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EP-4735003-A1 - COMPOSITIONS AND METHODS FOR TREATING USING A COMBINATION OF ALTERNATING ELECTRIC FIELDS AND DNA-DEPENDENT PROTEIN KINASE INHIBITORS

EP4735003A1EP 4735003 A1EP4735003 A1EP 4735003A1EP-4735003-A1

Abstract

Disclosed herein is the use of alternating electric fields and a DNA-dependent PK inhibitor to treat cancer. Disclosed herein is the use of alternating electric fields and a DNA-dependent PK inhibitor for inducing cell death. Disclosed herein is the use of alternating electric fields and a DNA-dependent PK inhibitor for inhibiting DNA repair in a cancer cell having DNA strand breaks, for example double stranded DNA breaks. Disclosed herein is the use of alternating electric fields and a DNA-dependent PK inhibitor for increasing efficacy of radiation therapy.

Inventors

  • DOR-ON, Eyal
  • COLLIS, SPENCER J.
  • JONES, Callum George
  • ROMINIYI, Ola
  • AVIGDOR, Lilach

Assignees

  • Novocure GmbH

Dates

Publication Date
20260506
Application Date
20240629

Claims (15)

  1. 1. A DNA-dependent protein kinase inhibitor for use in a method of treating a subject having cancer, wherein the method comprises: a) applying an alternating electric field to a target site of the subject for a period of time, wherein the target site comprises one or more cancer cells, and b) administering a therapeutically effective amount of the inhibitor to the subject.
  2. 2. A kit for treating cancer cells, the kit comprising: one or more DNA-dependent protein kinase PK inhibitors; and one or more materials for delivering alternating electric fields to a target site, wherein the target site comprises one or more cancer cells.
  3. 3. An in vitro method of treating a target site comprising: a) applying an alternating electric field to a target site for a period of time, wherein the target site comprises one or more cancer cells, and
  4. 4. b) administering a therapeutically effective amount of a DNA-dependent protein kinase (PK) inhibitor to the target site. A method of treating a subject having cancer comprising: a) applying an alternating electric field to a target site of the subject for a period of time, wherein the target site comprises one or more cancer cells, and b) administering a therapeutically effective amount of a DNA-dependent protein kinase (PK) inhibitor to the subject.
  5. 5. The DNA-dependent protein kinase (PK) inhibitor for use of claim 1, or the method of claim 4, wherein the cancer is ovarian cancer, hepatobiliary cancer, prostate cancer, pancreatic cancer, head and neck cancers, glioblastoma, gliosarcoma, leukemia, or non-small cell lung cancer.
  6. 6. The DNA-dependent protein kinase (PK) inhibitor for use of claim 1 or claim 5, or the method of any one of claims 4-5, wherein the subject having cancer has undergone or is currently undergoing radiation therapy or chemotherapy.
  7. 7. The DNA-dependent protein kinase (PK) inhibitor for use of claim 1 or of any of claims 5-6, or the method of any one of claims 3-6, wherein the one or more cancer cells at the target site have double stranded DNA breaks.
  8. 8. The DNA-dependent protein kinase (PK) inhibitor for use of claim 1 or of any of claims 5-7, or the method of any one of claims 3-7, wherein at least one DNA repair mechanism in the one or more cancer cells at the target site is inhibited.
  9. 9. The DNA-dependent protein kinase (PK) inhibitor for use of claim 7, or the method of claim 8, wherein the DNA repair mechanism inhibited is homologous recombination repair, non- homologous end joining repair, or both.
  10. 10. The DNA-dependent protein kinase (PK) inhibitor for use of claim 1 or of any of claims 5-9, or the method of any one of claims 3-9, wherein one or more cancer cells at the target site undergo cell death.
  11. 11. The DNA-dependent protein kinase (PK) inhibitor for use of claim 1 or of any of claims 5- 10, or the method of any one of claims 4-10, wherein the therapeutically effective amount of a DNA-dependent protein kinase (PK) inhibitor is administered orally, subcutaneously or intravenously.
  12. 12. A DNA-dependent protein kinase (PK) inhibitor for use in a method of inducing cell death of a cancer cell, wherein the cancer cell is in a subject, wherein the method comprises: a) exposing the cancer cell to an alternating electric field for a period of time, and b) exposing the cancer cell to the DNA-dependent PK inhibitor.
  13. 13. A DNA-dependent protein kinase (PK) inhibitor for use in a method of inhibiting DNA repair in a cancer cell exposed to or previously exposed to radiation, wherein the cancer cell is in a subject, wherein the method comprises: a) exposing the cancer cell to an alternating electric field for a period of time, and b) exposing the cancer cell to the DNA-dependent PK inhibitor.
  14. 14. A method of inducing cell death of a cancer cell comprising: a) exposing the cancer cell to an alternating electric field for a period of time, and b) exposing the cancer cell to a DNA-dependent PK inhibitor.
  15. 15. The DNA-dependent protein kinase (PK) inhibitor for use of claim 12, or the method of claim 14, wherein the cancer cell is simultaneously exposed to radiation or was previously exposed to radiation.

Description

COMPOSITIONS AND METHODS FOR TREATING USING A COMBINATION OF ALTERNATING ELECTRIC FIELDS AND DNA-DEPENDENT PROTEIN KINASE INHIBITORS BACKGROUND [0001] DNA is damaged from many different causes throughout a cell cycle, including a tumor cell cycle. In particular, radiotherapy and chemotherapy are used to induce DNA damage in tumor cells and cause tumor cell death. DNA damage is repaired through a variety of DNA repair pathways, depending on the type of DNA damage. DNA repair pathways consist of the direct repair (DR), base excision repair (BER), nucleotide repair (NER), mismatch repair (MMR), and DNA strand-break repair pathways, among others. DNA- Protein Kinase (DNA- PK) regulates the major pathway (nonhomologous end joining) responsible for repair of DNA double-strand breaks induced by radiation. [0002] When the normal repair process is impaired or altered, DNA damage is not repaired, triggering cell death in tumor cells. DNA repair status in tumor cells is associated with the therapeutic response to the anti-cancer drug, establishing DNA repair pathways as promising targets for cancer treatment. [0003] Tumor treating fields (TTFields), also referred to as alternating electric fields, delay DNA damage repair following radiation treatment of glioma cells. TTFields influence cellular DNA repair capacity by altering the homologous repair pathway. [0004] Thus, altering both homologous and non-homologous repair pathways can be an effective cancer treatment. [0005] BRIEF SUMMARY [0006] Disclosed are methods of treating a subject having cancer comprising applying an alternating electric field to a target site of the subject for a period of time, wherein the target site comprises one or more cancer cells, and administering a therapeutically effective amount of a DNA-dependent PK inhibitor to the subject. [0007] Also disclosed is a DNA-dependent protein kinase inhibitor for use in a method of treating a subject having cancer, wherein the method comprises: a) applying an alternating electric field to a target site of the subject for a period of time, wherein the target site comprises one or more cancer cells, and b) administering a therapeutically effective amount of the inhibitor to the subject. [0008] Also disclosed is a kit for treating cancer cells, the kit comprising: one or more DNA-dependent protein kinase PK inhibitors; and one or more materials for delivering alternating electric fields to a target site, wherein the target site comprises one or more cancer cells. [0009] Still further disclosed is an in vitro method of treating a target site comprising: a) applying an alternating electric field to a target site for a period of time, wherein the target site comprises one or more cancer cells, and b) administering a therapeutically effective amount of a DNA-dependent protein kinase (PK) inhibitor to the target site. [0010] Disclosed are methods of inducing cell death of a cancer cell comprising exposing the cancer cell to an alternating electric field for a period of time, and exposing the cancer cell to a DNA-dependent PK inhibitor. [0011] Also disclosed is a DNA-dependent protein kinase (PK) inhibitor for use in a method of inducing cell death of a cancer cell, wherein the cancer cell is in a subject, wherein the method comprises: exposing the cancer cell to an alternating electric field for a period of time, and exposing the cancer cell to the DNA-dependent PK inhibitor. [0012] Disclosed are methods of inhibiting DNA repair in a cancer cell exposed to or previously exposed to radiation comprising exposing the cancer cell to an alternating electric field for a period of time, and exposing the cancer cell to a DNA-dependent PK inhibitor. [0013] Further disclosed is a DNA-dependent protein kinase (PK) inhibitor for use in a method of inhibiting DNA repair in a cancer cell exposed to or previously exposed to radiation, wherein the cancer cell is in a subject, wherein the method comprises: exposing the cancer cell to an alternating electric field for a period of time, and exposing the cancer cell to the DNA- dependent PK inhibitor. [0014] Disclosed are methods of increasing the efficacy of radiation therapy in a subject comprising applying an alternating electric field to a target site of the subject for a period of time, wherein the target site comprises a site receiving or that has received radiation therapy, and administering a therapeutically effective amount of a DNA-dependent PK inhibitor to the subject. [0015] Also disclosed is a DNA-dependent protein kinase (PK) inhibitor for use in a method of increasing the efficacy of radiation therapy in a subject, wherein the method comprises: a) applying an alternating electric field to a target site of the subject for a period of time, the alternating electric field having a frequency and field strength, wherein the target site comprises a site receiving or that has received radiation therapy, and b) administering a therapeutically effective amount of the DNA-d