# US 2020/0370133 A1 · Compositions and methods for characterizing bladder cancer

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- Number: US 2020/0370133 A1
- Document ID: US20200370133A1
- Status: Published application
- Kind: A1
- Application number: 16/988,317
- Filed: 2020-08-07
- Published: 2020-11-26
- Earliest claimed: 2018-02-09
- Assignees: The Broad Institute, Inc.; The General Hospital Corporation; Baylor College of Medicine; The Brigham and Women S Hospital, Inc.; Northwestern University; The Johns Hopkins University; United States Government as represented by the U.S. Department of Veterans Affairs
- Applicants: The Broad Institute, Inc.; The General Hospital Corporation; Baylor College of Medicine; The Brigham and Women's Hospital, Inc.; Northwestern University; The Johns Hopkins University; United States Government as represented by the U.S. Department of Veterans
- Inventors: Jaegil Kim; Gad Getz; Seth Paul Lerner; David Kwiatkowski; Joshua Meeks; Joaquim Bellmunt; David McConkey
- Web page: https://patentgrep.com/patent/US20200370133A1

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- 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 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- 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

## Abstract

The present invention features methods for characterizing mutational profiles in patients with bladder cancer.

## Claims

### Claim 1

A method of characterizing bladder cancer in a subject, the method comprising detecting in a biological sample of the subject an alteration in the expression of a target selected from
luminal markers selected from the group consisting of uroplakin genes UPK2, UPK1A, urothelial differentiation markers FOXA1, GATA3, and PPARG, and genes KRT20, and SNX31;
luminal-papillary markers selected from the group consisting of FGFR, FGFR3-TACC3 fusions, lncRNAs DANCR, GAS5, MALAT1, NEAT1, NORAD (LINC00657), UCA1, ZNF667-AS1 (MORT), LINC00152, GATA3, FOXA1, PPARγ, TP63, sonic-hedgehog signaling (SHH);
luminal-infiltrated markers selected from the group consisting of CD274 (PD-L1) and PDCD1 (PD-1);
basal-squamous markers including basal and stem-like markers CD44, KRT5, KRT6A, KRT14, and COL17A1; squamous differentiation markers TGM1, DSC3, TP63, GSDMC, and PI3, TP53, CIS signature genes CRTAC1, CTSE, PADI3, MSN, and NR3C1, and immune markers CD274, PDCD1LG2, 1DO1, CXCL11, L1CAM, SAA1 and CTLA4;
neuronal markers selected from the group consisting of neuronal differentiation and development genes MSI1, PLEKHG4B, GNG4, PEG10, RND2, APLP1, SOX2, TUBB2B, TP53, RB1 and E2F3 and neuroendocrine markers CHGA, CHGB, SCG2, ENO2, SYP, NCAM1; and
targets from among those listed in Tables 2-4.

### Claim 2 (depends on 1)

The method of claim 1, further comprising detecting proteins selected from the group consisting of GATA3, EGFR, CDH1, and HER2;
detecting miRNAs selected from the group consisting of miR-200s, miR-99a, and miR-100;
detecting TP53 and RB1 mutations; and/or
detecting an RB1, CDKN1A4, CDKN2A, ATM, ERCC, FGFR3, PIK3CA, and RAS, ERBB2, KDM6A, KMT2A, KMT2C, KMT2D, CREBBP, EP300, KANSL1, ARID1A, ASXL1, and ASXL2 mutation or a homozygous deletion.

### Claim 3 (depends on 1)

The method of claim 1, wherein the biological sample was a urothelial tumor.

### Claim 4 (depends on 1)

A set of polynucleotide probes each of which hybridizes to a target of claim 1.

### Claim 5 (depends on 1)

A set of primer pairs each of which hybridizes to and amplifies a target of claim 1.

### Claim 6 (depends on 1)

A nucleic acid array for expression-based assessment of bladder cancer, said array comprising at least ten probes immobilized on a solid support, each of said probes being between about 15 and about 500 nucleotides in length, each of said probes being derived from a sequence corresponding to, or complementary to, a transcript of a target or marker of claim 1.

### Claim 7 (depends on 1)

A method for expression-based assessment of bladder cancer, said method comprising: (a) determining the expression level of one or more transcripts of one or more genes in a test sample obtained from said subject to provide an expression pattern profile, said one or more genes selected from a target or marker of claim 1, and (b) comparing said expression pattern profile with a reference expression pattern profile.

### Claim 8 (depends on 1)

A method of analyzing a bladder cancer in an individual in need thereof, comprising: (a) obtaining an expression profile from a sample obtained from the individual, wherein the expression profile comprises assaying a target or marker of claim 1; and (b) comparing the expression profile from the sample to an expression profile of a control or standard.

### Claim 9 (depends on 1)

A method of prescribing a treatment regimen for a bladder cancer to an individual in need thereof, comprising:
(a) obtaining an expression profile from a sample obtained from the individual, wherein the expression profile comprises a target or marker of claim 1;
(b) comparing the expression profile from the sample to an expression profile of a control or standard; and
(c) prescribing a treatment regimen based on (i) the deviation of the expression profile of the sample from a control or standard derived from a healthy individual or population of healthy individuals, or (ii) the similarity of the expression profiles of the sample and a control or standard derived from an individual or population of individuals who have or have had the cancer.

### Claim 10

A method of treating a selected subject for bladder cancer, the method comprising
(a) administering to the patient a checkpoint inhibitor, wherein the subject is selected by detecting increased expression of uroplakin genes and an umbrella cell phenotype in a biological sample from the subject;
(b) administering to the subject a tyrosine kinase inhibitor of FGFR3, wherein the subject is selected by identifying a luminal-papillary subtype, wherein the luminal-papillary subtype is characterized by an FGFR3 mutations, a fusion with TACC3, and/or amplification; by papillary histology; by active sonic hedgehog signaling; and by low CIS scores; or
(c) administering to the subject a tyrosine kinase inhibitor of FGFR3, wherein the subject is selected by identifying a luminal-papillary subtype, wherein the luminal-papillary subtype is characterized by an FGFR3 mutations, a fusion with TACC3, and/or amplification; by papillary histology; by active sonic hedgehog signaling; and by low CIS scores; or
(d) administering to the subject an immune checkpoint therapy, wherein the subject is selected by characterizing a biological sample of the subject as having a luminal-infiltrated subtype characterized by increased expression of EMT markers, myofibroblast markers, and of the miR-200s;
(e) administering to the subject a cisplatin-based NAC or immune checkpoint therapy, wherein the subject is selected by characterizing a biological sample of the subject as having a basal-squamous subtype comprising squamous differentiation, basal keratin expression, and increased expression of CD274 (PD-L1) and CTLA4 immune markers; or
(f) administering to the subject Etoposide-cisplatin therapy, wherein a biological sample from the subject is characterized by expression of neuroendocrine/neuronal markers; or
(g) administering to a selected patient atezolizumab, wherein the subject is selected by detecting increased expression of neuronal markers comprising or consisting of SOX2, TUBB2B, and PEG10 in a biological sample from the subject.

### Claim 11 (depends on 10)

The method of claim 10, wherein the inhibitor is AZ12908010, AZD4547, or PD173074.

### Claim 12 (depends on 10)

The method of claim 10, wherein the therapy is atezolizumab.

### Claim 13 (depends on 10)

The method of claim 10, wherein the biological sample is also characterized by a proliferative state.

### Claim 14 (depends on 10)

The method of claim 10, wherein the neuronal markers are MSI1, PLEKHG4B, GNG4, PEG10, RND2, APLP1, SOX2, TUBB2B, TP53, RB1 and E2F3 and the neuroendocrine markers are CHGA, CHGB, SCG2, ENO2, SYP, and NCAM1.

### Claim 15 (depends on 1)

A kit for analyzing a bladder cancer, comprising: (a) a probe set that hybridizes to a plurality of targets or marker of claim 1; and (b) a computer model or algorithm for analyzing an expression level and/or expression profile of the target sequences in a sample.

### Claim 16 (depends on 15)

The kit of claim 15, further comprising a computer model or algorithm for correlating the expression level or expression profile with disease state or outcome.

### Claim 17 (depends on 15)

The kit of claim 15, further comprising a computer model or algorithm for designating a treatment modality for the subject.

### Claim 18

A method of characterizing a neuronal subtype marker in a bladder cancer in a subject, the method comprising detecting in a biological sample of the subject an alteration in the expression of neuronal markers comprising or consisting of SOX2, TUBB2B, and PEG10.