# US 2014/0155400 A1 · Methods and compositions for typing molecular subgroups of medulloblastoma

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- Number: US 2014/0155400 A1
- Document ID: US20140155400A1
- Status: Published application
- Kind: A1
- Application number: 13/818,213
- Filed: 2011-09-30
- Published: 2014-06-05
- Earliest claimed: 2010-10-01
- Assignees: St. Jude Children's Research Hospital
- Inventors: David Ellison
- Web page: https://patentgrep.com/patent/US20140155400A1

## CPC

- G01N 33/57557: {of other specific parts of the body, e.g. brain}
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Immunohistochemical methods and compositions for the typing of molecular subgroups of medulloblastomas are provided. The methods comprise determining a protein expression profile for a sample obtained from a medulloblastoma by detecting expression of GAB 1, filamin A, or at least two biomarker proteins selected from the group consisting of β-catenin, YAP1, GAB1, and filamin A, and typing the medulloblastoma as a WNT pathway tumor, a SHH pathway tumor, or a non-WNT/non-SHH tumor based on this protein expression profile. Kits for typing a medulloblastoma according to these three molecular subgroups are provided. The kits comprise at least two antibodies, wherein each of said antibodies specifically binds to a distinct biomarker protein selected from the group consisting of β-catenin, YAP1, GAB1, and filamin A, and can optionally comprise one or more of instructions for use, reagents for detecting antibody binding to one or more of said biomarker proteins, and one or more positive control samples.

## Claims

### Claim 1

An immunohistochemical method for typing a medulloblastoma as a WNT pathway tumor, a sonic hedgehog (SHH) pathway tumor, or a non-WNT/non-SHH tumor, said method comprising determining a protein expression profile for a sample obtained from said medulloblastoma by detecting expression of β-catenin, YAP1, GAB1, or filamin A, and typing said medulloblastoma as a WNT pathway tumor, a SHH pathway tumor, or a non-WNT/non-SHH tumor based on said protein expression profile.

### Claim 2 (depends on 1)

The method of claim 1, comprising:
a) contacting a tissue sample obtained from said medulloblastoma with at least two antibodies specific to biomarker proteins selected from the group consisting of an antibody that specifically binds β-catenin, an antibody that specifically binds YAP1, an antibody that specifically binds GAB1, or an antibody that specifically binds filamin A;
b) determining a protein expression profile for said tissue sample based on detection of binding of said at least two antibodies to said biomarker proteins; and
c) typing said medulloblastoma as a WNT pathway tumor, a SHH pathway tumor, or a non-WNT/non-SHH tumor based on said protein expression profile.

### Claim 3 (depends on 2)

The method of claim 2, wherein at least one of said antibodies specifically binds β-catenin.

### Claim 4 (depends on 3)

The method of claim 3, wherein said protein expression profile is characterized by positive nuclear expression of β-catenin, wherein said medulloblastoma is typed as a WNT pathway tumor.

### Claim 5 (depends on 3)

The method of claim 3, wherein said protein expression profile is characterized by negative nuclear expression of β-catenin.

### Claim 6 (depends on 5)

The method of claim 5, wherein
(a) said protein expression profile is characterized by positive expression of one or more additional biomarker proteins selected from the group consisting of filamin A, GAB1, and YAP1, wherein said medulloblastoma is typed as a SHH pathway tumor; or,
(b) said protein expression profile is characterized by negative expression of one or more additional biomarker proteins selected from the group consisting of filamin A, GAB2, and YAP1, wherein said medulloblastoma is typed as a non-WNT/non-SHH tumor.

### Claim 7

(canceled)

### Claim 8 (depends on 2)

The method of claim 2, wherein at least one of said antibodies specifically binds GAB1.

### Claim 9 (depends on 8)

The method of claim 8, wherein said protein expression profile is characterized by positive expression of GAB1, wherein said medulloblastoma is typed as a SHH pathway tumor.

### Claim 10 (depends on 8)

The method of claim 8, wherein said protein expression profile is characterized by negative expression of GAB1.

### Claim 11 (depends on 10)

The method of claim 10, wherein
(a) said protein expression profile is characterized by positive nuclear expression of β-catenin, wherein said medulloblastoma is typed as a WNT pathway tumor; or,
(b) said protein expression profile is characterized by negative nuclear expression of β-catenin, wherein said medulloblastoma is typed as a non-WNT/non-SHH pathway-regulated tumor.

### Claim 12

(canceled)

### Claim 13 (depends on 2)

The method of claim 2, wherein said sample is contacted with at least three antibodies, wherein said antibodies are selected from the group consisting of an antibody that specifically binds to β-catenin, an antibody that specifically binds to YAP1, an antibody that specifically binds to GAB1, and an antibody that specifically binds to filamin A.

### Claim 14 (depends on 2)

The method of claim 2, wherein said sample is contacted with an antibody that specifically binds to β-catenin, an antibody that specifically binds to YAP1, an antibody that specifically binds to GAB1, and an antibody that specifically binds to filamin A.

### Claim 15 (depends on 2)

The method of claim 2, wherein said sample is contacted with said antibodies sequentially.

### Claim 16 (depends on 2)

The method of claim 2, wherein said sample is contacted with said antibodies simultaneously.

### Claim 17

An immunohistochemical method for typing a medulloblastoma as a SHH pathway tumor or a non-SHH tumor, said method comprising determining a protein expression profile for a sample obtained from said medulloblastoma by detecting expression of GAB1 and typing said medulloblastoma as a SHH pathway tumor or a non-SHH tumor based on said protein expression profile.

### Claim 18 (depends on 17)

The method of claim 17, wherein said protein expression profile is characterized by positive expression of GAB1, wherein said medulloblastoma is typed as a SHH pathway tumor.

### Claim 19 (depends on 17)

The method of claim 17, wherein said protein expression profile is characterized by negative expression of GAB1, wherein said medulloblastoma is typed as a non-SHH tumor.

### Claim 20

An immunohistochemical method for typing a medulloblastoma as a non-WNT/non-SHH tumor, said method comprising determining a protein expression profile for a sample obtained from said medulloblastoma by detecting expression of filamin A, and typing said medulloblastoma as a non-WNT/non-SHH tumor based on said protein expression profile.

### Claim 21 (depends on 20)

The method of claim 20, wherein said protein expression profile is characterized by negative expression of filamin A, wherein said medulloblastoma is typed as a non-WNT/non-SHH tumor.

### Claim 22 (depends on 4)

A method of identifying a subject with a medulloblastoma that would benefit from treatment with a WNT signaling pathway inhibitor or a sonic hedgehog (SHH) pathway signaling inhibitor, said method comprising typing said medulloblastoma as a WNT pathway tumor according to the method of claim 4, thereby identifying said subject.

### Claim 23 (depends on 22)

The method of claim 22, further comprising
(a) treating said subject with said WNT signaling pathway inhibitor when said medulloblastoma is typed as a WNT pathway tumor; or,
(b) treating said subject with said SHH signaling pathway inhibitor when said medulloblastoma is typed as a SHH pathway tumor.

### Claim 24

(canceled)

### Claim 25 (depends on 1)

A method for selecting a therapy for a subject with a medulloblastoma, said method comprising typing a sample obtained from said medulloblastoma according to the method of any one of claim 1, and selecting a therapy based on said typing.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20)

A method for determining whether a subject is eligible for entry into a clinical trial for treating medulloblastomas comprising:
(a) determining whether a subject is eligible for entry into a clinical trial for treating medulloblastomas regulated by the WNT signaling pathway, comprising typing a medulloblastoma in said subject according to the method of claim 1, wherein said subject is eligible if said medulloblastoma is typed as a WNT pathway tumor;
(b) determining whether a subject is eligible for entry into a clinical trial for treating medulloblastomas regulated by the SHH signaling pathway, comprising typing a medulloblastoma in said subject according to the method of any one of claims 1-18, wherein said subject is eligible if said medulloblastoma is typed as a SHH pathway tumor; or,
(c) determining whether a subject is eligible for entry into a clinical trial for treating medulloblastomas that are non-WNT/non-SHH tumors, comprising typing a medulloblastoma in said subject according to the method of any one of claims 1-16, 20, and 21, wherein said subject is eligible if said medulloblastoma is typed as a non-WNT/non-SHH tumor.

### Claim at position 27

-28. (canceled)

### Claim 29

A kit for typing a medulloblastoma as a WNT pathway tumor, a sonic hedgehog (SHH) pathway tumor, or a non-WNT/non-SHH tumor, said kit comprising at least two antibodies selected from the group consisting of an antibody that specifically binds β-catenin, an antibody that specifically binds YAP1, an antibody that specifically binds GAB1, and an antibody that specifically binds filamin A.

### Claim 30 (depends on 29)

The kit of claim 29, comprising at least three of said antibodies.

### Claim 31 (depends on 29)

The kit of claim 29, comprising
(a) an antibody that specifically binds β-catenin, an antibody that specifically binds YAP1, an antibody that specifically binds GAB1, and an antibody that specifically binds filamin A; or,
(b) said kit further comprises reagents for the detection of antibody binding to said β-catenin, YAP1, GAB1, filamin A, or any combination thereof.

### Claim at position 31

-34. (canceled)