Fgfr3 fusion gene and pharmaceutical drug targeting same
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsYoshito Nakanishi, Nukinori Akiyama, Yukari Nishito
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Abstract
The FGFR-encoding gene was studied extensively with regard to its expression, hyperamplification, mutation, translocation, or such in various cancer cells. As a result, novel fusion polypeptides in which the FGFR3 polypeptide is fused with a different polypeptide were identified and isolated from several types of bladder cancer-derived cells and lung cancer cells. The use of a fusion polypeptide of the present invention as a biomarker in FGFR inhibitor-based cancer therapy enables one to avoid side effects in cancer therapy and control the therapeutic condition to produce the best therapeutic effect, thereby enabling individualized medicine.
Claims127
-62. (canceled)
A method of treating a subject who has cancer, the method comprising
- (a) determining that a sample from the subject comprises:
- (i) a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 (fibroblast growth factor receptor 3) protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a BAIAP2L1 protein (brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1) whose sequence is at least 70% identical to SEQ ID NO:
- 8, or
- (ii) a polynucleotide encoding the fusion polypeptide;
- and
- (b) administering to the subject an FGFR inhibitor in an amount effective to treat cancer in the subject.
A method of reducing the likelihood that a subject will develop a tumor, the method comprising
- (a) determining that a sample from a human subject comprises:
- (i) a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a BAIAP2L1 protein whose sequence is at least 70% identical to SEQ ID NO:
- 8, or
- (ii) a polynucleotide encoding the fusion polypeptide;
- (b) determining that the subject is in need of a treatment to reduce the subject's likelihood of developing a tumor that expresses the fusion polypeptide;
- and
- (c) administering to the subject an FGFR inhibitor in an amount effective to reduce the subject's likelihood of developing a tumor that expresses the fusion polypeptide.
A method for treating a subject who has cancer, the method comprising:
- (a) determining that a sample from the subject comprises:
- (i) a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a TACC3 protein (transforming acidic coiled-coil protein 3) whose sequence is at least 70% identical to SEQ ID NO:
- 9, or
- (ii) a polynucleotide encoding the fusion polypeptide;
- and
- (b) administering to the subject an FGFR inhibitor in an amount effective to treat cancer in the subject.
A method of reducing the likelihood that a subject will develop a tumor, the method comprising
- (a) determining that a sample from a human subject comprises:
- (i) a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a TACC3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 9, or
- (ii) a polynucleotide encoding the fusion polypeptide;
- (b) determining that the subject is in need of a treatment to reduce the subject's likelihood of developing a tumor that expresses the fusion polypeptide;
- and
- (c) administering to the subject an FGFR inhibitor in an amount effective to reduce the subject's likelihood of developing a tumor that expresses the fusion polypeptide.
A method for identifying a compound that has FGFR inhibitory activity, the method comprising:
- (a) culturing, in the presence of a test compound, a first cell that expresses a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a BAIAP2L1 protein whose sequence is at least 70% identical to SEQ ID NO:
- 8;
- (b) determining that the level of proliferation of the first cell in the presence of the test compound is reduced compared to the level of proliferation of a control cell cultured in the absence of the test compound, the control cell being identical to the first cell;
- and
- (c) identifying the test compound as having FGFR inhibitory activity based on the determination of (b).
A method for identifying a compound that has FGFR inhibitory activity, the method comprising:
- (a) administering a test compound to a non-human mammal transplanted with a first cell that expresses a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a BAIAP2L1 protein whose sequence is at least 70% identical to SEQ ID NO:
- 8;
- (b) determining the growth rate of the first cell in the mammal;
- (c) comparing the growth rate of the first cell determined in (b) to the growth rate of a control cell in a control mammal of the same species as the mammal of (a), wherein the control cell is identical to the first cell and the control mammal does not receive the test compound;
- and
- (d) identifying the test compound as having FGFR inhibitory activity when the growth rate of the first cell determined in (b) is lower than the growth rate of the control cell in the control mammal.
A method for identifying a compound that has FGFR inhibitory activity, the method comprising:
- (a) culturing, in the presence of a test compound, a first cell that expresses a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a TACC3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 9;
- (b) determining that the level of proliferation of the first cell in the presence of the test compound is reduced compared to the level of proliferation of a control cell cultured in the absence of the test compound, the control cell being identical to the first cell;
- and
- (c) identifying the test compound as having FGFR inhibitory activity based on the determination of (b).
A method for identifying a compound that has FGFR inhibitory activity, the method comprising:
- (a) administering a test compound to a non-human mammal transplanted with a first cell that expresses a fusion polypeptide comprising part or all of the amino acid sequence of an FGFR3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 6 or 7, and part or all of the amino acid sequence of a TACC3 protein whose sequence is at least 70% identical to SEQ ID NO:
- 9;
- (b) determining the growth rate of the first cell in the mammal;
- (c) comparing the growth rate of the first cell determined in (b) to the growth rate of a control cell in a control mammal of the same species as the mammal of (a), wherein the control cell is identical to the first cell and the control mammal does not receive the test compound;
- and
- (d) identifying the test compound as having FGFR inhibitory activity when the growth rate of the first cell determined in (b) is lower than the growth rate of the control cell in the control mammal.
A method for detecting nucleic acid encoding a fusion polypeptide that comprises part or all of the amino acid sequence of an FGFR3 protein and part or all of the amino acid sequence of a BAIAP2L1 protein in a sample of nucleic acid from a subject, the method comprising subjecting the sample to Polymerase Chain Reaction (PCR) using a pair of oligonucleotide primers that, when used together in PCR on a sample comprising nucleic acid encoding (a) the fusion polypeptide, (b) a wild-type FGFR3 protein, and (c) a wild-type BAIAP2L1 protein, detects a nucleotide sequence encoding the fusion polypeptide and does not detect nucleic acid encoding wild-type FGFR3 protein or wild-type BAIAP2L1 protein.
A method for detecting nucleic acid encoding a fusion polypeptide that comprises part or all of the amino acid sequence of an FGFR3 protein and part or all of the amino acid sequence of a TACC3 protein in a sample of nucleic acid from a subject, the method comprising subjecting the sample to Polymerase Chain Reaction (PCR) using a pair of oligonucleotide primers that, when used together in PCR on a sample comprising nucleic acid encoding (a) the fusion polypeptide, (b) a wild-type FGFR3 protein, and (c) a wild-type TACC3 protein, detects a nucleotide sequence encoding the fusion polypeptide and does not detect nucleic acid encoding wild-type FGFR3 protein or wild-type TACC3 protein.
A method for detecting a fusion polypeptide that comprises part or all of the amino acid sequence of an FGFR3 protein and part or all of the amino acid sequence of a BAIAP2L1 protein in a sample, the method comprising:
- contacting the sample with an antigen-binding molecule that binds to the fusion polypeptide, but does not bind to wild-type FGFR3 protein or wild-type BAIAP2L1 protein;
- and
- detecting binding of the antigen-binding molecule to the fusion polypeptide in the sample.
A method for detecting a fusion polypeptide that comprises part or all of the amino acid sequence of an FGFR3 protein and part or all of the amino acid sequence of a TACC3 protein in a sample, the method comprising:
- contacting the sample with an antigen-binding molecule that binds to the fusion polypeptide, but does not bind to wild-type FGFR3 protein or wild-type TACC3 protein;
- and
- detecting binding of the antigen-binding molecule to the fusion polypeptide in the sample.
A cDNA or degenerate variant thereof encoding a fusion polypeptide consisting of the amino acid sequence of SEQ ID NO:
- 32 or 38.
A cDNA or degenerate variant thereof encoding a fusion polypeptide consisting of the amino acid sequence of SEQ ID NO:
- 28, 30, 34, or 36.
A DNA comprising the nucleotide sequence of SEQ ID NO:
- 27, 29, 31, 33, 35, or 37.
An antigen-binding molecule that specifically binds to a polypeptide consisting of the amino acid sequence of SEQ ID NO:
- 32 or 38, wherein the antibody does not bind to wild-type FGFR3 protein or to wild-type BAIAP2L1 protein.
An antigen-binding molecule that specifically binds to a polypeptide consisting of the amino acid sequence of SEQ ID NO:
- 28, 30, 34, or 36, wherein the antibody does not bind to wild-type FGFR3 protein or to wild-type TACC3 protein.
An oligoribonucleotide that binds to an mRNA encoding a fusion polypeptide consisting of the amino acid sequence of SEQ ID NO:
- 32 or 38, and inhibits translation of the mRNA into protein.
An oligoribonucleotide that binds to an mRNA encoding a fusion polypeptide consisting of the amino acid sequence of SEQ ID NO:
- 28, 30, 34, or 36, and inhibits translation of the mRNA into protein.
A fusion polypeptide comprising the amino acid sequence of SEQ ID NO:
- 32 or 38 and additional amino acid sequence.
A fusion polypeptide comprising the amino acid sequence of SEQ ID NO:
- 28, 30, 34, or 36 and additional amino acid sequence.
A kit comprising a pair of oligonucleotide primers consist of SEQ ID NOs:
- 3 and 4, and an instruction manual.
A kit comprising a pair of oligonucleotide primers consist of SEQ ID NOs:
- 1 and 2, and an instruction manual.
A kit comprising a pair of oligonucleotide primers consist of SEQ ID NOs:
- 1 and 5, and an instruction manual.
Dependencies are inferred from the claim text.