Compositions and methods for detecting and treating high grade subtypes of uterine cancer

Patent metadata

Field	Value
Publication number	US-2022049315-A1
Application number	US-202117380876-A
Country	US
Kind code	A1
Filing date	Jul 20, 2021
Priority date	Jul 24, 2020
Publication date	Feb 17, 2022
Grant date	—

Abstract

The present invention relates to methods and biomarkers for detection and characterization of conditions associated with aberrant function of the PPP2R1A subunit of the PP2A protein (e.g., high grade subtypes of uterine cancer) in biological samples (e.g., tissue samples, blood samples, plasma samples, cell samples, serum samples), and related methods of treatment. In particular, the present invention provides compositions and methods for characterizing a patient as having such a condition by identifying mutations in the PPP2R1A subunit of the PP2A gene or gene products, and related methods of treatment through administering to such a patient a DNA Damage Response Pathway (DDR) modulating agent (e.g., a ribonucleotide reductase inhibitor).

First claim

1 . A method of assessing the high grade uterine cancer disease status of an individual, comprising: (a) evaluating a sample containing nucleic acids from the individual to detect the presence of one or more mutations in the PPP2R1A subunit of the PP2A gene, wherein evaluating comprises hybridizing to a PPP2R1A subunit of the PP2A gene nucleic acid an oligonucleotide comprising a nucleotide sequence complementary with one or more PPP2R1A subunit of the PP2A gene mutations, and (b) identifying the individual as having a high grade subtype of uterine cancer if a mutation within the PPP2R1A subunit of the PP2A gene is detected.

2 . The method of claim 1 , wherein the one or more PPP2R1A subunit of the PP2A gene mutations are nucleic acid sequence mutations selected from the group consisting of P179R or S256F.

3 . The method of claim 1 , wherein said nucleic acid from the individual is RNA and the PPP2R1A subunit of the PP2A nucleic acid is cDNA.

4 . The method of claim 1 , wherein said sample is selected from the group consisting of blood, serum, and plasma.

5 . The method of claim 1 , wherein the sample is a uterine tumor tissue sample.

6 . The method of claim 1 , further comprising administering a treatment to the individual if the individual is assessed as having a mutation within the PPP2R1A subunit of the PP2A gene.

7 . The method of claim 6 , wherein the treatment is capable of mimicking wild-type function/activity of the PPP2R1A subunit of the PP2A protein.

8 . The method of claim 7 , the treatment comprises administration to the individual a DNA Damage Response Pathway (DDR) modulating agent.

9 . The method of claim 8 , wherein the DDR modulating agent is a ribonucleotide reductase inhibitor (e.g., clofarabine, cladribine).

10 . The method of claim 8 , wherein the DDR modulating agent is selected from a poly ADP ribose polymerase (PARP) inhibitor, a CDK1 inhibitor, and a CDCl 7 inhibitor.

11 . A method of treating a subject, comprising administering to the subject a ribonucleotide reductase inhibitor (e.g., clofarabine, cladribine), wherein the subject is diagnosed as suffering from a high grade subtype of uterine cancer, wherein the subject has a P179R mutation and/or S256F within the PPP2R1A subunit of the PP2A gene.

12 . A method, comprising: (a) evaluating a sample containing nucleic acids from a subject to detect the presence of one or more mutations in the PPP2R1A subunit of the PP2A gene, wherein evaluating comprises hybridizing to a PPP2R1A subunit of the PP2A gene nucleic acid an oligonucleotide comprising a nucleotide sequence complementary with one or more PPP2R1A subunit of the PP2A gene mutations.

13 . The method of claim 12 , further comprising (b) identifying the individual as having a high grade subtype of uterine cancer if a mutation within the PPP2R1A subunit of the PP2A gene is detected.

14 . The method of claim 12 , wherein the one or more PPP2R1A subunit of the PP2A gene mutations are nucleic acid sequence mutations selected from the group consisting of P179R or S256F.

15 . The method of claim 12 , wherein said nucleic acid from the individual is RNA and the PPP2R1A subunit of the PP2A nucleic acid is cDNA.

16 . The method of claim 12 , wherein said sample is selected from the group consisting of blood, serum, and plasma.

17 . The method of claim 12 , wherein the sample is a uterine tumor tissue sample.

18 . The method of claim 12 , further comprising administering a treatment to the individual if the individual is assessed as having a mutation within the PPP2R1A subunit of the PP2A gene.

19 . The method of claim 12 , wherein the treatment is capable of mimicking wild-type function/activity of the PPP2R1A subunit of the PP2A protein.

20 . The method of claim 19 , the treatment comprises administration to the individual a DNA Damage Response Pathway (DDR) modulating agent.

21 . The method of claim 20 , wherein the DDR modulating agent is a ribonucleotide reductase inhibitor (e.g., clofarabine, cladribine).

22 . The method of claim 20 , wherein the DDR modulating agent is selected from a poly ADP ribose polymerase (PARP) inhibitor, a CDK1 inhibitor, and a CDCl 7 inhibitor.

Assignees

• Univ Michigan Regents

Inventors

• O'Connor Caitlin
• Narla Goutham

Classifications

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• C12Q1/6886 Primary

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

• C12Q2600/112

  Disease subtyping, staging or classification · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q2600/118

  Prognosis of disease development · CPC title