Anti-cxcr4 as a sensitizer to cancer therapeutics

Abstract

Inhibition of CXCR4 can inhibit tumor growth and metastasis during certain therapeutic windows. Disclosed are novel methods for treating and preventing cancer in a subject related to administration of CXCR4 inhibitors during a therapeutic window following treatment with another anti-tumor therapy.

1 - 25 . (canceled) 
     
     
         26 . A method of treating or preventing a cancer tumor in a subject in need thereof, comprising:
 administering an anti-tumor therapy to the subject; and   administering a therapeutically effective amount of a CXCR4 inhibitor to the subject within 5 days of administering the anti-tumor therapy.   
     
     
         27 . The method of  claim 26 , wherein the method further comprises:
 measuring the level of CXCL12 expression in the subject;   comparing the level of CXCL12 expression in the subject to a reference level;   and administering a therapeutically effective amount of a CXCR4 inhibitor to the subject until CXCL12 expression is within 10% of the reference level.   
     
     
         28 . The method of  claim 26 , wherein the treatment comprises treating or preventing metastasis of a cancer tumor. 
     
     
         29 . The method of  claim 26 , wherein the CXCR4 inhibitor is selected from the group consisting of small organic or inorganic molecules; polysaccharides; peptides; polypeptides; proteins; antibodies; peptide analogs and derivatives; peptidomimetics; nucleic acids; nucleic acid analogs and derivatives; an extract made from biological materials such as bacteria, plants, fungi, animal cells, or tissues; and any combinations thereof. 
     
     
         30 . The method of  claim 29 , wherein the CXCR4 inhibitor is selected from the group consisting of 1,1′-[1,4-phenylene-bis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane (AMD-3100); Mozobil; Plerixafor; NOXA12; CTCE-9908; ALX40-4C; T22; T140; Met-SDFlbeta (Met-SDF-1β); T134; AMD-3465; N′-(1-Hbenzimidazol-2-yl methyl)-N1-(5,6,7, 8-tetrahydroquinoline8-yl)-butane-1,4-diamine; CTCF-0214; CTCF-9908; CP-1221 (linear peptides, cyclic peptides, natural amino-acids, unnatural amino acids, and peptidomimetic compounds); 4F-benzoylTN24003; KRH-1120; KRH-1636; KRH-2731; polyphemusin analogue; ALX40-4C; T-140; T-140 analogs and derivatives; TN14003; TC14012; TE14011; and any combinations thereof. 
     
     
         31 . The method of  claim 26 , wherein the anti-tumor therapy is selected from the group consisting of radiation therapy, chemotherapy, antiangiogenic therapy, and any combinations thereof. 
     
     
         32 . The method of  claim 31 , wherein the anti-tumor therapy increases the expression of CXCL12 by at least 10%. 
     
     
         33 . The method of  claim 26 , wherein the antitumor therapy comprises administering a VEGF inhibitor. 
     
     
         34 . The method of  claim 33 , wherein the VEGF inhibitor is selected from the group consisting of:
 ABT-869: AEE-788; AG-13736; AG-028262; Angiostatin; bevacizumab; AVE-8062; AZD-2171; sorafenib; BMS-387032; CEP-7055; CHIR-258; GFKI; CP-547632; CP-564959; E-7080; 786034; GW-654652; IMC-1C11; KRN-951; PKC-412; PTK-787; SU11248; SU-5416; SU-6668; AVE-0005; thalidomide; XL-647; XL-999; ZD-6474; ZK-304709; Pazopanib; CDP791; Enzastaurin; BIBF 1120; BAY 573952; BAY 734506; XL 184; IMC-1121B; CEP 701; SU 014813; SU 10944; SU 12662; OSI-930; BMS 582664; ZD-6126; Imatinib; Glivec; Gleevec; STI-571; CGP-57148; RAD-001; BMS-354825; Volociximab; CCI-779; 17-AAG; DMXAA; CI-1040; CI-1033; (5-[5-fluoro-2-oxo-1,2-dihydroindol(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [2-diethylaminoethyl]amide); 4TBPPAPC; AMG 706; Nexavar®; and PTK/ZK.   
     
     
         35 . The method of  claim 26 , wherein the anti-tumor therapy comprises administering a p38 MAPK inhibitor. 
     
     
         36 . The method of  claim 35 , wherein the p38 MAPK inhibitor is selected from the group consisting of antisense p38 MAPK nucleic acids and fragments thereof, antibodies that bind p38 MAPK and fragments thereof, EO-1428, SB239063, SB281832, VX-702, VX-745, ZM336372, RPR 200765A, N-(3-tert-butyl-1-methyl-5-pyrazolyl)N′-(4-(4-pyridinylmethyl)phenyl)urea, SB203580, SB202190, PD169316, fr-167653, trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2 methoxypyridimidin-4-yl)imidazole, 2-(4-Chlorophenyl)-4-)4-fluorophenyl)-5-pyridin-4-yl-1,2-dihydropyrazol-3-one, and any combinations thereof. 
     
     
         37 . The method of  claim 26 , wherein the cancer is selected from the group consisting of basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and CNS cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); lymphoma including Hodgkin's and non-Hodgkin's lymphoma; melanoma; myeloma; neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; as well as other carcinomas and sarcomas; as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome 
     
     
         38 . The method of  claim 26 , wherein the CXCR4 inhibitor administration is systemic administration. 
     
     
         39 . The method of  claim 26 , wherein the CXCR4 inhibitor administration is by injection, infusion, instillation, inhalation, or ingestion. 
     
     
         40 . The method of  claim 39 , wherein said injection is intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, or intrasternal injection. 
     
     
         41 . The method of  claim 26 , wherein the therapeutically effective amount of the CXCR4 inhibitor is 1 μg/kg to 150 mg/kg of bodyweight. 
     
     
         42 . The method of  claim 26 , wherein the CXCR4 inhibitor is administered for at least 1 day. 
     
     
         43 . The method of  claim 42 , wherein the CXCR4 inhibitor is administered for at least one week. 
     
     
         44 . The method of  claim 26 , wherein the subject is a human.