Compositions and methods for inhibiting arginase activity

Abstract

The invention relates to methods of treating cancer, with a combination of an arginase inhibitor and a chemotherapeutic agent. The invention further relates to methods of assessing efficacy of a cancer treatment by measuring arginine levels in a tumor.

We claim: 
     
         1 . A method of identifying a therapeutic agent effective to increase the level of arginine in a tumor, comprising:
 a) measuring a first level of arginine in a tumor;   b) contacting the tumor with a therapeutic agent; and   c) measuring a second level of arginine in the tumor;
 wherein when the second level of arginine is higher than the first level of arginine, then the therapeutic agent is effective to increase the level of arginine in the tumor. 
   
     
     
         2 . The method of  claim 1 , wherein the method is conducted in vitro. 
     
     
         3 . The method of  claim 1 , wherein the method is conducted in vivo. 
     
     
         4 . The method of  claim 3 , wherein the step of contacting the tumor with a therapeutic agent comprises administering the therapeutic agent to a subject. 
     
     
         5 . The method of  claim 4 , wherein the subject is a human. 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the first and second levels of arginine are measured in the tumor cells. 
     
     
         7 . The method of any one of  claims 1 - 5 , wherein the first and second levels of arginine are measured in stromal cells associated with the tumor. 
     
     
         8 . A method of identifying a therapeutic agent effective to increase the level of arginine in a tumor in a subject, comprising:
 a) measuring a first level of arginine in a tumor of a subject;   b) administering to the subject a therapeutic agent; and   c) measuring a second level of arginine in the tumor of the subject;
 wherein when the second level of arginine is higher than the first level of arginine, then the therapeutic agent is effective to increase the level of arginine in the tumor of the subject. 
   
     
     
         9 . The method of  claim 8 , wherein administering comprises oral administration. 
     
     
         10 . The method of  claim 8 , wherein administering comprises parenteral administration. 
     
     
         11 . The method of any one of  claims 8 - 10 , wherein the first and second levels of arginine are measured in the tumor cells. 
     
     
         12 . The method of any one of  claims 8 - 10 , wherein the first and second levels of arginine are measured in stromal cells associated with the tumor. 
     
     
         13 . The method of any one of  claims 8 - 12 , wherein the subject is a human. 
     
     
         14 . The method of any preceding claim, wherein the therapeutic agent is an arginase inhibitor. 
     
     
         15 . A method of assessing a response of a tumor to an agent of arginine therapy, comprising:
 a) measuring a first level of arginine in a tumor of a cancer patient;   b) administering to the patient an agent of arginine therapy; and   c) measuring a second level of arginine in the tumor of the patient, thereby assessing the response of the tumor to the agent of arginine therapy.   
     
     
         16 . A method of assessing the anti-cancer efficacy of an agent of arginine therapy, comprising:
 a) measuring a first level of arginine in a tumor of a cancer patient;   b) administering to the patient an agent of arginine therapy; and   c) measuring a second level of arginine in the tumor of the patient, thereby assessing the anti-cancer efficacy of an agent of arginine therapy.   
     
     
         17 . The method of  claim 16 , wherein when the second level of arginine is higher than the first level of arginine, then the agent of arginine therapy is efficacious for treating cancer in a patient. 
     
     
         18 . The method of any one of  claims 15 - 17 , wherein the first and second levels of arginine are measured in the tumor cells. 
     
     
         19 . The method of any one of  claims 15 - 17 , wherein the first and second levels of arginine are measured in stromal cells associated with the tumor. 
     
     
         20 . The method of any one of  claims 15 - 19 , wherein the agent of arginine therapy is an arginase inhibitor. 
     
     
         21 . A method of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an agent of arginine therapy. 
     
     
         22 . The method of  claim 21 , wherein administering the agent of arginine therapy effects an increase in a level of arginine in a tumor of the subject relative to the level of arginine in the tumor prior to administration. 
     
     
         23 . The method of  claim 22 , wherein administering the agent of arginine therapy effects an increase in a level of arginine in the tumor cells of the subject relative to the level of arginine in the tumor cells prior to administration. 
     
     
         24 . The method of  claim 22 , wherein administering the agent of arginine therapy effects an increase in a level of arginine in stromal cells associated with the tumor of the subject relative to the level of arginine in the stromal cells prior to administration. 
     
     
         25 . The method of any one of  claims 21 - 24 , further comprising conjointly administering one or more additional chemotherapeutic agents. 
     
     
         26 . The method of any one of  claims 21 - 25 , wherein the agent of arginine therapy is an arginase inhibitor. 
     
     
         27 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is a compound having the structure of Formula I, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from —OH, OR a , and NR b R c ;
 R a  is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, (heterocycloalkyl)alkyl, (heteroaryl)alkyl, and aralkyl; 
 R b  and R c  are each independently selected from H, —OH, substituted or unsubstituted alkyl, —SO 2 (alkyl), —SO 2 (aryl), (heterocycloalkyl)alkyl, and (heteroaryl)alkyl; 
 
 R 2  is selected from H, substituted or unsubstituted alkyl, and (alkyl)C(O)—; 
 W, X, Y, and Z are each independently selected from a bond, —C(R′)(R′″)—, —C(R″′) 2 —, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, and —S—, such that no more than three of W, X, Y, and Z simultaneously represent a bond; and no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, —N—, or —NR′″—; 
 l, m, n and p are each independently 1 or 2; 
 
       
         
           
           
               
               
           
         
       
       optionally represents one or more double bonds;
 R 3  and R 4  are each independently selected from hydrogen, substituted or unsubstituted alkyl, and C(O)—R′, or 
 R 3  and R 4  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated or partially saturated; 
 D is selected from substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene, and cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a cycloalkylenyl group (thereby forming a fused bicyclic system); 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; and 
 
 R′, R″ and R′″ are each independently selected from H, OH, S(O)R d , S(O) 2 R d , alkyl, aryl, —NH 2 , —NH(alkyl), —N(alkyl) 2 , —C(O)NR d R e , —C(O)(alkyl), —C(O)(aryl), —C(O)O(alkyl), —C(O)O(aryl), cycloalkyl, heterocycloalkyl, —C(O)(heterocycloalkyl), heteroaryl, aralkyl, —C(O)(aralkyl), —C(O)(aryl), (cycloalkyl)alkyl, (heteroaryl)alkyl-, and (heterocycloalkyl)alkyl; 
 wherein R d  and R e  are each independently selected from H, substituted or unsubstituted alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, NR′R″C(O)—, and (aryl)cycloalkylene-, 
 wherein any alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally further substituted; 
 
       or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
     
     
         28 . The method of  claim 27 , wherein:
 R 1  is selected from —OH, OR a , and NR b R c ;
 R a  is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
 R b  and R c  are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl-SO 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-; 
   R 2  is selected from H, straight or branched (C 1 -C 6 ) alkyl, and (C 1 -C 6 )alkyl-C(O)—;   W, X, Y, and Z are each independently selected from a bond, —C(R′)(R′″)—, —C(R″′) 2 —, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, and —S—, such that no more than three of W, X, Y, and Z simultaneously represent a bond; and no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, —N—, or —NR′″—;   l, m, n and p are each independently 1 or 2;   
       
         
           
           
               
               
           
         
       
       optionally represents one or more double bonds;
 R 3  and R 4  are each independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, and C(O)—R′, or 
 R 3  and R 4  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated or partially saturated; 
 D is selected from straight or branched (C 3 -C 5 )alkylene, straight or branched (C 2 -C 8 )alkenylene, straight or branched (C 2 -C 8 )alkynylene, (C 3 -C 14 )arylene, and (C 3 -C 14 )cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a (C 3 -C 14 )-cycloalkylenyl group; 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; and 
 
 R′, R″ and R′″ are each independently selected from H, OH, S(O)R d , S(O) 2 R d , (C 1 -C 8 )alkyl, (C 3 -C 6 )aryl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —C(O)NR d R e , —C(O)(C 1 -C 6 )alkyl, —C(O)(C 3 -C 14 )aryl, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(C 3 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 14 )heterocycloalkyl, —C(O)(C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, —C(O)(C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, —C(O)(C 3 -C 14 )aryl, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heterocycle-(C 1 -C 6 )alkylene-; 
 wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkoxy, (C 3 -C 14 )aryl, (C 1 -C 6 )haloalkyl and (C 3 -C 14 )aryloxy;
 wherein R d , R e , R g , and R h  are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3  -C 6 )cycloalkyl, optionally substituted (C 3  -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, NR′R″C(O)—, and (C 3 -C 6 )aryl-(C 3 -C 14 )-cycloalkylene-, 
 
 
       or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
     
     
         29 . The method of  claim 27  or  claim 28 , wherein:
 R 1  is selected from —OH, OR a , and NR b R c ;
 R a  is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
 R b  and R c  are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl-SO 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-; 
 
 R 2  is selected from H, straight or branched (C 1 -C 6 ) alkyl, and (C 1 -C 6 )alkyl-C(O)—; 
 W, X, Y, and Z are each independently selected from a bond, —C(R′″) 2 —, —CR′″—, —NR′″—, —N—, —O—, —C(O)—, and —S—, such that
 no more than three of W, X, Y, and Z simultaneously represent a bond; and 
 no two adjacent members of W, X, Y, and Z are simultaneously —O—, —S—, —N—, or —NR′″—; 
 
 l, m, n and p are each independently 1 or 2; 
 
       
         
           
           
               
               
           
         
       
       optionally represents one or more double bonds;
 R 3  and R 4  are each independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, and C(O)—R′, or 
 R 3  and R 4  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated or partially saturated; 
 D is selected from straight or branched (C 3 -C 5 )alkylene, straight or branched (C 2 -C 8 )alkenylene, straight or branched (C 2 -C 8 )alkynylene, (C 3 -C 14 )arylene, and (C 3 -C 14 )cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a (C 3 -C 14 )-cycloalkylenyl group; 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; and 
 
 R′, R″ and R′″ are each independently selected from H, OH, (C 1 -C 8 )alkyl, (C 3 -C 6 )aryl, —NH 2 , —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —C(O)(C 1 -C 6 )alkyl, —C(O)(C 3 -C 14 )aryl, —C(O)O(C 1 -C 6 )alkyl, —C(O)O(C 3 -C 14 )aryl, (C 3 -C 6 )cycloalkyl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heterocycle-(C 1 -C 6 )alkylene-; 
 wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkoxy, and (C 3 -C 14 )aryloxy;
 wherein R d , R e , R g , and R h  are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, NR′R″C(O)—, and (C 3 -C 6 )aryl-(C 3 -C 14 )-cycloalkylene-, 
 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
 
 
     
     
         30 . The method of any one of  claims 27 - 29 , wherein D is selected from:
 -L 1 -L 2 -CH 2 —CH 2 —,   —CH 2 -L 1 -L 2 -CH 2 —   —CH 2 —CH 2 -L 1 -L 2 ,   -L 1 -CH 2 —CH 2 -L 2 -,   -L 1 -CH 2 -L 2 -CH 2 —,   —CH 2 -L 1 -CH 2 -L 2 -,   -L 1 -CH 2 —CH 2 —,   —CH 2 -L 1 -CH 2 —,   —CH 2 —CH 2 -L 1 -,   -L 2 -CH 2 —CH 2 —,   —CH 2 -L 2 -CH 2 —, and   —CH 2 —CH 2 -L 2 -,   wherein L 1  and L 2  are independently selected from O, NR′, S, SO, SO 2 , and CR′R″; and   when L 1  and L 2  are adjacent to each other, then L 1  and L 2  are not simultaneously O, NR′, S, SO, or SO 2 .   
     
     
         31 . The method of any one of  claims 27 - 30 , wherein D is straight or branched (C 3 -C 5 )alkylene. 
     
     
         32 . The method of any one of  claims 27 - 31 , wherein D is propylene. 
     
     
         33 . The method of any one of  claims 27 - 32 , wherein R 1  is —OH. 
     
     
         34 . The method of any one of  claims 27 - 33 , wherein each of R 2 , R 3  and R 4  is hydrogen. 
     
     
         35 . The method of any one of  claims 27 - 34 , wherein each of W, X, Y and Z is —C(R″′) 2 —. 
     
     
         36 . The method of  claim 35 , wherein R′″ is H. 
     
     
         37 . The method of any one of  claims 27 - 35 , wherein at least one occurrence of R′″ is not H. 
     
     
         38 . The method of any one of  claims 35 - 37 , wherein l+m+n+p=3. 
     
     
         39 . The method of any one of  claims 35 - 37 , wherein l+m+n+p=4. 
     
     
         40 . The method of any one of  claims 35 - 39 , wherein each of W, X, Y and Z is —CR′″—, and 
       
         
           
           
               
               
           
         
       
       represents one or more double bonds. 
     
     
         41 . The method of any one of  claims 27 - 34 , wherein at least one of W, X, Y, or Z is selected from —NR′″—, —N—, —O—, and —S—. 
     
     
         42 . The method of  claim 41 , wherein any one of W, X, Y and Z is —NH— and each instance of the remaining three is —C(R″′) 2 —. 
     
     
         43 . The method of  claim 41  or  claim 42 , wherein R′″ is H. 
     
     
         44 . The method of  claim 41  or  claim 42 , wherein at least one occurrence of R′″ is not H. 
     
     
         45 . The method of any one of  claims 41 - 44 , wherein X is —NH—. 
     
     
         46 . The method of  claim 41 , wherein any one of W, X, Y and Z is —N— and each of the remaining three is —CR′″—, and 
       
         
           
           
               
               
           
         
       
       represents one or more double bonds. 
     
     
         47 . The method of  claim 46 , wherein X is —N—. 
     
     
         48 . The method of  claim 46  or  claim 47 , wherein R′″ is H. 
     
     
         49 . The method of  claim 46  or  claim 47 , wherein at least one occurrence of R′″ is not H. 
     
     
         50 . The method of  claim 46  or  claim 47 , wherein l+m+n+p=4. 
     
     
         51 . The method of any one of  claims 27 - 50 , wherein the compound of Formula I is not 1-amino-2-(3-boronopropyl)cyclohexane carboxylic acid. 
     
     
         52 . The method of  claim 27 , wherein the sum of l, m, n, and p is 3, 4, 5, or 6. 
     
     
         53 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is selected from the following table: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. 
     
     
         54 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is selected from the following table: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. 
     
     
         55 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is a compound having the structure of Formula II, 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from —OH, OR a , and NR b R c ;
 R a  is selected from hydrogen, substituted or unsubstituted alkyl, aryl, (heterocycloalkyl)-alkyl, heteroaralkyl, and aralkyl; 
 R b  and R c  are each independently selected from H, —OH, substituted or unsubstituted alkyl, —S(O) 2 (alkyl), —S(O) 2 (aryl), (heterocycloalkyl)alkyl, and heteroaralkyl; 
 
 (A) R 2  is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heteroaralkyl, heteroaryl, heterocycloalkyl, (heterocycloalkyl)alkyl, (heteroaryl)heterocycloalkylene, (aryl)heterocycloalkylene, (aralkyl)heterocycloalkylene, (heteroaralkyl)heterocycloalkylene, ((heterocycloalkyl)alkyl)heterocycloalkylene, and —(CH 2 ) m —(X) u —(CH 2 ) n —(Y) v —R f ;
 wherein
 u and v are each independently 0 or 1, and u+v   1; 
 m and n are each independently 0, 1, 2, 3, 4, 5, or 6, wherein m+n≥1; 
 X and Y are independently selected from —NH, —O— and —S—; 
 R f  is selected from H, hydroxyl, substituted or unsubstituted alkyl and aryl; and 
 
 R 5  is selected from substituted or unsubstituted alkyl or alkyl-C(O)—; or 
 
 (B) R 2  is (heterocycloalkyl)alkyl; and
 R 5  is selected from H, substituted or unsubstituted alkyl, and alkyl-C(O)—; 
 
 R 3  and R 4  are each independently selected from hydrogen, substituted or unsubstituted alkyl, and C(O)—R′,
 or R 3  and R 4  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully or partially saturated, and that optionally contains 1-3 additional heteroatom ring members selected from O, S, and N; 
 
 D is selected from substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene, and cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a cycloalkylenyl group; 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; and 
 
 R′ and R″ are each independently selected from H, substituted or unsubstituted alkyl, and aryl; 
 wherein any alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally further substituted; 
 
       or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
     
     
         56 . The method of  claim 55 , wherein the arginase inhibitor is a compound having the structure of Formula II, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from the group consisting of —OH, OR a , and NR b R c ;
 R a  is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
 R b  and R c  are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —S(O) 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl-S(O) 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-; 
 
 (A) R 2  is selected from straight or branched (C 1 -C 6 )alkyl, straight or branched (C 2 -C 6 )alkenyl, straight or branched (C 2 -C 6 )alkynyl, (C 3 -C 14 )aryl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 3 -C 6 )heterocycloalkylene-, (C 3 -C 14 )aryl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )-aryl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, and —(CH 2 ) m —(X) u —(CH 2 ) n —(Y) v —R f ;
 wherein
 u and v are each independently 0 or 1, and u+v   1; 
 m and n are each independently 0, 1, 2, 3, 4, 5, or 6, wherein m+n≥1; 
 X and Y are independently selected from —NH, —O— and —S—; 
 R f  is selected from H, hydroxyl, straight or branched (C 1 -C 6 )alkyl and (C 3 -C 14 )aryl; and 
 
 R 5  is selected from straight or branched (C 1 -C 6 ) alkyl or (C 1 -C 6 )alkyl-C(O)—; or 
 
 (B) R 2  is (C 3 -C 14 )heterocycloalkyl-(C 1 -C 2 )alkylene-; and
 R 5  is selected from H, straight or branched (C 1 -C 6 ) alkyl, and (C 1 -C 6 )alkyl-C(O)—; 
 
 R 3  and R 4  are each independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, and C(O)—R′, or 
 R 3  and R 4  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully or partially saturated, and that optionally contains 1-3 additional heteroatom ring members selected from O, S, and N; and 
 D is selected from straight or branched (C 1 -C 6 )alkylene, straight or branched (C 2 -C 8 )alkenylene, straight or branched (C 2 -C 8 )alkynylene, (C 3 -C 14 )arylene, and (C 3 -C 14 )cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a (C 3 -C 14 )-cycloalkylenyl group; 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; 
 
 wherein any alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkoxy, and (C 3 -C 14 )aryloxy;
 wherein R d , R e , R g , and R h  are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, NR′R″C(O)—, and (C 3 -C 6 )aryl-(C 3 -C 14 )-cycloalkylene-, and 
 R′ and R″ are each independently selected from H, (C 1 -C 8 )alkyl, and (C 3 -C 6 )aryl; and 
 
 wherein any aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, —OH, oxo, —COOH, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, —CN, —NO 2 , —NH 2 , (C 1 -C 6 )alkyl-S—, (C 3 -C 14 )cycloalkyl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heteroaryl, —C(O)NH—(C 1 -C 6 )alkyl, —NHC(O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )hydroxyalkyl; 
 
       or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
     
     
         57 . The method of  claim 55  or  56 , wherein D is selected from:
 -L 1 -L 2 -CH 2 —CH 2 —, 
 —CH 2 -L 1 -L 2 -CH 2 — 
 —CH 2 —CH 2 -L 1 -L 2 , 
 -L 1 -CH 2 —CH 2 -L 2 -, and 
 -L 1 -CH 2 -L 2 -CH 2 —, 
 
       wherein L 1  and L 2  are independently selected from O, NR′, S, SO, SO 2 , and CR′R″. 
     
     
         58 . The method of any one of  claims 55 - 57 , wherein D is straight or branched (C 3 -C 5 )alkylene. 
     
     
         59 . The method of any one of  claims 55 - 58 , wherein D is butylene. 
     
     
         60 . The method of any one of  claims 55 - 59 , wherein R 1  is —OH. 
     
     
         61 . The method of any one of  claims 55 - 60 , wherein
 (A) R 2  is selected from straight or branched (C 1 -C 6 )alkyl, straight or branched (C 2 -C 6 )alkenyl, straight or branched (C 2 -C 6 )alkynyl, (C 3 -C 14 )aryl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-,
 (C 3 -C 14 )heteroaryl-(C 3 -C 6 )heterocycloalkylene-, (C 3 -C 14 )aryl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )-aryl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, 
 (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, and —(CH 2 ) m —(X) u —(CH 2 ) n —(Y) v —R f ; and 
 each of R 3 and R 4  is hydrogen 
 OR 
   (B) R 2  is (C 3 -C 14 )heterocycloalkyl-(C 1 -C 2 )alkylene-; and
 each of R 3 , and R 4  and R 5  is hydrogen. 
   
     
     
         62 . The method of any one of  claims 55 - 61 , wherein
 R 2  is selected from (C 1 -C 6 )alkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene- and —(CH 2 ) n —(X) u —(CH 2 ) m —(Y) v —R f , and   R 5  is selected from straight or branched (C 1 -C 6 ) alkyl or (C 1 -C 6 )alkyl-C(O)—.   
     
     
         63 . The method of any one of  claims 55 - 62 , wherein R 2  is alkyl optionally substituted by hydroxy or —NR d R e . 
     
     
         64 . The method of  claim 63 , wherein each of R d  and R e  is independently selected from H, straight or branched (C 1 -C 6 )alkyl, (C 1 -C 6 )aminoalkyl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 14 )aryl, and optionally substituted (C 3 -C 6 )cycloalkyl. 
     
     
         65 . The method of  claim 64 , wherein each of R d  and R e  is (C 1 -C 6 )aminoalkyl. 
     
     
         66 . The method of any one of  claims 55 - 62 , wherein R 2  is —(CH 2 ) n —(X) u —(CH 2 ) m —(Y) v —R f . 
     
     
         67 . The method of  claim 66 , wherein X and Y are each independently —NH—. 
     
     
         68 . The method of  claim 66 , wherein m is 1 and n is 2. 
     
     
         69 . The method of  claim 66 , wherein each of u and v is 1. 
     
     
         70 . The method of any one of  claims 55 - 62 , wherein R 2  is (C 3 -C 6 )heterocycloalkyl-(C 1 -C 2 )alkylene optionally substituted with one or more members selected from —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )alkyl, and —OH. 
     
     
         71 . The method of any one of  claims 55 - 62 , wherein R 2  is (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-. 
     
     
         72 . The method of any one of  claims 55 - 71 , wherein the compound of Formula II is not 2-amino-4-borono-2-methylbutanoic acid. 
     
     
         73 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is selected from the following table: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. 
     
     
         74 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is a compound having the structure of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein
 R 6  is selected from OR a , and NR b R c ;
 R a  is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, (heterocycloalkyl)alkyl, heteroaralkyl, and aralkyl; 
 R b  and R c  are each independently selected from H, —OH, substituted or unsubstituted alkyl, —S(O) 2 (alkyl), —S(O) 2 (aryl), (heterocycloalkyl)alkyl, and heteroaralkyl; 
 
 R 7  is selected from H, substituted or unsubstituted alkyl, aralkyl, heteroaralkyl, (heterocycloalkyl)alkyl and (alkyl)C(O)—; 
 X is selected from cycloalkylene and heterocycloalkylene, 
 Y is selected from H, alkyl, —NR′R″, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, (heteroaryl)heterocycloalkyl, (aryl)heterocycloalkyl, (aralkyl)heterocycloalkyl, (heteroaralkyl)heterocycloalkyl, and ((heterocycloalkyl)alkyl)heterocycloalkyl; 
 M is selected from a bond, alkylene, —O—, —C(O)—, —C(S)—, —C(O)NH—, —C(S)NH—, —S—, —S(O)—, —S(O) 2 —, —NR′—, and —C═NR 11 —; 
 R 8  and R 9  are independently selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl, and C(0)-R′, 
 or R 8  and R 9  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated or partially saturated and that optionally contains 1-3 additional heteroatom ring members selected from O, S, and N, wherein the ring is optionally fused with a cycloalkyl, heterocyclic or aromatic ring; 
 D is selected from substituted or unsubstituted alkylene, alkenylene, alkynylene, arylene, and cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a cycloalkylenyl group; and 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; and 
 
 R′ and R″ are independently selected from H, substituted or unsubstituted alkyl, —C(O)(alkyl), aryl, aralkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, heteroaryl; 
 wherein any alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally further substituted; 
 
       or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
     
     
         75 . The method of  claim 74 , wherein the arginase inhibitor is a compound having the structure of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein
 R 6  is selected from OR a , and NR b R c ;
 R a  is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-; 
 R b  and R c  are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —S(O) 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl-S(O) 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-; 
 
 R 7  is selected from H, straight or branched (C 1 -C 6 ) alkyl, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene- and (C 1 -C 6 )alkyl-C(O)—; 
 X is selected from (C 3 -C 14 )-cycloalkylene and (C 3 -C 14 ) heterocycloalkylene, 
 Y is selected from H, hydroxy(C 1 -C 6 )alkylene, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )-cycloalkyl-(C 1 -C 6 )alkylene, (C 3 -C 14 )aryl, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene, (C 3 -C 14 )heteroaryl-(C 3 -C 6 )heterocycloalkylene-, (C 3 -C 14 )aryl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )-aryl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkyl-(C 3 -C 14 )heterocycloalkylene-, and (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkyl-(C 3 -C 14 ) heterocycloalkylene-; 
 M is selected from a bond, —(C 1 -C 6 )alkylene-, —O—, —C(O)—, —C(S)—, —C(O)NH—, —C(S)NH—, —S—, —S(O)—, —S(O) 2 —, and —C═NR 11 —; 
 R 8  and R 9  are independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 14 )aryl, and C(O)—R′, 
 or R 8  and R 9  together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully saturated, or partially saturated and that optionally contains 1-3 additional heteroatom ring members selected from O, S, and N, wherein the ring is optionally fused with a cycloalkyl, heterocyclic or aromatic ring; 
 D is selected from straight or branched (C 3 -C 5 )alkylene, straight or branched (C 2 -C 8 )alkenylene, straight or branched (C 2 -C 8 )alkynylene, (C 3 -C 14 )arylene, and (C 3 -C 14 )cycloalkylene,
 wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or 
 wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a (C 3 -C 14 )-cycloalkylenyl group; 
 provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ; and 
 
 R′ and R″ are independently selected from H, (C 1 -C 8 )alkyl, —C(O)—(C 1 -C 8 )alkylene, optionally substituted (C 3 -C 6 )aryl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, optionally substituted (C 1 -C 6 )aminoalkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl; 
 wherein any alkyl, alkylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )alkoxy, (C 3 -C 14 )aryl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene and (C 3 -C 14 )aryloxy;
 wherein R d , R e , R g , and R h  are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, and NR′R″C(O)—, 
 
 
       or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof. 
     
     
         76 . The method of  claim 74  or  75 , wherein D is selected from:
 -L 1 -L 2 -CH 2 —CH 2 —, 
 —CH 2 -L 1 -L 2 -CH 2 — 
 —CH 2 —CH 2 -L 1 -L 2 , 
 -L 1 -CH 2 —CH 2 -L 2 -, and 
 -L 1 -CH 2 -L 2 -CH 2 —, 
 
       wherein L 1  and L 2  are independently selected from O, NR′, S, SO, SO 2 , and CR′R″. 
     
     
         77 . The method of any one of  claims 74 - 76 , wherein D is straight or branched (C 3 -C 5 )alkylene. 
     
     
         78 . The method of any one of  claims 74 - 77 , wherein D is butylene. 
     
     
         79 . The method of any one of  claims 74 - 78 , wherein R 1  is —OH. 
     
     
         80 . The method of any one of  claims 74 - 78 , wherein R 7 , R 8  and R 9  are hydrogen. 
     
     
         81 . The method of any one of  claims 74 - 80 , wherein:
 X is (C 3 -C 14 )-cycloalkylene;   M is selected from a bond, —(C 1 -C 6 )alkylene-, —O—, —C(O)—, —C(S)—, —C(O)NH—, —C(S)NH—, —S—, —S(O)—, —S(O) 2 —, —NR′—, and —C═NR 11 —; and   Y is —NR′R″.   
     
     
         82 . The method of  claim 81 , wherein M is a bond and Y is —NH 2 . 
     
     
         83 . The method of any one of  claims 74 - 80 , wherein
 X is (C 3 -C 14 )heterocycloalkylene;   M is selected from a bond, —(C 1 -C 6 )alkylene-, —O—, —C(O)—, —C(S)—, —C(O)NH—, —C(S)NH—, —S—, —S(O)—, —S(O) 2 —, —NR′—, and C═NR 11 —; and   Y is selected from (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene, (C 3 -C 14 )heteroaryl and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene.   
     
     
         84 . The method of any one of  claims 14 ,  20 , and  26 , wherein the arginase inhibitor is selected from the following table: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof. 
     
     
         85 . The method of any one of  claims 23 - 84 , wherein the cancer is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumor, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi Sarcoma, Kidney Cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ (LCIS), Lung Cancer, Lymphoma, AIDS-Related Lymphoma, Macroglobulinemia, Male Breast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma, Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma, Pituitary Tumor, Plasma Cell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis Cancer, Ureter Cancer, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Szary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Stomach Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma, Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Gestational Trophoblastic Tumor, Unknown Primary, Unusual Cancer of Childhood, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Waldenstrm Macroglobulinemia, or Wilms Tumor. 
     
     
         86 . The method of any one of  claims 23 - 85 , wherein the cancer is selected from acute myeloid leukemia (AML), breast cancer, colorectal cancer, chronic myelogenous leukemia (CML), esophageal cancer, gastric cancer, lung cancer, melanoma, non-small cell lung carcinoma (NSCLC), pancreatic cancer, prostate cancer, and renal cancer. 
     
     
         87 . The method of any one of  claims 23 - 86 , wherein the one or more additional chemotherapeutic agents includes aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette-Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, rucaparib, selumetinib, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, or vinorelbine. 
     
     
         88 . The method of any one of  claims 24 - 86 , wherein the one or more additional chemotherapeutic agents includes abagovomab, adecatumumab, afutuzumab, anatumomab mafenatox, apolizumab, blinatumomab, catumaxomab, durvalumab, epratuzumab, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, nivolumab, ocaratuzumab, olatatumab, pembrolizumab, pidilizumab, ticilimumab, samalizumab, or tremelimumab. 
     
     
         89 . The method of  claim 88 , wherein the one or more additional chemotherapeutic agents includes ipilimumab, nivolumab, pembrolizumab, or pidilizumab. 
     
     
         90 . The method of any one of  claims 23 - 89 , wherein the method further comprises administering one or more non-chemical methods of cancer treatment, such as radiation therapy, surgery, thermoablation, focused ultrasound therapy, cryotherapy, or a combination of the foregoing. 
     
     
         91 . A method of assessing the anti-cancer efficacy of a combination therapy regimen, comprising:
 a) measuring a first level of arginine in a tumor of a cancer patient;   b) conjointly administering to the patient an agent of arginine therapy and one or more additional chemotherapeutic agents; and   c) measuring a second level of arginine in the tumor of the patient, thereby assessing the anti-cancer efficacy of the combination therapy regimen.   
     
     
         92 . The method of  claim 91 , wherein when the second level of arginine is higher than the first level of arginine, then the combination therapy regimen is efficacious for treating cancer in the patient. 
     
     
         93 . The method of  claim 91  or  claim 92 , wherein the first and second levels of arginine are measured in the tumor cells. 
     
     
         94 . The method of  claim 91  or  claim 92 , wherein the first and second levels of arginine are measured in stromal cells associated with the tumor. 
     
     
         95 . The method any one of  claims 91 - 94 , wherein the agent of arginine therapy is an arginase inhibitor, such as a compound of any one of Formulae I, II, or III. 
     
     
         96 . A pharmaceutical kit comprising:
 a chemotherapeutic agent;   an arginase inhibitor; and   optionally directions on how to administer the chemotherapeutic agent and arginase inhibitor.