# US 2014/0193426 A1 · Markers for early diagnosis of ovarian cancer, monitoring during therapy, and new therapy options during and after chemotherapy

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- Number: US 2014/0193426 A1
- Document ID: US20140193426A1
- Status: Published application
- Kind: A1
- Application number: 14/107,751
- Filed: 2013-12-16
- Published: 2014-07-10
- Earliest claimed: 2011-06-17
- Assignees: Board of Trustees of the University of Arkansas
- Applicants: The Board of Trustees of the University of Arkansas
- Inventors: Timothy J. O'Brien; John Beard; Wilbur C. Hitt, JR.
- Web page: https://patentgrep.com/patent/US20140193426A1

## CPC

- C12Q 1/37: involving peptidase or proteinase
- G01N 33/57545: of the ovaries
- G01N 33/5755: of the uterine cervix, uterine corpus or endometrium
- 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 2800/56: Staging of a disease; Further complications associated with the disease
- 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
- 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

The inventors have identified several proteases and a protease inhibitor that are overexpressed in ovarian cancer tumors. They have developed monoclonal antibodies against the proteins and shown that they can be detected in serum and the levels of the proteins in serum fluctuate during cancer treatment. They have shown that serum assays for the proteases and protease inhibitor can be used for early detection of ovarian cancer, and for monitoring cancer treatment.

## Claims

### Claim 1

A method of early diagnosis of cancer comprising:
measuring in a human blood sample protein levels of two or more proteins selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, KLK6, and hepsin; and
comparing the levels of the two or more proteins to normal range levels of the two or more proteins to identify whether the level of at least one of the two or more proteins is elevated.

### Claim 2 (depends on 1)

The method of claim 1 wherein the method further comprises if at least one of the levels of the two or more proteins is elevated conducting one or more further tests on the human to identify if the human has cancer.

### Claim 3 (depends on 2)

The method of claim 2 wherein the further tests comprise an imaging method selected from the group consisting of an X-ray, a CT scan, an MRI, a PET scan, and an ultrasound.

### Claim 4 (depends on 2)

The method of claim 2 wherein the further tests comprise a biopsy.

### Claim 5 (depends on 1)

The method of claim 1 wherein the cancer is ovarian cancer.

### Claim 6 (depends on 1)

The method of claim 1 wherein the method comprises:
comparing the levels of the two or more proteins to normal range levels of the two or more proteins to identify whether the levels of at least two of the two or more proteins are elevated.

### Claim 7 (depends on 6)

The method of claim 6 wherein the method further comprises, if at least two of the levels of the two or more proteins are elevated, conducting one or more further tests on the human to identify if the human has cancer.

### Claim 8 (depends on 1)

The method of claim 1 wherein the method comprises:
measuring in a human serum protein levels of two or more proteins selected from the group consisting of CA125, TADG15, and ALP; and
comparing the levels of the two or more proteins to normal range levels of the two or more proteins to identify whether the level of at least one of the two or more proteins is elevated.

### Claim 9 (depends on 8)

The method of claim 8 wherein the method further comprises, if at least one of the levels of the two or more proteins is elevated, conducting one or more further tests on the human to identify if the human has cancer.

### Claim 10 (depends on 1)

The method of claim 1 wherein the two or more proteins are selected from the group consisting of TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, and hepsin.

### Claim 11 (depends on 1)

The method of claim 1 wherein the two or more proteins are selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, and hepsin;

### Claim 12 (depends on 1)

The method of claim 1 wherein the two or more proteins are selected from the group consisting of CA125, TADG15, and hepsin.

### Claim 13 (depends on 1)

The method of claim 1 comprising:
measuring in the cancer patient serum protein levels of three or more of the proteins selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, KLK6, and hepsin; and
comparing the levels of the three or more proteins to normal range levels of the three or more proteins to identify whether the level of at least one of the three or more proteins is elevated above normal range levels or is increasing or decreasing.

### Claim 14 (depends on 13)

The method of claim 13 wherein the three or more proteins are selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, and hepsin.

### Claim 15

A method of monitoring progress of cancer in a cancer patient comprising:
measuring in the cancer patient blood protein levels of two or more proteins selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, KLK6, and hepsin; and
comparing the levels of the two or more proteins to normal range levels of the two or more proteins and/or to previous levels of the two or more proteins in the same patient to identify whether the level of at least one of the two or more proteins is elevated above normal range levels or is increasing or decreasing.

### Claim 16 (depends on 15)

The method of claim 15 wherein the two or more proteins are selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, and hepsin.

### Claim 17 (depends on 15)

The method of claim 15 comprising:
measuring in the cancer patient blood protein levels of one or more proteases selected from the group consisting of TADG12, TADG14, TADG15, SCCE, MMP-7, KLK6, and hepsin;
comparing the levels of the one or more proteases to normal range levels of the one or more proteases and/or to previous levels of the one or more proteases in the same patient to identify whether the level of at least one of the one or more proteases is elevated above normal range levels or is increasing or decreasing; and
if the level of at least one of the one or more proteases is elevated or increasing, treating the patient with an inhibitor of the one or more proteases whose level is elevated or increasing.

### Claim 18 (depends on 17)

The method of claim 17 wherein the protease inhibitor is Bowman-Birk inhibitor, ALP, aprotinin, HAI-1, PEBP (phosphatidylethanoloamine-binding protein), FOY-305 (FOYPAN), probucol, or an antibody or antibodies against one or more of the one or more proteases whose level is elevated or increasing.

### Claim 19 (depends on 15)

The method of claim 15 wherein the cancer is ovarian cancer.

### Claim 20 (depends on 15)

The method of claim 15 wherein the cancer is a cancer other than ovarian cancer.

### Claim 21 (depends on 20)

The method of claim 20 wherein the cancer is cervical cancer.

### Claim 22 (depends on 15)

The method of claim 15 comprising:
measuring in the cancer patient blood protein levels of three or more of the proteins selected from the group consisting of CA125, TADG14, TADG15, TADG12, SCCE, MMP-7, ALP, KLK6, and hepsin; and
comparing the levels of the three or more proteins to normal range levels of the three or more proteins and/or to previous levels of the three or more proteins in the same patient to identify whether the level of at least one of the three or more proteins is elevated above normal range levels or is increasing or decreasing.

### Claim 23 (depends on 15)

The method of claim 15 wherein the method comprises
measuring in the cancer patient blood protein levels of the proteins CA125, TADG15, and ALP; and
comparing the levels of the proteins to normal range levels of the proteins and/or to previous levels of the proteins in the same patient to identify whether the level of at least one of the proteins is elevated above normal range levels or is increasing or decreasing.

### Claim 24 (depends on 15)

The method of claim 15 wherein the method comprises:
measuring in the cancer patient blood protein levels of two or more proteins selected from the group consisting of CA125, TADG15, and ALP; and
comparing the levels of the two or more proteins to normal range levels of the two or more proteins and/or to previous levels of the two or more proteins in the same patient to identify whether the level of at least one of the two or more proteins is elevated above normal range levels or is increasing or decreasing.

### Claim 25

A method of treating cancer comprising:
measuring in a cancer patient blood protein levels of one or more proteases;
comparing the levels of the one or more proteases to normal range levels of the one or more proteases and/or to previous levels of the one or more proteases in the same patient to identify whether the level of at least one of the one or more proteases is elevated above normal range levels or is increasing; and
if the level of at least one of the one or more proteases is elevated or increasing, treating the patient with an inhibitor of the elevated or increasing at least one protease.

### Claim 26 (depends on 25)

The method of claim 25 wherein the one or more proteases are selected from the group consisting of TADG12, TADG14, TADG15, SCCE, MMP-7, KLK6, and hepsin.

### Claim 27 (depends on 25)

The method of claim 25 wherein the protease is selected from the group consisting of TADG12, TADG14, TADG15, SCCE, MMP-7, and hepsin.

### Claim 28 (depends on 25)

The method of claim 25 wherein the level of a first protease of the one or more proteases is elevated or increasing and the method comprises treating the patient with a first inhibitor that inhibits the first protease; the method further comprising:
repeating the measuring and comparing steps at least one week after the treatment; and
if the level of a second protease of the one or more proteases is elevated or increasing, treating the patient with a second inhibitor that inhibits the second protease, wherein the first inhibitor and the second inhibitor are different inhibitors and the first protease and second protease are different proteases.

### Claim 29 (depends on 28)

The method of claim 28 wherein the second inhibitor does not inhibit the first protease.

### Claim 30 (depends on 25)

The method of claim 25 wherein the inhibitor is a kinetic inhibitor of the elevated or increasing at least one protease.

### Claim 31 (depends on 25)

The method of claim 25 wherein the inhibitor is an antibody against the elevated or increasing at least one protease.

### Claim 32 (depends on 31)

The method of claim 31 wherein the antibody is a kinetic inhibitor of the elevated or increasing at least one protease.