Treatment of BRCA1-defective cancer or resistant cancers
Provided herein are methods of treating cancer in a subject, by administering COH29 ((N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide)). The methods of treating include treating a BRCA1-defective subject, a PARP1 inhibitor-resistant subject or a DNA-damaging anti-cancer agent resistant subject. The methods include treating cancer by administering COH29 and a DNA-damaging anti-cancer agent in a combined synergistic amount.
1. A method of treating breast cancer or ovarian cancer in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound having a structure:
wherein said subject is suffering from cancer and wherein said subject is a BRCA1-defective subject or a PARP1 inhibitor-resistant subject.
2. The method of claim 1 , wherein said administering inhibits DNA repair in said subject.
3. The method of claim 1 , wherein said administering inhibits base excision repair (BER), nucleotide excision repair (NER) or double stranded DNA break repair in said subject.
4. The method of claim 1 , wherein said administering increases y-H2AX protein activity or expression in said subject.
5. The method of claim 1 , wherein said administering lowers Rad51 protein activity or expression in said subject.
6. The method of claim 1 , wherein said administering lowers BRCA1 protein activity or expression in said subject.
7. The method of claim 1 , wherein said administering lowers PARP1 protein activity or expression in said subject.
8. A method of treating breast cancer or ovarian cancer in a subject in need thereof, said method comprising administering to the subject a compound having a structure:
and a DNA-damaging anti-cancer agent in a combined synergistic amount, wherein the subject is suffering from cancer and is a BRCA1-defective subject or a PARP1 inhibitor-resistant subject, and the DNA-damaging anti-cancer agent is an ethylenimine, methylmelamine, nitrosourea, nitrogen mustard, busulfan, cyclophosphamide, procarbazine, a Topoisomerase I agent, a Topoisomerase II agent, camptothecin, irinotecan, topotecan, cisplatin, carboplatin, gemcitabine, y-irradiation, oxaliplatin, adriamycin, doxorubicin, etoposide, a single-strand break agent, BCNU carmustine, CCNU, DTIC, cytoxan, ifosfamide, bleomycin, or mitomycin C.
9. The method of claim 8 , wherein said alkylating agent is an ethylenimine, methylmelamine, nitrosourea, nitrogen mustard, busulfan, cyclophosphamide, or procarbazine.
10. The method of claim 8 , wherein said DNA-damaging anti-cancer agent is a Topoisomerase I agent, a Topoisomerase II agent, camptothecin, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, adriamycin, doxorubicin, etoposide, a single-strand break agent, BCNU carmustine, CCNU, DTIC, cytoxan, ifosfamide, bleomycin, or mitomycin C.
11. The method of claim 8 , wherein said DNA-damaging anti-cancer agent is cisplatin, gemcitabine or y-irradiation.
12. A method of treating breast cancer or ovarian cancer in a subject in need thereof, said method comprising administering to the subject an effective amount of a compound having a structure:
wherein said subject is suffering from cancer, and wherein said subject is a BRCA1-defective subject or a PARP1 inhibitor-resistant subject, and a pharmaceutically-acceptable excipient.
13. The method of claim 12 , wherein said administration is oral, intravenous, or intramuscular.
14. The method of claim 12 , further comprising administering a DNA damaging anti-cancer agent, wherein the DNA damaging anti-cancer agent is an ethylenimine, methylmelamine, nitrosourea, nitrogen mustard, busulfan, cyclophosphamide, procarbazinea, Topoisomerase I agent, a Topoisomerase II agent, camptothecin, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, adriamycin, doxorubicin, etoposide, a single-strand break agent, BCNU carmustine, CCNU, DTIC, cytoxan, ifosfamide, bleomycin, or mitomycin C.