Biomarkers for Pin1-associated disorders

Patent metadata

Field	Value
Publication number	US-10351914-B2
Application number	US-201515326981-A
Country	US
Kind code	B2
Filing date	Jul 16, 2015
Priority date	Jul 17, 2014
Publication date	Jul 16, 2019
Grant date	Jul 16, 2019

Abstract

Biomarkers and driver mutations for diagnosis and prognosis of Pin 1-associated diseases are disclosed. In one embodiment, the methods for diagnosis of Pin 1-associated diseases may include detecting the level of Pin1 to stage abnormal cell growth, such as breast or prostate cancer. In another embodiment, the methods include evaluating the efficacy of a treatment of abnormal cell growth, such as cancer, by monitoring the levels of Pin1. In another embodiment, the methods include using driver mutations to determine the pharmacogenetics of abnormal cell growth, such as cancer. In the present disclosure, elevated active monomeric Pin1 levels may be detected by Pin1 biomarkers, which may include Pin1 Q33K or E100D driver mutations, Pin1 protein or transcript overexpression, dephosphorylation of Pin1 on Ser71, dephosphorylation of S16, phosphorylation of S65, phosphorylation of S138, deacetylation of Pin1 on K13 and deacetylation of K46, and/or desumoylation of Pin1 on K6 and desumolation of K63, among others.

First claim

The invention claimed is:

1. A method of treating a proliferative or immune disorder in a subject, said method comprising:
(a) obtaining a sample from said subject;
(b) determining whether an aberrant mutation is present in the gene encoding Pin1 in said sample; and
(c) treating said subject with a retinoic acid compound if at least one of said aberrant mutations is present;
wherein said aberrant mutation encodes an amino acid substitution in Pin1 selected from: Q33K or E100D.

2. The method of claim 1 , wherein said step of determining whether an aberrant mutation is present comprises sequencing all or a portion of the Pin1 gene.

3. The method of claim 1 , wherein said step of determining whether an aberrant mutation is present comprises contacting said sample with a nucleic acid probe specific for Pin1.

4. The method of claim 3 , wherein said probe is bound to a microarray.

5. The method of claim 1 , said method further comprising determining whether an aberrant post-translational modification of Pin1 is present and treating said subject with a retinoic acid compound if at least one of said aberrant post-translational modifications is present, wherein said post-translational modification is selected from the group consisting of deacetylation of K13, deacetylation of K46, dephosphorylation of S16, desumoylation of K6, desumoylation of K63, phosphorylation of S65, phosphorylation of S138, and dephosphorylation of S71.

6. The method of claim 1 , wherein said disorder is a proliferative disorder.

7. The method of claim 1 , wherein said disorder is an immune disorder.

8. The method of claim 1 , wherein said retinoic acid compound is part of a pharmaceutical composition formulated for long-term delivery of said retinoic acid compound after injection of said composition into said subject.

9. The method of claim 8 , wherein said composition is formulated as an injectable depot system, an injectable drug suspension, an injectable microsphere, or an injectable gel.

10. The method of claim 9 , wherein said injectable drug suspension is:
(a) an oil-based suspension,
(b) formulated for intravenous injection or intramuscular injection,
(c) formulated as an injectable gel and for intramuscular injection,
(d) formulated to delay the metabolism of said retinoic acid compound,
(e) further comprises a pharmaceutically acceptable excipient, or
(f) said retinoic acid compound is all-trans retinoic acid.

11. The method of claim 1 , wherein said retinoic acid compound is all-trans retinoic acid.

12. A method of treating a proliferative or immune disorder in a subject, wherein said subject has an aberrant mutation in the gene encoding Pin1 that produces an amino acid substitution selected from Q33K or E100D, said method comprising administering a retinoic acid compound to said subject.

13. The method of claim 12 , wherein said Pin1 further comprises an aberrant post-translational modification selected from the group consisting of deacetylation of K13, deacetylation of K46, dephosphorylation of S16, desumoylation of K6, desumoylation of K63, phosphorylation of S65, phosphorylation of S138, and dephosphorylation of S71.

14. The method of claim 12 , wherein said disorder is a proliferative disorder.

15. The method of claim 12 , wherein said disorder is an immune disorder.

16. The method of claim 12 , wherein said retinoic acid compound is all-trans retinoic acid.

17. A method of treating a proliferative or immune disorder in a subject, said method comprising:
(a) obtaining a sample from said subject;
(b) determining whether an aberrant post-translational modification of Pin1 is present; and
(c) treating said subject with a retinoic acid compound if at least one of said aberrant post-translational modifications is present;
wherein said post-translational modification is selected from deacetylation of K13 or aRet deacetylation of K46.

18. The method of claim 17 , said method further comprising determining whether a further aberrant post-translational modification of Pin1 is present and treating said subject with a retinoic acid compound if at least one of said further aberrant post-translational modification is present, wherein said post-translational modification is selected from the group consisting of dephosphorylation of S16, desumoylation of K6, desumoylation of K63, phosphorylation of S65, phosphorylation of S138, and dephosphorylation of S71.

19. The method of claim 17 , wherein said retinoic acid compound is all-trans retinoic acid.

20. The method of claim 17 , wherein said disorder is a proliferative disorder.

21. The method of claim 17 , wherein said disorder is an immune disorder.

22. A method of treating a proliferative or immune disorder in a subject, wherein said subject has an aberrant post-translational modification of Pin1 selected from deacetylation of K13 or deacetylation of K46, said method comprising administering a retinoic acid compound to said subject.

23. The method of claim 22 , wherein said Pin1 further comprises an aberrant post-translational modification selected from the group consisting of dephosphorylation of S16, desumoylation of K6, desumoylation of K63, phosphorylation of S65, phosphorylation of S138, and dephosphorylation of S71.

24. The method of claim 22 , wherein said disorder is a proliferative disorder.

25. The method of claim 22 , wherein said disorder is an immune disorder.

26. The method of claim 22 , wherein said retinoic acid compound is all-trans retinoic acid.

Assignees

• Beth Israel Deaconess Medical Ct Inc

Inventors

• Lu Kun Ping
• Zhou Xiao Zhen
• Wei Shuo

Classifications

• A61K31/203 Primary

  Retinoic acids {; Salts thereof} · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• C12Q1/6883

  for diseases caused by alterations of genetic material · CPC title

• C12Q2600/158

  Expression markers · CPC title

• C12Q1/6886 Primary

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