Tumor-selective combination therapy
The therapies described herein can be selectively lethal toward a variety of different cancer cell types and cancer conditions in a subject. The combination therapies described herein can be useful for the management, treatment, control, or adjunct treatment of diseases, where the selective lethality is beneficial in chemotherapeutic therapy, particularly where the disease is accompanied by elevated levels of NQO1.
1. A method of killing or inhibiting the growth of cancer cells of a solid tumor in a patient in need thereof comprising administering to said patient a NQO1 bioactivatable drug in combination with administration of a poly(ADP-ribosyl) polymerase I (PARP1) inhibitor, wherein the NQO1 bioactivatable drug is administered at least about 2 hours after the PARP1 inhibitor, wherein the NQO1 bioactivatable drug is deoxynyboquinone (DNQ)
2. The method of claim 1 , wherein the cancer cells have base excision repair (BER) defects or vulnerabilities due to faulty DNA repair processes.
3. The method of claim 2 , wherein the BER defect or vulnerability comprises defective levels of X-ray cross complementing 1 (XRCC1) RNA or protein.
4. The method of claim 1 , further comprising the administration of a DNA damaging agent.
5. The method of claim 1 , further comprising administration of an additional chemotherapeutic agent or radiotherapy.
6. The method of claim 1 , wherein the cancer cells have elevated levels of NQO1.
7. The method of claim 1 , wherein the cancer cells are non-small cell lung cancer cells, prostate cancer cells, pancreatic cancer cells, breast cancer cells, head and neck cancer cells, or colon cancer cells.
8. The method of claim 1 , wherein the NQO1 bioactivatable drug is DNQ.
9. The method of claim 1 , wherein the NQO1 bioactivatable drug is
10. The method of claim 1 , wherein said administering comprises contacting the cancer cell with an effective amount of an NQO1 bioactivatable drug in combination with a poly(ADP-ribosyl) polymerase I (PARP1) inhibitor, thereby killing or inhibiting the growth of the cancer cell.
11. The method of claim 1 , wherein the NQO1 bioactivatable drug is administered at least about 24 hours, 28 hours, about 31 hours, about 35 hours, about 38 hours, about 42 hours, about 45 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 8 days, about 9 days, about 12 days, about 15 days, about 16 days, about 18 days, or about 20 days after administration of the PARP1 inhibitor.
12. The method of claim 1 , wherein the NQO1 bioactivatable drug is administered at about 1 day to about 21 days after administration of the PARP1 inhibitor.
13. The method of claim 1 , wherein the NQO1 bioactivatable drug is DNQ and the PARP1 inhibitor is selected from the group consisting of AG-014699 (Rucaparib), ABT-888 (Veliparib), BSI-201 (Iniparib), AZD2281 (Olaparib), AG14361 and INO-1001.
14. The method of claim 1 , wherein the NQO1 bioactivatable drug is
and the PARP1 inhibitor is selected from the group consisting of AG-014699 (Rucaparib), ABT-888 (Veliparib), BSI-201 (Iniparib), AZD2281 (Olaparib), AG14361 and INO-1001.
15. The method of claim 1 , wherein the NQO1 bioactivatable drug is
and the PARP1 inhibitor is Rucaparib.
16. The method of claim 1 , wherein the NQO1 bioactivatable drug is
and the PARP1 inhibitor is Veliparib.
17. The method of claim 1 , wherein the NQO1 bioactivatable drug is
and the PARP1 inhibitor is Olaparib.
18. The method of claim 1 , wherein the NQO1 bioactivatable drug is DNQ, and the PARP1 inhibitor is Rucaparib.
19. The method of claim 1 , wherein the NQO1 bioactivatable drug is DNQ, and the PARP1 inhibitor is Veliparib.
20. The method of claim 1 , wherein the NQO1 bioactivatable drug is DNQ, and the PARP1 inhibitor is Olaparib.