Prognostic, diagnostic, and cancer therapeutic uses of FANCI and FANCI modulating agents
First Claim
1. A method of diagnosing or determining if a subject has cancer or is at increased risk of cancer, the method comprising testing a sample from the subject for the presence of FANCI-containing foci using an antibody or antigen binding fragment thereof specific for FANCI, wherein said presence of FANCI-containing foci is indicative of cancer or an increased risk of cancer in said subject.
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Accused Products
Abstract
Disclosed herein are methods and compositions for the treatment of cancer. In particular, the present invention identifies and characterizes the FANCI polypeptide as a vital component of the Fanconi anemia pathway and discloses inhibitors of FANCI and methods of using same. Such inhibitors are useful in inhibiting DNA damage repair and can be useful, for example, in the treatment of cancer.
85 Citations
55 Claims
- 1. A method of diagnosing or determining if a subject has cancer or is at increased risk of cancer, the method comprising testing a sample from the subject for the presence of FANCI-containing foci using an antibody or antigen binding fragment thereof specific for FANCI, wherein said presence of FANCI-containing foci is indicative of cancer or an increased risk of cancer in said subject.
- 9. A method of diagnosing or determining if a subject has cancer or is at increased risk of cancer, the method comprising testing a FANCI gene of the subject for the presence of a cancer-associated coding change, wherein said presence of one or more cancer-associated coding changes is indicative of cancer or an increased risk of cancer in the subject.
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13. A method of determining if a subject has cancer, or is at increased risk of developing cancer, said method comprising the steps of:
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(a) providing a DNA sample from said subject; (b) amplifying the FANCI gene from said subject with any of the FANCI gene-specific polynucleotide primers shown in Example 1; (c) sequencing the amplified FANCI gene; and (d) comparing the FANCI gene sequence from said subject to a reference FANCI gene sequence, where a discrepancy between the two gene sequences indicates the presence of a cancer-associated defect, wherein the presence of one or more cancer-associated defects indicates said subject has cancer or is at an increased risk of developing cancer. - View Dependent Claims (14)
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15. A method of diagnosing or determining if a subject has Fanconi anemia or is at increased risk of developing Fanconi anemia, the method comprising testing a FANCI gene of the subject for the presence of a Fanconi anemia-associated coding change, wherein said presence of one or more Fanconi anemia-associated coding changes is indicative of Fanconi anemia or an increased risk of Fanconi anemia in the subject.
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16. A method of determining if a subject has cancer, or is at increased risk of developing cancer comprising the steps of:
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(a) providing a DNA sample from said subject; (b) amplifying the FANCI gene from said subject with FANCI gene-specific polynucleotide primers; (c) sequencing the amplified FANCI gene; and (d) comparing the FANCI gene sequence from said subject to a reference FANCI gene sequence, wherein a discrepancy between the two gene sequences indicates the presence of a cancer-associated coding change, wherein the presence of one or more cancer-associated coding changes indicates said subject has cancer or is at an increased risk of developing cancer. - View Dependent Claims (17)
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- 18. A method of predicting whether a subject with a neoplastic disorder will respond to a genotoxic anti-neoplastic agent comprising determining the size or number of FANCI-containing foci in a sample from the subject using an antibody or antigen binding fragment thereof specific for FANCI, wherein if the number or size of said foci is reduced relative to the number or size of said foci in a sample from a control subject, then the subject is predicted to respond to a genotoxic anti-neoplastic agent.
- 25. A method of predicting whether a subject with a neoplastic disorder will respond to a genotoxic anti-neoplastic agent comprising determining the degree of ubiquitination of FANCI polypeptide in a sample from the subject, wherein if the degree of ubiquitination of said FANCI polypeptide in the sample is reduced when compared with a sample from a control subject, then the subject is predicted to respond to a genotoxic anti-neoplastic agent.
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27. A method of identifying a tumor that is sensitive to a genotoxic anti-neoplastic agent comprising determining the size or number of FANCI-containing foci in a sample from a test subject, wherein if the number or size of said foci is reduced relative to the number or size of said foci in a sample from a control subject, then the sample from the test subject is identified as a tumor sensitive to a genotoxic anti-neoplastic agent.
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28. A method of identifying an inhibitor of a Fanconi anemia DNA repair pathway, comprising:
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(a) contacting a cell with a test compound; (b) contacting the cell with a genotoxic anti-neoplastic compound before, after, or simultaneous with step (a); (c) quantifying FANCI-containing foci in the cell using an antibody or antigen binding fragment thereof specific for FANCI;
wherein if the quantity of said foci is less than in a control cell, wherein the control cell was contacted with said genotoxic anti-neoplastic agent but not with said test compound, then the test compound is identified as an inhibitor of a Fanconi anemia DNA repair pathway. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35, 51)
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36. A method of identifying an inhibitor of a non-Fanconi anemia DNA repair pathway, comprising:
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(a) contacting a test cell that has a functional Fanconi anemia pathway with a test compound and a genotoxic anti-neoplastic agent; (b) measuring the sensitivity of the test cell to the genotoxic anti-neoplastic agent; and (c) comparing the sensitivity of the test cell to the agent to that of a control cell; wherein the control cell is isogenic to the test cell but has a mutant FANCI gene; and
if the sensitivity of the test cell is greater than the sensitivity of the control cell, the test compound is identified as an inhibitor of a non-Fanconi anemia DNA repair pathway. - View Dependent Claims (37, 38, 52)
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39. A method of screening for a cancer therapeutic, the method comprising the steps of:
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(a) providing one or more cells containing a FANCI gene having one or more cancer associated defects; (b) growing said cells in the presence of a potential cancer therapeutic; and (c) determining the rate of growth of said cells in the presence of said potential cancer therapeutic relative to the rate of growth of equivalent cells grown in the absence of said potential cancer therapeutic, wherein a reduced rate of growth of said cells in the presence of said potential cancer therapeutic, relative to the rate of growth of equivalent cells grown in the absence of said potential cancer therapeutic, indicates that the potential cancer therapeutic is a cancer therapeutic. - View Dependent Claims (40)
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41. A method of screening for a chemosensitizing agent, said method comprising the steps of:
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(a) providing a potential inhibitor of FANCI; (b) providing a tumor cell line that is resistant to one or more anti-neoplastic agents; (c) contacting said tumor cell line and said potential inhibitor of FANCI with said one or more anti-neoplastic agents; and (d) measuring the growth rate of said tumor cell line in the presence of said inhibitor of FANCI and said anti-neoplastic agent, wherein a reduced growth rate of the tumor cell line, relative to cells of the tumor cell line in the presence of the anti-neoplastic agent and the absence of said inhibitor of FANCI, is indicative that the potential inhibitor is a chemosensitizing agent.
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- 42. A method of sensitizing a subject to treatment with a genotoxic anti-neoplastic agent, the method comprising administering an inhibitor of FANCI to a subject who is receiving a genotoxic anti-neoplastic agent but is resistant to said agent.
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45. A method of sensitizing a subject to treatment with a genotoxic anti-neoplastic agent, the method comprising:
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(a) administering an inhibitor of FANCI to a subject who is receiving treatment with a genotoxic anti-neoplastic agent but is resistant to said agent; and (b) administering an inhibitor of a non-Fanconi anemia DNA repair pathway to the subject. - View Dependent Claims (46, 47)
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48. A method of predicting the efficacy of a therapeutic agent in a cancer patient, comprising the steps of:
- (a) providing a tissue sample from said cancer patient who is being treated with said therapeutic agent;
(b) inducing DNA damage in the cells of said tissue sample;
(c) detecting the presence of ubiquitinated FANCI protein in said cells;
wherein the presence of ubiquitinated FANCI is indicative of a reduced efficacy of said therapeutic agent in said cancer patient.
- (a) providing a tissue sample from said cancer patient who is being treated with said therapeutic agent;
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53. An isolated nucleotide sequence comprising the mutant FANCI nucleotide sequence of BD0952 cells.
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54. An isolated polypeptide sequence comprising a polypeptide sequence selected from the group consisting of the mutant FANCI polypeptide sequence of BD0952 cells shown in
FIG. 9 and a GST polypeptide fused to the N-terminal 200 amino acid residues of the FANCI polypeptide.
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55. An anti-FANCI siRNA to a FANCI target selected from the group consisting of SEQ ID NO:
- 22, SEQ ID NO;
23, and SEQ ID NO;
24.
- 22, SEQ ID NO;
Specification