Niclosamide and its derivatives for use in the treatment of solid tumors

A pharmaceutical composition comprising a cytostatic compound according to formula I, II or III

• wherein
• A is carbonyl, methylene, hydroxymethinyl, alkoxymethinyl, aminomethinyl, oxime, hydrazone, arylhydrazone, or semicarbazone;
• B if present is CR25R26, O, S or NR27;
• R1, R3, R4, R8, R10, and R11 are independently hydrogen, hydroxyl, alkoxy, halogen or C1 to C6 alkyl;
• R2 and R7 are independently halogen, hydroxyl or hydrogen,
• R5 if present is hydroxyl, phosphate, hydrogen, halogen, alkyl, cycloalykyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio or amino;
• R6 if present is hydrogen or C1 to C6 alkyl;
• R9 is nitro, hydrogen, hydroxyl, amino, halogen, alkyl, alkenyl, alkynyl, or aryl;
• and
• R21, R22, R23, and R24, if present are independently hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl;
• R25 and R26 if present are independently hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl;
• and
• R27 if present is hydrogen or C1 to C6 alkyl:
• or salt thereof;
• an alkylating agent;
• and a pharmaceutically acceptable excipient.

A method of treating a solid tumor characterized by a decreased expression level of NFκBIA, comprising administering a cytostatic compound according to formula I, II or III

• to a subject, wherein
• A is carbonyl, methylene, hydroxymethinyl, alkoxymethinyl, aminomethinyl, oxime, hydrazone, arylhydrazone, or semicarbazone;
• B if present is CR25R26, O, S or NR27;
• R1, R3, R4, R8, R10, and R11 are independently hydrogen, hydroxyl, alkoxy, halogen or C1 to C6 alkyl;
• R2 and R7 are independently halogen, hydroxyl or hydrogen,
• R5 if present is hydroxyl, phosphate, hydrogen, halogen, alkyl, cycloalykyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio or amino;
• R6 if present is hydrogen or C1 to C6 alkyl;
• R9 is nitro, hydrogen, hydroxyl, amino, halogen, alkyl, alkenyl, alkynyl, or aryl;
• and
• R21, R22, R23, and R24, if present are independently hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl;
• R25 and R26 if present are independently hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl;
• and
• R27 if present is hydrogen or C1 to C6 alkyl.

A method for determining if therapy with a cytostatic compound according to formula I, II or III

• wherein
• A is carbonyl, methylene, hydroxymethinyl, alkoxymethinyl, aminomethinyl, oxime, hydrazone, arylhydrazone, or semicarbazone;
• B if present is CR25R26, O, S or NR27;
• R1, R3, R4, R8, R10, and R11 are independently hydrogen, hydroxyl, alkoxy, halogen or C1 to C6 alkyl;
• R2 and R7 are independently halogen, hydroxyl or hydrogen,
• R5 if present is hydroxyl, phosphate, hydrogen, halogen, alkyl, cycloalykyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio or amino;
• R6 if present is hydrogen or C1 to C6 alkyl;
• R9 is nitro, hydrogen, hydroxyl, amino, halogen, alkyl, alkenyl, alkynyl, or aryl;
• and
• R21, R22, R23, and R24, if present are independently hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl;
• R25 and R26 if present are independently hydrogen, hydroxyl, halogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl;
• and
• R27 if present is hydrogen or C1 to C6 alkyl,
• is suitable for treating a patient with a solid tumor comprising the steps of
• a) determining the expression level of NFκBIA in a sample of tumor cells or tumor tissue of the patient;
• b) comparing the determined expression level with a reference value;
• c) determining if the therapy with niclosamide is suitable for the patient based on the result of the comparison of step b), wherein underexpression or a deletion of NFκBIA indicates that the combination therapy is suitable for the patient.

A method for determining the molar ratio of niclosamide to temozolomide to be administered to a patient with a solid tumor comprising the steps of

• a) determining the expression level of NFκBIA in a sample of tumor cells or tumor tissue of the patient;
• b) comparing the determined expression level with a reference value;
• c) determining the molar ratio of niclosamide to temozolomide based on the result of the comparison of step b), wherein
• (i) an expression above the reference value indicates that the molar ratio shall be below 40% niclosamide;
• and
• (ii) an expression level below the reference value indicates that the molar ratio shall be equal to or larger than 40% niclosamide.