IP Library › Granted Patent US 12,201,620
Granted Patent B2
US 12,201,620 · App. 17/688,222 · Granted Jan 21, 2025

Compositions and methods for treating chemotherapy resistant cancer

Inventors: Josephine Kahn (Boston, MA); Siddhartha Jaiswal (Boston, MA); Benjamin Ebert (Boston, MA)
Assignee: The Brigham and Women's Hospital, Inc.
A61K31/4436A61K31/381A61K31/675A61K31/704A61K31/7068A61K33/243A61P35/00
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Quick Facts
Patent No.
US 12,201,620
App. No.
17/688,222
Granted
Jan 21, 2025
Kind
B2
Abstract

The present invention features methods for increasing sensitivity and/or reversing resistance to chemotherapy, methods for treating or preventing a cancer in a subject, methods for treating clonal hematopoiesis of indeterminate potential in a subject, and methods of identifying resistance or sensitivity to chemotherapy in a subject. In some embodiments, the methods contain the step of administering an agent that inhibits the expression or activity of a Protein phosphatase 1D (PPM1D) polypeptide or polynucleotide. The present invention also features compositions for increasing sensitivity and/or reversing resistance to chemotherapy.

Claims (22)

1. A method of treating or preventing clonal hematopoiesis of indeterminate potential (CHIP) or a chemotherapy-resistant hematologic or blood cancer or malignancy in a subject, the method comprising:

administering a protein phosphatase 1D (PPM1D) inhibitor to a subject identified as having, or having a propensity to develop, CHIP or a chemotherapy-resistant hematologic or blood cancer or malignancy; wherein the subject is identified as having, or having the propensity to develop, CHIP or a chemotherapy-related hematologic or blood cancer or malignancy by detection of a truncating and/or a gain-of-function mutation in the PPM1D polynucleotide or polypeptide in a hematopoietic or blood cell or stem cell of the subject, wherein the PPM1D mutation causes clonal dominance and resistance to chemotherapy or a chemotherapeutic agent; and

treating or preventing CHIP or a chemotherapy-related hematologic or blood cancer or malignancy in the subject following administration of the PPM1D inhibitor by selectively targeting PPM1D-mutant cells and reversing clonal dominance and resistance to chemotherapy or a chemotherapeutic agent.

2. The method of claim 1 , wherein the cell is in a subject having hematologic or blood cancer.

3. The method of claim 1 , wherein the cell is in a subject having a hematologic or blood malignancy.

4. The method of claim 1 , wherein the cell is a blood cell.

5. The method of claim 1 , wherein the cancer is a chemotherapy-related myeloid neoplasm.

6. The method of claim 1 , wherein the biological sample is a blood, bone marrow, or tumor sample.

7. The method of claim 1 , wherein the PPM1D inhibitor is selected from the group consisting of GSK2830371, CCT007093, and analogs thereof.

8. The method of claim 1 , wherein the chemotherapeutic agent is a DNA damaging agent selected from the group consisting of Cytarabine, Doxorubicin, Cyclophosphamide, and Cisplatin.

9. The method of claim 1 , wherein the PPM1D inhibitor inhibits the activity of a PPM1D polypeptide comprising the truncation mutation and/or a gain-of-function mutation.

10. A method of treating clonal hematopoiesis of indeterminate potential (CHIP) in a pre-identified subject, the method comprising administering to the subject an effective amount of a protein phosphatase 1D (PPM1D) inhibitor, wherein the subject is pre-identified as having a truncation mutation and/or a gain-of-function mutation in a PPM1D polynucleotide or polypeptide relative to a reference in a biological sample obtained from the subject; and

treating CHIP and preventing emergence of PPM1D-mutant CHIP clones in the subject by reversing clonal dominance and chemotherapy resistance of the PPM1D-mutant CHIP clones following administration of the PPM1D inhibitor.

11. The method of claim 10 , wherein said treatment selectively targets a cell comprising the mutation in the PPM1D polynucleotide or polypeptide.

12. The method of claim 11 , wherein the cell is in a subject having a cancer.

13. The method of claim 12 , wherein the cancer is a hematologic cancer or a chemotherapy-related myeloid neoplasm.

14. The method of claim 10 , wherein the biological sample is a blood, bone marrow, or tumor sample.

15. The method of claim 10 , wherein the PPM1D inhibitor is selected from the group consisting of GSK2830371, CCT007093, and analogs thereof.

16. The method of claim 10 , wherein the PPM1D inhibitor inhibits the activity of a PPM1D polypeptide comprising a truncation mutation and/or a gain-of-function mutation.

17. The method of claim 10 , wherein the subject is pre-identified as having a PPM1D truncation mutation and/or a gain-of-function mutation and/or a cancer that is resistant to a chemotherapeutic agent by

measuring a level and/or sequence of a mutant PPM1D polynucleotide or polypeptide in a biological sample obtained from the subject relative to the level of a PPM1D polynucleotide or polypeptide in a normal, healthy, or wild-type reference sample; and/or

detecting in a biological sample obtained from the subject a truncation mutation and/or a gain-of-function mutation in a PPM1D polynucleotide or polypeptide relative to a reference sequence.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 16, 2024
From: EBERT, BENJAMIN
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 068594/0992 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 16, 2024
From: KAHN, JOSEPHINE; JAISWAL, SIDDHARTHA
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 068595/0001 →
Continuity (3)
Division 16083687
Provisional Application 62306952 · Mar 11, 2016
Related Publication 20220362228A1 · Nov 17, 2022
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