Composition and method for treating a drug-resistant cancer

1. A method for treating a TMZ-resistant cancer in a patient, which comprises administering to the patient a therapeutically effective amount of a combination of Temozolomide (TMZ) and a Compound A having the structure of Formula A, or a pharmaceutically acceptable salt or enantiomer thereof:

wherein

R 1 is hydrogen, alkyl, alkenyl, C 5 -C 6 cycloalkyl, 5-membered or 6-membered unsaturated carbocycle or 5-membered or 6-membered heterocycle, or (CH 2 )mR 4 ;

X is C, —O—, —N— or —S—;

Y is —O—, —NH or —O—C 1 -C 4 alkyl;

n is an integer of 0 to 10;

m is an integer of 0 to 5;

R 2 and R 3 is independently C 1 -C 6 alkyl;

R 4 is C 5 -C 6 cycloalkyl or 5-membered or 6-membered unsaturated carbocycle or heterocycle which may be substituted with halogen, —CF 3 , —OR 7 or —NR 7 R 8 , wherein R 7 and R 8 are independently hydrogen or C 1 -C 6 alkyl;

R 5 is OH, NH 2 or C 5 -C 8 cycloalkyl, 5-membered or 6-membered unsaturated carbocycle or heterocycle wherein the cycloalkyl, carbocycle and heterocycle may be optionally substituted with halogen, NH 2 , NO 2 , C 1 -C 6 alkoxy, C 1-6 alkylthio, OR 7 ″, NR 7 R 8 or CF 3 ; and

R 6 is H, C 1 -C 10 alkyl which may be substituted by hydroxy or C 2 -C 10 alkenyl, or together with R 1 being —C 2 H 2 —; and

wherein TMZ and the compound A are combined at a relative ratio to effectively overcome TMZ resistance.

2. The method of claim 1 , wherein the compound A is a compound BMX having the structure of

3. The method of claim 1 , wherein the compound A provides an efficacy in enhancement of TMZ-mediated cytotoxic effect to overcome the TMZ resistance.

4. The method of claim 3 , wherein the enhancement of TMZ-mediated cytotoxic effect is by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated MGMT inhibition the resistant.

5. The method of claim 1 , wherein TMZ and the compound A are separately or sequentially administered.

6. The method of claim 1 , wherein the cancer is glioblastoma multiforme (GBM) or colorectal cancer (CRC).

7. A combination for treating a TMZ-resistant cancer in a patient, which comprises TMZ and the compound A as defined in claim 1 .

8. The combination of claim 7 , wherein the compound A is BMX having the structure of

9. The combination of claim 7 , wherein the TMZ and compound A are separately or sequentially administered.

10. The combination of claim 8 , wherein the TMZ and BMX are separately or sequentially administered.

11. The combination of claim 7 , wherein the cancer is glioblastoma multiforme (GBM) or colorectal cancer (CRC).

12. A method for a precision personal treatment for a drug-resistant cancer in a patient, which comprises determining the expression of WT-p53 in the patient, and administering the patient a therapeutically effective amount of the compound A as defined in claim 1 or its combination with said drug if the expression of WT-p53 is present in the patient.

13. The method of claim 12 , wherein the drug is TMZ.

14. The method of claim 12 , wherein the cancer is glioblastoma multiforme (GBM) or colorectal cancer (CRC).

15. The method of claim 12 , wherein the drug-resistant cancer is TMZ-resistant GBM or CRC.

16. The method of claim 12 , wherein the compound A is BMX as having the structure of

17. The method of claim 12 , wherein the compound A provides an efficacy in enhancement of drug-mediated cytotoxic effect to overcome the drug resistance.

18. The method of claim 13 , wherein the compound A provides an efficacy in enhancement of TMZ-mediated cytotoxic effect to overcome the TMZ resistance.

19. The method of claim 18 , wherein the enhancement of TMZ-mediated cytotoxic effect is by downregulating the β-catenin/c-Myc/SOX2 signaling pathway and upregulating WT-p53 mediated M GMT inhibition the resistant.