# US 12,000,003 B2 · Platform and sample type independent single sample classifier for treatment decision making in pancreatic ductal adenocarcinoma cancer

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- Number: US 12,000,003 B2
- Document ID: US12000003B2
- Status: Granted
- Kind: B2
- Application number: 17/601,002
- Filed: 2020-04-01
- Published: 2022-06-02
- Granted: 2024-06-04
- Earliest claimed: 2019-04-01
- Assignees: The University of North Carolina at Chapel Hill
- Applicants: The University of North Carolina at Chapel Hill
- Inventors: Jen Jen Yeh; Richard Moffitt; Naim Ur Rashid
- Web page: https://patentgrep.com/patent/US12000003B2

## CPC

- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- G16B 25/00: ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B 25/10: Gene or protein expression profiling; Expression-ratio estimation or normalisation
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/158: Expression markers
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY

## Abstract

Provided are methods for identifying pancreatic cancer subtypes in a subject and treating the same. In some embodiments, the method comprise obtaining gene expression levels for each of the following genes in the biological sample: GPR87, KRT6A, BCAR3, PTGES, 1TGA3, C16orf74, S100A2, KRT5, REG4, ANXA10, GATA6, CLDN18, LGALS4, DDC, SLC40A1, CLRN3; performing pair-wise comparisons of gene expression levels for combinations of these genes, and calculating a Raw Score for the biological sample, wherein the Raw Score is indicative of the pancreatic cancer subtype in the subject. Also provided are methods for identifying differential treatment strategies for subjects diagnosed with PDAC, methods for treating PDAC patients based on the subtype of PD AC the patients have; and methods for classifying subjects diagnosed with PDAC as having a basal-like subtype or a classical subtype of PDAC.

## Claims

### Claim 1

A method for treating a subject diagnosed with pancreatic ductal adenocarcinoma (PDAC), the method comprising:
(a) obtaining nucleic acid expression levels for each of the following genes in a biological sample comprising PDAC cells isolated from the subject: GPR87, KRT6A, BCAR3, PTGES, ITGA3, C16orf74, S100A2, KRT5, REG4, ANXA10, GATA6, CLDN18, LGALS4, DDC, SLC40A1, CLRN3, KRT15, KRT17, TFF1, PLA2G10, CDH17, DCBLD2 and TSPAN8, wherein the nucleic acid expression levels were determined using an amplification, hybridization or sequencing assay on the biological sample;
(b) performing a pair-wise comparison of the nucleic acid expression levels for each gene pair in either Gene Pairs 1-8 or Gene Pairs A-H, wherein Gene Pairs 1-8 and Gene Pairs A-H are as follows:
GENE
GENE
GENE
PAIR
A
B
Coefficient
1
GPR87
REG4
1.994
2
KRT6A
ANXA10
2.031
3
BCAR3
GATA6
1.618
4
PTGES
CLDN18
0.922
5
ITGA3
LGALS4
1.059
6
C16orf74
DDC
0.929
7
S100A2
SLC40A1
2.505
8
KRT5
CLRN3
0.485
A
GPR87
REG4
3.413
B
KRT6A
ANXA10
3.437
C
KRT17
LGALS4
2.078
D
S100A2
TFF1
2.651
E
C16orf74
DDC
0.901
F
KRT15
PLA2G10
2.677
G
PTGES
CDH17
2.911
H
DCBLD2
TSPAN8
1.903
(c) calculating a Raw Score for the biological sample, wherein the calculating comprises:
(i) assigning a value of 1 for each Gene Pair from either Gene Pairs 1-8 or Gene Pairs A-H for which Gene A of the Gene Pair has a higher nucleic acid expression level than Gene B of the Gene Pair, and a value of 0 for each Gene Pair from either Gene Pairs 1-8 or Gene Pairs A-H for which Gene A of the Gene Pair has a lower nucleic acid expression level than Gene B of the Gene Pair;
(ii) multiplying each assigned value by the coefficient listed above for each Gene Pair from either Gene Pairs 1-8 or Gene Pairs A-H to calculate eight individual Gene Pair scores from either Gene Pairs 1-8 or Gene Pairs A-H; and
(iii) adding a sum of the eight individual Gene Pair scores from either Gene Pairs 1-8 or Gene Pairs A-H to a respective baseline effect for either Gene Pairs 1-8 or Gene Pairs A-H to calculate a Raw Score for the biological sample, wherein the respective baseline effect is −6.815 for Gene Pairs 1-8 and −12.414 for Gene Pairs A-H, wherein if the calculated Raw Score is greater than or equal to 0, the tumor subtype is determined to be a basal-like subtype, and if the calculated Raw Score if less than 0, the tumor subtype is determined to be a classical subtype;
(d) administering a treatment to the subject based on the subtype assigned, wherein:
(i) if the assigned subtype is a basal-like subtype, the treatment strategy comprises gemcitabine; and
(ii) if the assigned subtype is a classical subtype, the treatment comprises FOLFIRINOX.

### Claim 2 (depends on 1)

The method of claim 1, wherein the biological sample comprises a biopsy sample, or a frozen or archival sample derived therefrom.

### Claim 3 (depends on 2)

The method of claim 2, wherein the biopsy sample comprises a fine needle biopsy aspiration or a percutaneous core needle biopsy.

### Claim 4 (depends on 1)

The method of claim 1, wherein the obtaining nucleic acid expression levels employs a technique selected from the group consisting of microarray analysis, RNAseq, quantitative RT-PCR, NanoString, or any combination thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein the technique comprises NanoString and employs probes comprising the following SEQ ID NOs:
GENE
GENE
SEQ ID
GENE
SEQ ID
PAIR
A
NO:
B
NO:
1
GPR87
64
REG4
71
2
KRT6A
65
ANXA10
59
3
BCAR3
81
GATA6
82
4
PTGES
70
CLDN18
84
5
ITGA3
85
LGALS4
68
6
C16orf74
60
DDC
63
7
S100A2
72
SLC40A1
86
8
KRT5
87
CLRN3
83
A
GPR87
64
REG4
71
B
KRT6A
65
ANXA10
59
C
KRT17
67
LGALS4
68
D
S100A2
72
TFF1
73
E
C16orf74
60
DDC
63
F
KRT15
66
PLA2G10
69
G
PTGES
70
CDH17
61
H
DCBLD2
62
TSPAN8
74.

### Claim 6 (depends on 1)

The method of claim 1, wherein the treatment comprises gemcitabine in combination with nab-paclitaxel.