Splice variants associated with neomorphic SF3B1 mutants

Patent metadata

Field	Value
Publication number	US-11761045-B2
Application number	US-202017098940-A
Country	US
Kind code	B2
Filing date	Nov 16, 2020
Priority date	Sep 1, 2015
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

Splice variants associated with neomorphic SF3B1 mutations are described herein. This application also relates to methods of detecting the described splice variants, and uses for diagnosing cancer, evaluating modulators of SF3B1, and methods of treating cancer associated with mutations in SF3B1.

First claim

The invention claimed is:

1. A method of treating a patient having a neoplastic disorder, comprising administering an SF3B1-modulating compound to the patient, wherein a sample from the patient has been tested to determine expression levels of aberrant and canonical splice variants of TMEM14C, and the sample expresses an elevated ratio of aberrant to canonical splice variants of TMEM14C relative to the ratio in a control sample, wherein the aberrant splice variant comprises SEQ ID NO: 95 and wherein the canonical splice variant comprises SEQ ID NO: 96.

2. The method of claim 1 , wherein the sample comprises a blood sample, a bone marrow aspirate, and/or a bone marrow biopsy.

3. The method of claim 1 , wherein the sample from the patient treated with the SF3B1-modulating compound further comprises a neomorphic SF3B1 mutation.

4. The method of claim 3 , wherein the neomorphic SF3B1 mutation comprises a mutation at one or more of positions selected from E622, H662, R625, K666, K700, and V701 in SF3B1.

5. The method of claim 3 , wherein the neomorphic SF3B1 mutation comprises a mutation at one or more of positions selected from H662, R625, and K700 in SF3B1.

6. The method of claim 3 , wherein the neomorphic SF3B1 mutation comprises R625C and/or K700E.

7. The method of claim 3 , wherein the control sample expresses a wild type or non-neomorphic SF3B1 protein.

8. The method of claim 1 , wherein the neoplastic disorder is a myeloid neoplasm.

9. The method of claim 8 , wherein the myeloid neoplasm is myelodysplastic syndrome, acute myeloid leukemia, or chronic myelomonocytic leukemia.

10. The method of claim 1 , wherein the neoplastic disorder is myelodysplastic syndrome.

11. The method of claim 1 , wherein the SF3B1-modulating compound comprises a compound of formula 2:

12. A method of treating a patient having a neoplastic disorder, comprising:
a) identifying an elevated ratio of aberrant to canonical splice variants of TMEM14C in a sample from the patient relative to the ratio in a control sample; and
b) administering an SF3B1-modulating compound to the patient,
wherein the aberrant splice variant comprises SEQ ID NO: 95 and wherein the canonical splice variant comprises SEQ ID NO: 96.

13. The method of claim 12 , wherein identifying an elevated ratio comprises nucleic acid barcoding, real-time polymerase chain reaction (RT-PCR), microarray, nucleic acid sequencing, nanoparticle probes, and/or in situ hybridization.

14. The method of claim 12 , wherein identifying an elevated ratio comprises nucleic acid barcoding.

15. The method of claim 12 , wherein identifying an elevated ratio comprises RT-PCR.

16. The method of claim 12 , wherein the sample comprises a blood sample, a bone marrow aspirate, and/or a bone marrow biopsy.

17. The method of claim 12 , wherein the sample from the patient treated with the SF3B1-modulating compound further comprises a neomorphic SF3B1 mutation.

18. The method of claim 17 , wherein the neomorphic SF3B1 mutation comprises a mutation at one or more of positions selected from E622, H662, R625, K666, K700, and V701 in SF3B1.

19. The method of claim 17 , wherein the neomorphic SF3B1 mutation comprises a mutation at one or more of positions selected from H662, R625, and K700 in SF3B1.

20. The method of claim 17 , wherein the neomorphic SF3B1 mutation comprises R625C and/or K700E.

21. The method of claim 17 , wherein the control sample expresses a wild type or non-neomorphic SF3B1 protein.

22. The method of claim 12 , wherein the neoplastic disorder is a myeloid neoplasm.

23. The method of claim 22 , wherein the myeloid neoplasm is myelodysplastic syndrome, acute myeloid leukemia, or chronic myelomonocytic leukemia.

24. The method of claim 12 , wherein the neoplastic disorder is myelodysplastic syndrome.

25. The method of claim 12 , wherein the SF3B1-modulating compound comprises a compound of formula 2:

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Yu Lihua
• Lim Kian Huat
• Feala Jacob D
• Buonamici Silvia
• Mizui Yoshiharu
• Smith Peter G
• Zhu Ping
• Park Eunice Sun
• Seiler Michael W
• Fekkes Marco Peter

Classifications

• A61K31/55 Primary

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q2600/106

  Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism · CPC title

• C12Q2600/158

  Expression markers · CPC title

• A61P35/00

  Antineoplastic agents · CPC title