# US 2019/0170731 A1 · Method to measure relative utilization of aerobic glycolysis by positional isotopic discrimination

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- Number: US 2019/0170731 A1
- Document ID: US20190170731A1
- Status: Published application
- Kind: A1
- Application number: 16/308,950
- Filed: 2017-06-20
- Published: 2019-06-06
- Earliest claimed: 2016-06-20
- Inventors: Da-Qing YANG; Adrian HEGEMAN; Dana FREUND; Margot CLEARY
- Web page: https://patentgrep.com/patent/US20190170731A1

## CPC

- G01N 33/5038: {involving detection of metabolites per se}
- G01N 33/58: involving labelled substances (G01N33/53 takes precedence)
- G01N 33/6848: {Methods of protein analysis involving mass spectrometry}
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- 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 2800/54: Determining the risk of relapse
- 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

Methods to detect aerobic glycolysis that employ isotopically labelled glucose are provided.

## Claims

### Claim 1

A method to detect aerobic glycolysis in a sample comprising cells, comprising:
a) providing a mixture comprising a sample obtained from mammalian cells and isotopically labelled glucose;
b) measuring in the mixture the conversion of isotopically labelled glucose to isotopically labelled lactate using liquid chromatography-mass spectrometry (LC-MS) or; and
c) determining glucose uptake, lactate concentration or the rate of aerobic glycolysis in the cells in the sample based on the presence or amount of the labelled lactate, the rate of conversion of the labelled glucose to the labelled lactate, in the mixture, or comparing the amount of converted lactate to the amount of converted lactate in corresponding cells.

### Claim 2 (depends on 1)

The method of claim 1 wherein the label is 13C or deuterium (2H).

### Claim 3 (depends on 1)

The method of claim 1 wherein the labelled glucose is [1-13C]glucose, [1,2-13C2]glucose, [13C6]glucose, or 6,6-deuterium labelled glucose.

### Claim 4 (depends on 1)

The method of claim 1 wherein the presence of amount of [3-13C]lactate, the rate of conversion of [1-13C]glucose to [3-13C]lactate or the rate of conversion of deuterium labeled glucose to deuterium labelled lactate, is determined.

### Claim at position 5

5-6. (canceled)

### Claim 7 (depends on 1)

The method of claim 1 wherein the cells are breast cancer cells, prostate cancer cells, liver cancer cells, or ovarian cancer cells or have a selected genetic mutation.

### Claim at position 7

8-11. (canceled)

### Claim 12 (depends on 1)

The method of claim 1 wherein the glucose uptake, lactate concentration or the rate of aerobic glycolysis in the mixture is compared to a corresponding mixture having control cells or no cells.

### Claim at position 9

13-32. (canceled)

### Claim 33

A method to monitor cancer recurrence in a mammal, comprising:
a) providing a mixture comprising a sample from the mammal treated for cancer comprising cells and an amount of 13C or deuterium labelled glucose;
b) measuring in the mixture the conversion of the 13C or deuterium labelled glucose to 13C or deuterium labelled lactate using LC-MS; and
c) determining whether the mammal is at risk of recurrence based on the presence or amount of the 13C or deuterium labelled lactate, or the rate of conversion of the 13C or deuterium labelled glucose to 13C or deuterium labelled lactate, in the mixture.

### Claim 34 (depends on 33)

The method of claim 33 wherein the mammal is a human treated for breast cancer.

### Claim 35 (depends on 33)

The method of claim 33 wherein the presence or amount of [3-13C]lactate, or the rate of conversion of [1-13C]glucose to [3-13C]lactate, in the mixture is compared to the presence or amount of [3-13C]lactate, or the rate of conversion of [1-13C]glucose to [3-13C]lactate, in a control mixture or one or more samples from the mammal taken at an earlier point in time.

### Claim 36 (depends on 33)

The method of claim 33 wherein the labelled glucose is [1-13C]glucose, [1,2-13C2]glucose, [13C6]glucose, or 6,6-deuterium labelled glucose.

### Claim 37 (depends on 33)

The method of claim 33 wherein the sample is a physiological fluid sample.

### Claim 38

A method to monitor a therapeutic response to a cancer therapy in a mammal having cancer, comprising:
a) providing a mixture comprising a sample from the mammal comprising cells and an amount of 13C or deuterium labelled glucose;
b) measuring in the mixture the conversion of the 13C or deuterium labelled glucose to 13C or deuterium labelled lactate using LC-MS; and
c) determining whether the mammal has a therapeutic response to the therapy based on the presence or amount of the 13C or deuterium labelled lactate, or the rate of conversion of the 13C or deuterium labelled glucose to 13C or deuterium labelled lactate, in the mixture.

### Claim 39 (depends on 38)

The method of claim 38 wherein the mammal is a human.

### Claim 40 (depends on 38)

The method of claim 38 wherein the presence or amount of [3-13C]lactate, or the rate of conversion of [1-13C]glucose to [3-13C]lactate, in the mixture is compared to the presence or amount of [3-13C]lactate, or the rate of conversion of [1-13C]glucose to [3-13C]lactate, in a control mixture or one or more samples from the mammal taken at an earlier point in time.

### Claim 41 (depends on 38)

The method of claim 38 wherein the labelled glucose is [1-13C]glucose, [1,2-13C2]glucose, [13C6]glucose, or 6,6-deuterium labelled glucose.

### Claim 42 (depends on 38)

The method of claim 38 wherein the sample is a physiological fluid sample.

### Claim 43 (depends on 38)

The method of claim 38 wherein the sample is a physiological tissue sample.

### Claim 44 (depends on 42)

The method of claim 42 wherein the sample is a blood sample, a urine sample or a milk sample.

### Claim 45 (depends on 38)

The method of claim 38 wherein the mammal has breast cancer, prostate cancer, liver cancer or ovarian cancer.

### Claim 46 (depends on 38)

The method of claim 38 wherein the ratio of [3-13C]lactate/unlabeled lactate or deuterium labeled lactate/unlabeled lactate is determined.