# US 2016/0257937 A1 · HUMAN FIBROLAMELLAR HEPATOCELLULAR CARCINOMAS (hFL-HCCS)

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- Number: US 2016/0257937 A1
- Document ID: US20160257937A1
- Status: Published application
- Kind: A1
- Application number: 15/061,626
- Filed: 2016-03-04
- Published: 2016-09-08
- Earliest claimed: 2015-03-06
- Assignees: The University of North Carolina at Chapel Hill
- Applicants: University of North Carolina at Chapel Hill
- Inventors: Eliane WAUTHIER; Tsunekazu OIKAWA; Timothy Anh-Hieu DINH; Praveen SETHUPATHY; Lola M. REID
- Web page: https://patentgrep.com/patent/US20160257937A1

## CPC

- C12N 5/0693: {Tumour cells; Cancer cells}
- A01K 67/0271: Chimeric vertebrates, e.g. comprising exogenous cells
- A61P 35/00: Antineoplastic agents
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G01N 33/5067: {Liver cells}
- G01N 33/57525: of the liver or pancreas
- A01K 2207/12: Animals modified by administration of exogenous cells
- A01K 2227/105: Murine
- C12N 2503/02: Drug screening
- C12N 2513/00: 3D culture
- C12Q 2600/158: Expression markers
- C12Y 305/01098: Histone deacetylase (3.5.1.98), i.e. sirtuin deacetylase
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)
- C12Y: ENZYMES

## Abstract

The present disclosure provides a model of human fibrolamellar hepatocellular carcinoma (FL-HCC) cells maintained as a transplantable tumor line in a host and a method to establish a transplantable human FL-HCC tumor line. Methods of ex vivo cultures of the FL-HCC are provided. Methods of diagnosing and treating FL-HCC tumors are also provided.

## Claims

### Claim 1

A transplantable tumor line of human fibrolamellar hepatocellular carcinoma (hFL-HCC) cells maintained in a non-human animal.

### Claim 2 (depends on 1)

The transplantable tumor line of claim 1, wherein the non-human animal is a NOD scid gamma (NSG) mouse.

### Claim 3 (depends on 1)

The transplantable tumor line of claim 1, wherein the hFL-HCC cells are derived from a tumor removed from the liver, from the biliary tree, from a subcutaneous tumor or from an intraperitoneal (ascites) tumor.

### Claim 4 (depends on 1)

The transplantable tumor line of claim 1, wherein the tumor line comprises hFL-HCC cells and mesenchymal cells of the non-human animal.

### Claim 5 (depends on 1)

The transplantable tumor line of claim 1, wherein at least 50% of the hFL-HCC cells in the transplantable tumor are cancer stem cells.

### Claim 6 (depends on 1)

The transplantable tumor line of claim 1, wherein the hFL-HCC cells express the fusion transcript DNAJB1-PRKACA.

### Claim 7 (depends on 1)

The transplantable tumor line of claim 1, wherein the hFL-HCC cells overexpress at least one C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163, or TNRC6C relative to a control sample.

### Claim 8 (depends on 7)

The transplantable tumor line of claim 7, wherein the control sample is selected from the group consisting of hepatocellular carcinomas (HCCs), hepatoblastomas, cholangiocarcinomas (CCAs), pancreatic cancer, biliary tree stem cells, hepatic stem cells, hepatoblasts, pancreatic stem cells, hepatic, pancreatic committed progenitors, and normal mature hepatic or pancreatic cells.

### Claim 9 (depends on 1)

A tissue sample obtained from the tumor line of claim 1.

### Claim 10 (depends on 1)

A population of hFL-HCC cells isolated from the tumor line of claim 1.

### Claim 11 (depends on 10)

The population of claim 10, wherein the hFL-HCC cells are cultured on tissue culture plastic or on or in hyaluronans.

### Claim 12 (depends on 11)

The composition of claim 11, wherein the hFL-HCC cells are cultured in cells in serum-free medium.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the serum-free medium is Kubota's Medium.

### Claim 14 (depends on 12)

The composition of claim 12, wherein the serum-free medium further contains hyaluronans, HGF and/or VEGF.

### Claim 15

A method of determining whether a patient has fibrolamellar hepatocellular carcinoma (FL-HCC), comprising: (a) measuring gene expression levels of at least one of C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163, and TNRC6C; and (b) comparing the gene expression profile to one or more control samples.

### Claim 16 (depends on 15)

The method of claim 15, wherein overexpression of C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163 or TNRC6C relative to the control sample is associated with presence of FL-HCC.

### Claim 17 (depends on 16)

The method of claim 16, wherein overexpression of PCSK1, CA12, NOVA1, SLC16A14, TNRC6C, TMEM163, and RPS6KA2 relative to the control sample is associated with presence of FL-HCC.

### Claim 18 (depends on 16)

The method of claim 16, wherein overexpression of C10orf128, OAT, PAK3, PCSK1, PHACTR2, SLC16A14, TMEM163, and TNRC6C relative to the control sample is associated with presence of FL-HCC.

### Claim 19 (depends on 15)

The method of claim 15, wherein the control sample is selected from the tumor cells from hepatocellular carcinomas (HCCs), hepatoblastomas, cholangiocarcinomas (CCAs) and/or pancreatic cancers or selected from normal cells consisting of biliary tree stem cells, hepatic stem cells, hepatoblasts, pancreatic stem cells, hepatic or pancreatic committed progenitors, and normal mature hepatic or pancreatic cells.

### Claim 20

A method of treating a patient determined to have hFL-HCC by administering to the patient an effective amount of at least one therapeutic that decreases expression of at least one of C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163, or TNRC6C.

### Claim 21 (depends on 20)

The method of claim 20, wherein the at least one therapeutic is selected from the group consisting of a small molecule, RNA interference, a locked nucleic acid (LNA), an immunotherapy, a hedgehog signaling inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, and a regulator of substrate targets of PRKACA.

### Claim 22

A method for drug screening, comprising (a) introducing a candidate drug to cultured hFL-HCC cells that are in the form of monolayers, hydrogels, spheroids or organoids, and (b) monitoring the effect of the candidate drug on the cultured hFL-HCC cells.

### Claim 23

A transplantable tumor cell line comprising human fibrolamellar hepatocellular carcinoma (hFL-HCC) cells, which can be maintained in a non-human animal.