Method for the prognosis and treatment of cancer metastasis

1. A method for inhibiting, treating or reducing bone metastasis in a subject suffering triple negative (including basal-like) breast cancer, wherein the subject has been determined to have an elevated c-MAF expression level, copy number, or amplification in a primary breast tumor sample as compared to a control sample, comprising administering a c-MAF inhibitory agent to the subject, wherein an elevated c-MAF expression level, copy number, or amplification in a primary breast tumor sample is predictive of bone metastasis.

2. A method for inhibiting, treating or reducing bone metastasis in a subject suffering triple negative (including basal-like) breast cancer, wherein the subject has been determined to have an elevated c-MAF expression level, copy number, or amplification in a primary breast tumor sample as compared to a control sample, comprising administering an agent capable of avoiding or preventing bone degradation to the subject, wherein an elevated c-MAF expression level, copy number, or amplification in a primary breast tumor sample is predictive of bone metastasis.

3. The method of claim 1 , wherein said c-MAF inhibitory agent is selected from the group consisting of a c-MAF specific siRNA, a c-MAF specific antisense oligonucleotide, a c-MAF specific ribozyme, a c-MAF inhibitory antibody or nanobody, a dominant negative c-MAF variant, catalytic RNAs, DNA enzymes, inhibitory antibodies, inhibitory peptides, a c-MAF specific small molecule, a c-MAF specific antibody, a c-MAF specific antibody-like molecule, a c-MAF specific structurally constrained (cyclical) peptide, a c-MAF specific stapled peptide, a c-MAF specific alphabody, and a compound selected from the list below:

TABLE 1

Small molecules with c-MAF inhibiting capacity

1

Endiandric acid H derivatives of the general formula

wherein

R 1 and R 2 are, independently of one another,

1.0 H or

2.0 a O—C 1 -C 6 -alkyl, —O—C 2 -C 6 -alkenyl, —O—C 2 -C 6 -alkynyl or

—O-C 6 -C 10 -aryl group, in which alkyl, alkenyl and alkynyl are

straight-chain or branched, and in which the alkyl, alkenyl and

alkynyl groups are mono- or disubstituted with:

2.1 —OH,

2.2 ═O,

2.3 —O—C 1 -C 6 -alkyl, in which alkyl is straight-chain or branched,

2.4 —O—C 2 -C 6 -alkenyl, in which alkenyl is straight-chain or

branched,

2.5 C 6 -C 10 -aryl,

2.6 —NH—C 1 -C 6 -alkyl, in which alkyl is straight-chain or branched,

2.7 —NH—C 2 -C 6 -alkenyl, in which alkenyl is straight-chain or

branched,

2.8 —NH 2 or

2.9 halogen,

and in which the aryl group, is optionally mono- or disubstituted with

the substituent 2.1 or 2.3 to 2.9,

in which the substituents 2.3, 2.4, 2.6 and 2.7 may be further

substituted with CN or —CN, -amide or -oxime functions, and 2.5

may be further substituted with —CN or amide functions, or R 1

and R 2 together form a ring, wherein R 1 and R 2 mean a

—O—[(C 1 -C 6 )-alkylene]—O— group,

R 3 is

1.0 H or

2.0 a —O—C 1 -C 6 -alkyl, —O—C 2 -C 6 -alkenyl, —O—C 2 -C 6 -alkynyl

or —O—C 6 -C 10 -aryl group, in which alkyl, alkenyl and alkynyl are

straight-chain or branched, and in which the alkyl, alkenyl and

alkynyl groups are mono-or disubstituted with:

2.1 —OH,

2.2 ═O,

2.3 —O—C 1 -C 6 -alkyl, in which alkyl is straight-chain or branched,

2.4 —O—C 2 -C 6 -alkenyl, in which alkenyl is straight-chain or

branched,

2.5 —C 6 -C 10 -aryl,

2.6 —NH—C 1 -C 6 -alkyl, in which alkyl is straight-chain or branched,

2.7 —NH—C 2 -C 6 -alkenyl, in which alkenyl is straight-chain or

branched,

2.8 —NH 2 or

2.9 halogen,

and in which the aryl group, is optionally mono- or disubstituted with

the substituent 2.1 or 2.3 to 2.9,

in which the substituents 2.3, 2.4, 2.6 and 2.7 may be further

substituted with —CN, -amide or -oxime functions, and 2.5

may be further substituted with —CN or amide functions

R 4 is CO 2 R 3 , CO 2 NHR 3 , CHO, CH 2 OR 3 , CH 2 OSi(R 3 ) 3 , CH 2 Br,

CH 2 CN, in which R 3 is as defined above,

2

8-hydroxyquinoline derivatives of the general formula

wherein

R 1 is selected from the group consisting of NO 2 , NH 2 ,

NH(C 1 -C 6 -alkyl) and N(C 1 -C 6 -alkyl)(C 1 -C 6 -alkyl);

R 2 is selected from H, halogen, C 1 -C 6 alkyl, and fluoro-

substituted C 1 —C 6 alkyl, or

R 1 is Cl and R 2 is Br or H,

3

Clioquinol (5-chloro-7-iodoquinolin-8-ol)

4

Compounds of the general formula

wherein

==-:-:-: is a single or double bond,

R 1 is selected from the group consisting of H, C 1 -C 4 alkyl, C(O)O

C 1 -C 4 alkyl, C(O) C 1 -C 4 alkyl and C(O)NH C 1 -C 4 alkyl;

R 2 is selected from H and C 1 -C 4 alkyl;

R 3 is selected from H and C 1 -C 4 alkyl;

or R 2 and R 3 are bound together along with the carbon and

nitrogen atoms to which they are bound to form a piperidine ring,

R 4 and R 5 are independently selected from H, halogen, hydroxy,

C 1 -C 4 alkyl, fluoro-substituted

C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and

X is selected from C and N,

5

Nivalenol (12,13-epoxy-3,4,7,15-tetrahydroxytrichothec-9-

en-8-one)

6

Purvalanol

7

2-(Hydroxyethylamino)-6-benzylamino-9-methylpurine (Olomoucine);

2-(2′-Hydroxyethylamino)-6-benzylamino-9-isopropylpurine (N 9 -

isopropylolomoucine)

8

6-(Benzylamino)-2(R)-[[1-(hydroxymethyl)propyl]amino]-9-

isopropylpurine; 2-(R)-[[9-(1-methylethyl)-6-[(phenylmethyl)amino]-

9H-purin-2-yl]amino]-1-butanol

(Roscovitine), methoxyroscovitine

9

N2-(cis-2-Aminocyclohexyl)-N6-(3-chlorophenyl)-9-ethyl-9H-purine-

2,6-diamine (CGP74514)

10

3-((9-ethyl-2-((trans-4-hydroxycyclohexyl)amino)-9H-purin-6-yl)

amino)-Benzonitrile (CGP79807)

11

O6-(Cyclohexylmethyl)guanine (NU2058)

12

4-[[6-(cyclohexylmethoxy)-9H-purin-2-yl]amino]-benzenesulfonamide

(NU6102)

13

Isopentenyl-adenine

14

Indirubin

15

Indenopyrazoles

16

Quinazoline

17

Thiazole

18

Flavopiridol

19

Alkaloid

20

Paullone

21

Hymenialdisine

22

phenylaminopyrimidine

23

3-[[4-[2-[(3 -Chlorophenyl)amino]-4-pyrimidinyl]-2-pyridinyl]amino]-

1-propanol (CGP60474)

24

Diarylurea

25

(2R)-2,5-Dihydro-4-hydroxy-2-[(4-hydroxy-3-(3-methyl-2-

butenyl)phenyl)methyl]-3-(4-hydroxyphenyl)-5-oxo-2-furancarboxylic

acid methyl ester (butyrolactone-I)

26

4-(7-butyl-1,5-dihydropyrrolo[2,3-b]pyrazin-6-ylidene)cyclohexa-2,5-

dien-1-one (aloisine A)

4. The method of claim 2 , wherein said agent is selected from the group consisting of a bisphosphonate, a RANKL inhibitor, a PTH or PTHLH inhibitor or a PRG analog, strontium ranelate, a DKK-1 inhibitor, a dual MET and VEGFR2 inhibitor, an estrogen receptor modulator, calcitonin, Radium-223 and a cathepsin K inhibitor.

5. The method according to claim 4 , wherein the RANKL inhibitor is selected from the group consisting of: a RANKL specific antibody, a RANKL-specific nanobody and osteoprotegerin.

6. The method according to claim 5 , wherein the RANKL specific antibody is denosumab.

7. The method according to claim 5 , wherein the RANKL specific nanobody is ALX-0141.

8. The method according to claim 4 , wherein the bisphosphonate is zoledronic acid.

9. The method according to claim 4 , wherein the dual MET and VEGFR2 inhibitor is Cabozantinib.

10. The method according to claim 4 , wherein the Radium-223 is alpharadin.

11. The method according to claim 1 , wherein the bone metastasis is osteolytic metastasis.

12. The method according to claim 4 , wherein the bisphosphonate is clodronate.

13. The method according to claim 2 , wherein the bone metastasis is osteolytic metastasis.

14. The method of claim 1 , wherein the increase in c-MAF expression is at least about 1.1 times, 1.5 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times or greater than the control sample.

15. The method of claim 2 , wherein the increase in c-MAF expression is at least about 1.1 times, 1.5 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times or greater than the control sample.

16. The method of claim 1 , wherein the expression level, copy number or amplification is quantified by means of quantifying the messenger RNA (mRNA) of said gene, or a fragment of said mRNA, the complementary DNA (cDNA) of said gene, or a fragment of said cDNA or the levels of protein encoded by said gene or of a variant thereof.

17. The method of claim 16 , wherein the expression level, copy number or amplification is quantified by means of a quantitative polymerase chain reaction (PCR) or a DNA or RNA array, nucleotide hybridization technique, Western blot, in situ hybridization, ELISA, immunohistochemistry or a protein array.

18. The method of claim 2 , wherein the expression level, copy number or amplification is quantified by means of quantifying the messenger RNA (mRNA) of said gene, or a fragment of said mRNA, the complementary DNA (cDNA) of said gene, or a fragment of said cDNA or the levels of protein encoded by said gene or of a variant thereof.

19. The method of claim 18 , wherein the expression level, copy number or amplification is quantified by means of a quantitative polymerase chain reaction (PCR) or a DNA or RNA array, nucleotide hybridization technique, Western blot, in situ hybridization, ELISA, immunohistochemistry or a protein array.