Treating Tumors with TTFields and an Aurora Kinase Inhibitor

• US 20190307781A1
• Filed: 04/08/2019
• Published: 10/10/2019
• Est. Priority Date: 04/09/2018
• Status: Active Grant

• Current Assignee: Novocure GmbH (NovoCure Limited)
• Original Assignee: NovoCure Limited
• Inventors: KREX, Dietmar, TEMME, Achim, SHNAIDERMAN, Rosa S., GILADI, Moshe
• Granted Patent: US 11,298,422 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 33/42 Phosphorus; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 1/32 alternating or intermittent currents applying electric fields by inductive or capacitive coupling A61N1/40; microwave apparatus A61N5/02
• CPC Class Codes: A61N 1/36002 Cancer treatment, e.g. tumour
• CPC Class Codes: A61N 1/40 Applying electric fields by inductive or capacitive coupling microwave apparatus A61N5/00; Applying radio-frequency signals
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The viability of cancer cells can be reduced by administering an Aurora kinase inhibitor (e.g., MLN8237 or another Aurora A kinase inhibitor, AZD1152 or another Aurora B kinase inhibitor) to the cancer cells, and applying an alternating electric field with a frequency between 100 and 300 kHz (e.g., 200 kHz) to the cancer cells. Furthermore, cancer (e.g., glioblastoma) in a subject may be treated by administering an Aurora kinase inhibitor to the subject, and applying an alternating electric field with frequency between 100 and 300 kHz (e.g., 200 kHz) to a target region of the subject (e.g., the brain).

Claims

1. A method of reducing viability of cancer cells, the method comprising:

administering an Aurora kinase inhibitor to the cancer cells; and

applying an alternating electric field to the cancer cells, the alternating electric field having a frequency between 100 and 300 kHz.

2. The method of claim 1, wherein the Aurora kinase inhibitor comprises an Aurora A kinase inhibitor.

3. The method of claim 1, wherein the Aurora kinase inhibitor comprises an Aurora B kinase inhibitor.

4. The method of claim 1, wherein the Aurora kinase inhibitor comprises MLN8237.

5. The method of claim 1, wherein the Aurora kinase inhibitor comprises AZD1152.

6. The method of claim 1, wherein the Aurora kinase inhibitor comprises an Aurora kinase inhibitor selected from the group consisting of AZD1152, Alisertib (MLN8237), Danusertib (PHA-739358), AT9283, PF-03814735, and AMG 900.

7. The method of claim 1, wherein at least a portion of the applying step is performed simultaneously with at least a portion of the administering step.

8. The method of claim 1, wherein the applying step has a duration of at least 72 hours.

9. The method of claim 1, wherein the frequency of the alternating electric field is between 180 and 220 kHz.

10. The method of claim 1, wherein the Aurora kinase inhibitor is administered to the cancer cells at a therapeutically effective concentration, and wherein the alternating electric field has a field strength of at least 1 V/cm in at least some of the cancer cells.

11. The method of claim 10, wherein the therapeutically effective concentration of the Aurora kinase inhibitor is reduced by at least 50% with respect to a dosage of the Aurora kinase inhibitor known to be therapeutically effective in the absence of an alternating electric field.

12. The method of claim 10, wherein the therapeutically effective concentration of the Aurora kinase inhibitor is from about 12.5 nM to about 100 nM.

13. The method of claim 10, wherein the therapeutically effective concentration of the Aurora kinase inhibitor is from 25 nM to 75 nM.

14. A method of treating cancer in a subject, the method comprising:

administering a therapeutically effective dose of an Aurora kinase inhibitor to the subject; and

applying an alternating electric field to a target region of the subject, the alternating electric field having a frequency between 100 and 300 kHz.

15. The method of claim 14, wherein the Aurora kinase inhibitor comprises an Aurora A kinase inhibitor.

16. The method of claim 14, wherein the Aurora kinase inhibitor comprises an Aurora B kinase inhibitor.

17. The method of claim 14, wherein the Aurora kinase inhibitor comprises AZD1152.

18. The method of claim 14, wherein the Aurora kinase inhibitor comprises MLN8237.

19. The method of claim 14, wherein the cancer comprises Glioblastoma.

20. The method of claim 14, wherein the Aurora kinase inhibitor comprises an Aurora kinase inhibitor selected from the group consisting of AZD1152, Alisertib (MLN8237), Danusertib (PHA-739358), AT9283, PF-03814735, and AMG 900.

21. The method of claim 14, wherein at least a portion of the applying step is performed after the administering step and before the Aurora kinase inhibitor is eliminated from the subject'"'"'s body or exhausted.

22. The method of claim 14, wherein the applying step has a duration of at least 72 hours.

23. The method of claim 14, wherein the frequency of the alternating electric field is between 180 and 220 kHz.

24. The method of claim 14, wherein the alternating electric field has a field strength of at least 1 V/cm in at least a portion of the target region.

25. The method of claim 14, wherein the therapeutically effective dose of the Aurora kinase inhibitor is reduced by at least 50% with respect to a dosage of the Aurora kinase inhibitor known to be therapeutically effective in the absence of an alternating electric field.

26. The method of claim 14, wherein the therapeutically effective dose of the Aurora kinase inhibitor is from about 12.5 nM to about 100 nM.

27. The method of claim 14, wherein the therapeutically effective dose of the Aurora kinase inhibitor is from 25 nM to 75 nM.