Method and compositions for treating cancer and related methods
The present invention relates to anti-cancer therapeutics. In certain aspects, cancers are treated with a combination of an anti-EGFR agent and an agent that increases the activity of the KLF6 tumor suppressor gene and/or an agent that increases activity of the FOXO1 tumor suppressor gene. In a preferred aspect, the anti-EGFR agent erlotinib a tricyclic agent compound, are used in combination to treat non-small cell lung cancer in a patient with primary or acquired drug resistance to erlotinib, and wherein the tricyclic agent is administered in an amount that does not lead to a substantial central nervous system effect. In additional aspects, the invention relates to compositions and kits useful for treating cancers, methods for screening for compounds that enhance the activity of anti-EGFR agent, and methods for determining whether a patient will respond to anti-EGFR therapy.
1. A method of enhancing sensitivity to an anti epidermal growth factor receptor (anti-EGFR) agent comprising administering to a subject in need thereof a first agent, wherein said first agent increases activity of Krüppel-like factor 6 (KLF6) in an amount effective for said enhancing sensitivity to said anti-EGFR agent.
2. The method according to claim 1 wherein said anti-EGFR agent is erlotinib.
3. The method according to claim 1 wherein said first agent increases nuclear accumulation of forkhead box O1 (FOXO1).
4. The method according to claim 3 wherein said first agent that increases nuclear accumulation of FOXO1 is a tricyclic agent.
5. The method according to claim 4 wherein said tricyclic agent is a phenothiazine, dibenzazepine, or thioxanthene.
6. The method according to claim 4 wherein said tricyclic agent is administered at a dose such that said administration does not lead to a substantial central nervous system effect.
7. The method according to claim 1 wherein said subject suffers from an EGFR-based neoplastic disease.
8. The method according to claim 7 wherein said subject suffers from non-small cell lung cancer (NSCLC).
9. The method according to claim 1 further comprising administering said anti-EGFR agent to said subject.
10. The method according to claim 1 , further comprising administering to the subject a second agent, wherein the second agent increases activity of FOXO1.
11. The method according to claim 10 , wherein said second agent increases nuclear accumulation of FOXO1.
12. The method according to claim 10 wherein said second agent is a tricyclic agent.
13. The method according to claim 12 wherein said tricyclic agent is a phenothiazine, dibenzazepine, or thioxanthene.
14. The method according to claim 12 wherein said tricyclic agent is administered at a dose such that said administration does not lead to a substantial central nervous system effect.
15. A method of enhancing sensitivity to an anti-EGFR agent comprising administering to a subject in need thereof a first agent and a second agent in an amount effective for said enhancing sensitivity to said anti-EGFR agent, wherein the first agent increases activity of KLF6 and the second agent increases activity of FOXO1.
16. The method according to claim 15 wherein said anti-EGFR agent is erlotinib.
17. The method according to claim 15 wherein said first agent increases nuclear accumulation of FOXO1.
18. The method according to claim 17 wherein said first agent is a tricyclic agent.
19. The method according to claim 18 wherein said tricyclic agent is a phenothiazine, dibenzazepine, or thioxanthene.
20. The method according to claim 18 wherein said tricyclic agent is administered at a dose such that said administration does not lead to a substantial central nervous system effect.
21. The method according to claim 15 wherein said subject suffers from an EGFR-based neoplastic disease.
22. The method according to claim 15 wherein said subject suffers from NSCLC.
23. The method according to claim 15 further comprising administering said anti-EGFR agent to said subject.
24. The method according to claim 15 , wherein said second agent increases nuclear accumulation of FOXO1.
25. The method according to claim 24 wherein said second agent is a tricyclic agent.
26. The method according to claim 25 wherein said tricyclic agent is a phenothiazine, dibenzazepine, or thioxanthene.
27. The method according to claim 25 wherein said tricyclic agent is administered at a dose such that said administration does not lead to a substantial central nervous system effect.