 1. 
     
     
         11 . The method of  claim 1 , wherein the SAP polypeptide comprises one or more modified amino acid residues. 
     
     
         12 . The method of  claim 11 , wherein the one or more modified amino acid residues comprise a PEGylated amino acid, a prenylated amino acid, an acetylated amino acid, a biotinylated amino acid, and/or an amino acid conjugated to an organic derivatizing agent. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the method further comprises administering to the patient the anti-cancer therapeutic. 
     
     
         16 . The method of  claim 15 , wherein the anti-cancer therapeutic is selected from: chemotherapy agents, antibody-based agents, tyrosine kinase inhibitors, immunomodulatory agents, biologic agents, and combinations thereof. 
     
     
         17 . The method of  claim 16 , wherein
 (a) the chemotherapy agent is selected from: actinomycin D, aldesleukin, alitretinoin, all-trans retinoic acid/ATRA, altretamine, amascrine, asparaginase, azacitidine, azathioprine,  bacillus  calmette-guerin/BCG, bendamustine hydrochloride, bexarotene, bicalutamide, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, cisplatin/cisplatinum, cladribine, cyclophosphamide/cytophosphane, cytabarine, dacarbazine, daunorubicin/daunomycin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil (5-FU), gemcitabine, goserelin, hydrocortisone, hydroxyurea, idarubicin, ifosfamide, interferon alfa, irinotecan CPT-11, lapatinib, lenalidomide, leuprolide, mechlorethamine/chlormethine/mustine/HN2, mercaptopurine, methotrexate, methylprednisolone, mitomycin, mitotane, mitoxantrone, octreotide, oprelvekin, oxaliplatin, paclitaxel, pamidronate, pegaspargase, pegfilgrastim, PEG interferon, pemetrexed, pentostatin, phenylalanine mustard, plicamycin/mithramycin, prednisone, prednisolone, procarbazine, raloxifene, romiplostim, sargramostim, streptozocin, tamoxifen, temozolomide, temsirolimus, teniposide, thalidomide, thioguanine, thiophosphoamide/thiotepa, thiotepa, topotecan hydrochloride, toremifene, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, zoledronic acid, and combinations thereof:   (b) the antibody-based agent is selected from: alemtuzumab, bevacizumab, cetuximab, fresolimumab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, trastuzumab DM1, and combinations thereof;   (c) the tyrosine-kinase is selected from: axitinib, bafetinib, bosutinib, cediranib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, neratinib, nilotinib, pazopanib, ponatinib, quizartinib, regorafenib, sorafenib, sunitinib, vandetanib, vatalanib, and combinations thereof;   (d) The immunomodulatory agent is selected from: thalidomide, lenalidomide, pomalidomide, methotrexate, leflunomide, cyclophosphamide, cyclosporine A, minocycline, azathioprine, tacrolimus, methylprednisolone, mycophenolate mofetil, rapamycin, mizoribine, deoxyspergualin, brequinar, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), lactoferrin, poly AU, polyI:polyC12U, poly-ICLC, imiquimod, resiquimod, unmethylated CpG dinucleotide (CpG-ODN), and ipilumumab;   (e) the tyrosine kinase inhibitor is a Janus kinase inhibitor selected from AC-430, AZD1480, baricitinib, BMS-911453, CEP-33779, CYT387, GLPG-0634, INCB18424, lestaurtinib, LY2784544, NS-018, pacritinib, ruxolitinib, TG101348 (SAR302503), tofacitinib, VX-509, R-348, R723, and combinations thereof; and   (f) the biologic agent is selected from: IL-2, IL-3, erythropoietin, G-CSF, filgrastim, interferon alfa, bortezomib, and combinations thereof.   
     
     
         18 .- 22 . (canceled) 
     
     
         23 . The method of  claim 15 , wherein the anti-cancer therapeutic is selected from the group consisting of: AB0024, AZD1480, AT-9283, BMS-911543, CYT387, everolimus, givinostat, imetelstat, lestaurtinib, LY2784544, NS-018, oral arsenic, pacritinib, panobinostat, peginterferon alfa-2a, pomalidomide, pracinostat, ruxolitinib, TAK-901, TG101438 (SAR302503), and combinations thereof. 
     
     
         24 . The method of  claim 15 , wherein the anti-cancer therapeutic is ruxolitinib. 
     
     
         25 . The method of  claim 15 , wherein the SAP agonist and the anti-cancer therapeutic are co-formulated. 
     
     
         26 . The method of  claim 15 , wherein the SAP agonist and the anti-cancer therapeutic are administered simultaneously. 
     
     
         27 . The method of  claim 15 , wherein the SAP agonist and the anti-cancer therapeutic are administered within a time of each other to produce overlapping therapeutic effects in the patient. 
     
     
         28 .- 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the myelofibrosis is primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. 
     
     
         31 . The method of  claim 30 , wherein the SAP agonist, alone or in combination with the anti-cancer therapeutic, is administered according to a dosage regimen effective to do one or more of:
 (a) reduce spleen volume by at least 25% relative to baseline;   (b) reduce MPN-SAF Total Symptom Score by at least 25% relative to baseline;   (c) increase hemoglobin levels by at least 1 g/L relative to baseline;   (d) increase hemoglobin levels to at least 100 g/L wherein baseline hemoglobin was less than 100 g/L at baseline;   (e) reduce red blood cell (RBC) transfusions by at least 25% relative to baseline;   (f) achieve RBC transfusion independence; or   (g) reduce platelet transfusions by at least 25%.   
     
     
         32 .- 48 . (canceled) 
     
     
         49 . A method for treating myelofibrosis or improving the efficacy of an anti-cancer therapeutic in a patient with myelofibrosis, the method comprising administering to said patient a therapeutically effective amount of a glycosylated human serum amyloid P (SAP) polypeptide in combination with the anti-cancer therapeutic; wherein said SAP polypeptide is to be administered multiple times in an initial loading dose during a first week of administration followed by one time every one to four weeks, and wherein the anti-therapeutic agent is ruxolitinib. 
     
     
         50 . The method of  claim 49 , wherein the SAP polypeptide is administered at around 10 mg/kg. 
     
     
         51 . The method of  claim 50 , wherein after the initial loading dose the SAP polypeptide is administered once every four weeks (Q4W). 
     
     
         52 . The method of  claim 49 , wherein the SAP polypeptide is administered at around 20 mg/kg. 
     
     
         53 . The method of  claim 52 , wherein after the initial loading dose the SAP polypeptide is administered once every four weeks (Q4W). 
     
     
         54 . A method for treating myelofibrosis in a patient with myelofibrosis, the method comprising administering to said patient 10 mg/kg of a glycosylated human serum amyloid P (SAP) polypeptide in combination with ruxolitinib, wherein the SAP polypeptide is administered once every four weeks (Q4W) and the ruxolitinib is administered Q4W. 
     
     
         55 . A method for treating myelofibrosis in a patient with myelofibrosis, the method comprising administering to said patient 20 mg/kg of a glycosylated human serum amyloid P (SAP) polypeptide in combination with ruxolitinib, wherein the SAP polypeptide is administered once every four weeks (Q4W) and the ruxolitinib is administered Q4W.