Inos-inhibitory compositions and their use as breast cancer therapeutics

Abstract

Disclosed are methods for treating one or more mammalian cancers, and in particular, methods for treating human breast cancer employing one or more iNOS pathway-inhibitory compounds, either alone, or in combination with one or more selected antihypertensive agents, including calcium channel antagonists, either alone, and further in combination with one or more conventional chemotherapeutic or anti-cancer regimens. Also disclosed are particular therapeutic formulations including these compositions, and methods for their use in treating refractory, metastatic, and relapsed cancers, and for managing or reversing treatment resistance in human triple-negative breast cancers in particular.

What is claimed is: 
     
         1 . A composition, comprising:
 1) a chemotherapeutically-effective amount of a first iNOS inhibitor;   
       and
 2) a therapeutically-effective amount of:
 a) a first antihypertensive agent; 
 b) a first chemotherapeutic agent; or 
 c) a combination of a) and b). 
 
 
     
     
         2 . The composition of  claim 1 , wherein the first iNOS inhibitor comprises N G -monomethyl-L-arginine [L-NMMA], (N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide) [1400 W], or (N 5 -[imino(nitroamino) methyl]-L-ornithine methyl ester) [L-NAME]. 
     
     
         3 . The composition of  claim 1 , wherein the first antihypertensive agent comprises a first calcium channel antagonist. 
     
     
         4 . The composition of  claim 1 , wherein the first anti-hypertensive agent comprises a first calcium channel antagonist selected from the group consisting of amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, clinidipine, clevidipine, diltiazem, efonidipine, fendiline, felodipine, gallopamil, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, pranidipine, and verapamil. 
     
     
         5 . The composition of  claim 1 , further comprising 3) a second distinct iNOS inhibitor. 
     
     
         6 . The composition of  claim 1 , further comprising: d) one or more of an immunomodulating agent, a neuroactive agent, an anti-inflammatory agent, an anti-lipidemic agent, a hormone, a receptor agonist, a receptor antagonist, an anti-infective agent, a protein, a peptide, an antibody, an antigen-binding fragment of an antibody, an enzyme, an RNA, a DNA, an siRNA, an mRNA, a ribozyme, a hormone, a cofactor, a steroid, an antisense molecule, a second distinct antihypertensive agent, a second distinct chemotherapeutic agent, or any combination thereof. 
     
     
         7 . The composition of  claim 6 , wherein the antibody is an anti-PD1 antibody, or an antigen-binding fragment thereof. 
     
     
         8 . The composition of  claim 1 , wherein the first chemotherapeutic agent comprises: one or more antineoplastic compounds, one or more cytotoxic compounds, one or more cytostatic compounds, one or more cytoreductive compounds, or any combination thereof. 
     
     
         9 . The composition of  claim 1 , wherein the first chemotherapeutic agent is selected from the group consisting of cyclophosphamide, doxorubicin, 5-fluorouracil, docetaxel, paclitaxel, trastuzumab, methotrexate, epirubicin, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, mitoxantrone, isabepilone, eribulin, lapatinib, carmustine, a nitrogen mustard, a sulfur mustard, a platin tetranitrate, vinblastine, etoposide, camptothecin, and any combination thereof. 
     
     
         10 . The composition of  claim 1 , wherein a) the first iNOS inhibitor comprises L-NMMA; and b) the first antihypertensive agent comprises amlodipine or the first chemotherapeutic agent comprises docetaxel. 
     
     
         11 . The composition of  claim 1 , wherein a) the first iNOS inhibitor comprises L-NMMA; b) the first antihypertensive agent comprises amlodipine, and c) the first chemotherapeutic agent comprises docetaxel. 
     
     
         12 . The composition of  claim 1 , further comprising a liposome, a surfactant, a niosome, an ethosome, a transferosome, a phospholipid, a sphingosome, a nanoparticle, a microparticle, or any combination thereof. 
     
     
         13 . The composition of  claim 1 , further comprising a pharmaceutically-acceptable carrier, buffer, diluent, vehicle, excipient, or any combination thereof. 
     
     
         14 . The composition of  claim 13 , formulated for systemic or localized administration to a human. 
     
     
         15 . The composition of  claim 13 , adapted and configured as part of a therapeutic kit that comprises the composition, and at least a first set of instructions for administration of the composition to a human in need thereof. 
     
     
         16 . A method of treating or ameliorating one or more symptoms of cancer in an animal in need thereof, the method comprising administering to the animal an effective amount of the composition of  claim 1 , for a time sufficient to treat or ameliorate the one or more symptoms of the cancer in the animal. 
     
     
         17 . The method of  claim 16 , wherein the cancer is diagnosed as, or is identified as, a refractory, a metastatic, a relapsed, or a treatment-resistant cancer. 
     
     
         18 . The method of  claim 16 , wherein the cancer is diagnosed as, or is identified as, a treatment-resistant or a metastatic cancer, and in particular, a treatment-resistant, triple-negative human breast cancer. 
     
     
         19 . The method of  claim 16 , wherein the method further comprises administering a therapeutically-effective amount of radiation to the animal. 
     
     
         20 . The method of  claim 16 , wherein the method further comprises administering a therapeutically-effective amount of an anti-PD1 antibody, or an antigen-binding fragment thereof to the animal. 
     
     
         21 . The method of  claim 16 , wherein the pharmaceutical composition is administered systemically to the animal, in a single administration, or in a series of multiple administrations over a period of from one or more days, over a period of one or more weeks, or over a period of one or more months or longer. 
     
     
         22 . The method of  claim 16 , wherein the pharmaceutical composition further comprises a second distinct chemotherapeutic agent, or a second distinct iNOS inhibitor in accordance with  claim 1 .